# antiserotonin drugs?



## pdb (Jun 28, 2001)

From the reading I've done here regarding the role that serotonin plays in IBS, am I correct to assume that IBS-D sufferers have too much serotonin in their body, while IBS-C sufferers have too little? Is this an over-simplification of things?How then do anti-depressants help IBS? There are different types of serotonin - is that correct? Or are there just different types of serotonin receptors?I am taking Remeron right now, which is an anti-depressant. Anti-depressants typically boost serotonin levels. But Remeron is also a 5HT-3 antagonist. Does this mean that it is reducing the amount of that type of serotonin in my body, while boosting levels of other types of serotonin? Are there any drugs out there which inhibit the production of all serotonin in the body across the board? Would these types of drugs be useful to treat IBS-D?My search at webmd.com came across a drug called cyproheptadine which is described as "a histamine and serotonin antagonist used as an antipruritic and antihistaminic." What effect would this have on IBS?Sorry for all the questions but the search function is gone and my doctor is completely clueless. He keeps telling me to eat more fiber, as if that would be the answer to all my problems.


----------



## eric (Jul 8, 1999)

PDB, this is extremely complicated. Its gonna take you a while perhaps to learn it all, but its worth it.However, it the regulation or inn IBS dysregulation of serotonin and not the amounts in the body.You can't eliminate it, as it is very important to function.There are different types of receptors both in the gut and the brain. Its basically the serotonin in the gut and how its regulated that is a problem, although the signals sent to the brain from the gut and back are part of the problem also.This is some info http://www.aboutibs.org/Publications/serotonin.html Remeron works on the 5ht 3 receptor in the gut.There is an article in medsscape wortth reading on serotonin and IBS. I can't post the link because for some reason I can't get into medscape. But if yopu go there and type in IBS and sertonin it should come up and it helps to explain all this.The last drug I am not sure about, but it may help.I could not post all the info on this as it would take me a long time to explain it all.There are cells that line the gut wall that are pressure sensitive. When the bowel expands it puts pressure on these cells and they release serotonin, in d there is to much and that causes the gut to overly contract and in c to little and this causes the gut not to contract enough hence c. This is over simplified however, but easier to understand. Then the serotonin goes to the wrong area in the brain, in normal people it activates the ACC part of the brain, the acc is a part of the pain regulation of the brain for digestion and it releases endorphines for digestion to stop any pain. In IBS this part of the brain is not activated and the endorphines for pain are not released like they should be. hence the pain. The serotonin instead goes to an anxiety part of the brain and turns up "The volume" so to speak.There is a lot more to it then this but its a good start and reading that medscape article will help you out.Serotonin is invovled also in emotions, appetite, sleep, digestion, sex and other things.


----------



## eric (Jul 8, 1999)

PDB, this is extremely complicated. Its gonna take you a while perhaps to learn it all, but its worth it.However, it the regulation or inn IBS dysregulation of serotonin and not the amounts in the body.You can't eliminate it, as it is very important to function.There are different types of receptors both in the gut and the brain. Its basically the serotonin in the gut and how its regulated that is a problem, although the signals sent to the brain from the gut and back are part of the problem also.This is some info http://www.aboutibs.org/Publications/serotonin.html Remeron works on the 5ht 3 receptor in the gut.There is an article in medsscape wortth reading on serotonin and IBS. I can't post the link because for some reason I can't get into medscape. But if yopu go there and type in IBS and sertonin it should come up and it helps to explain all this.The last drug I am not sure about, but it may help.I could not post all the info on this as it would take me a long time to explain it all.There are cells that line the gut wall that are pressure sensitive. When the bowel expands it puts pressure on these cells and they release serotonin, in d there is to much and that causes the gut to overly contract and in c to little and this causes the gut not to contract enough hence c. This is over simplified however, but easier to understand. Then the serotonin goes to the wrong area in the brain, in normal people it activates the ACC part of the brain, the acc is a part of the pain regulation of the brain for digestion and it releases endorphines for digestion to stop any pain. In IBS this part of the brain is not activated and the endorphines for pain are not released like they should be. hence the pain. The serotonin instead goes to an anxiety part of the brain and turns up "The volume" so to speak.There is a lot more to it then this but its a good start and reading that medscape article will help you out.Serotonin is invovled also in emotions, appetite, sleep, digestion, sex and other things.


----------



## LotronexLover (Jan 10, 2001)

If you are IBS D. Remeron should help you. If it doesn't you may want to increase the mgs.There are 5 receptors in your brain that release seratonin. 5ht1, 5ht2, 5ht3, 5ht4 ,& 5ht5If you block the 5ht3 receptor, like in Remeron or Lotronex, you are blocking the receptor that controls gut mobility. The 5ht3 receptor makes the gut functions speed up causing diahreah.If you block the 5ht4 receptor, ex. Zoloft or Zelnorm, that one controls gut mobility also. The 5ht4 receptor slows down gut mobility causing constipation. Therefor, why try to block the rest of the receptors? If you suffer from diahreah, block the 5ht3 receptor with Remeron.Do I make any sense to you? If not let me know & I will try to break it down better. Oh, by the way...I too take Remeron for IBS D. Love the stuff! I take 45 mgs. That did the trick for me.


----------



## LotronexLover (Jan 10, 2001)

If you are IBS D. Remeron should help you. If it doesn't you may want to increase the mgs.There are 5 receptors in your brain that release seratonin. 5ht1, 5ht2, 5ht3, 5ht4 ,& 5ht5If you block the 5ht3 receptor, like in Remeron or Lotronex, you are blocking the receptor that controls gut mobility. The 5ht3 receptor makes the gut functions speed up causing diahreah.If you block the 5ht4 receptor, ex. Zoloft or Zelnorm, that one controls gut mobility also. The 5ht4 receptor slows down gut mobility causing constipation. Therefor, why try to block the rest of the receptors? If you suffer from diahreah, block the 5ht3 receptor with Remeron.Do I make any sense to you? If not let me know & I will try to break it down better. Oh, by the way...I too take Remeron for IBS D. Love the stuff! I take 45 mgs. That did the trick for me.


----------



## trbell (Nov 1, 2000)

interesting info, lotronexlover. where does it come from?I don't think the idea is to block receptors, though. if a receptor controls the regulation of motility, for example, motility is a process and i would think it might be like a thermostat and the idea is to have the temperature stay between 65 and 75 degrees not off or on?tom


----------



## trbell (Nov 1, 2000)

interesting info, lotronexlover. where does it come from?I don't think the idea is to block receptors, though. if a receptor controls the regulation of motility, for example, motility is a process and i would think it might be like a thermostat and the idea is to have the temperature stay between 65 and 75 degrees not off or on?tom


----------



## LotronexLover (Jan 10, 2001)

My doctor tries to teach me about the drugs I take & what they do. She pulls out little charts & gives me lessons. The Remeron site also has cute little diagram pics too, redirecting the seratonin. I have never taken Zoloft or Zelnorm, obviously, but I sent a friend of mine to her that was C. She gave me a lesson on Zoloft & the 5ht4 receptors anyway. My doctor & I are totally engrossed in the role that seratonin antagonist drugs work. It is very interesting. I didn't have much luck with Levbid, Bentyl, Librax, etc. So, when Lotronex came out. She immediately put me on it. She explained the whole 5ht3 receptor & its role. When they took it off the market we had 2 sister drugs to choose from...Remeron or Zofran. I went on Remeron May of last year & it has been working really well ever since. Lotronex worked better, but Remeron definetly comes close.If I can find the little Remeron diagram again I will give you the web site address.


----------



## LotronexLover (Jan 10, 2001)

My doctor tries to teach me about the drugs I take & what they do. She pulls out little charts & gives me lessons. The Remeron site also has cute little diagram pics too, redirecting the seratonin. I have never taken Zoloft or Zelnorm, obviously, but I sent a friend of mine to her that was C. She gave me a lesson on Zoloft & the 5ht4 receptors anyway. My doctor & I are totally engrossed in the role that seratonin antagonist drugs work. It is very interesting. I didn't have much luck with Levbid, Bentyl, Librax, etc. So, when Lotronex came out. She immediately put me on it. She explained the whole 5ht3 receptor & its role. When they took it off the market we had 2 sister drugs to choose from...Remeron or Zofran. I went on Remeron May of last year & it has been working really well ever since. Lotronex worked better, but Remeron definetly comes close.If I can find the little Remeron diagram again I will give you the web site address.


----------



## bonniei (Jan 25, 2001)

The search function is not available but there was this thread in which kmottus and flux explain this nicely. The way I remember it is there is all this serotonin floating around in the gut.The serotonin re-uptake back into the nerves which go back to the brain is blocked at the 5Ht3 receptor by a 5HT3 antagonist


----------



## LotronexLover (Jan 10, 2001)

Oh, I forgot to tell you...Remeron not only blocks the 5ht3 receptor but also the 5ht2 receptor.


----------



## bonniei (Jan 25, 2001)

The search function is not available but there was this thread in which kmottus and flux explain this nicely. The way I remember it is there is all this serotonin floating around in the gut.The serotonin re-uptake back into the nerves which go back to the brain is blocked at the 5Ht3 receptor by a 5HT3 antagonist


----------



## LotronexLover (Jan 10, 2001)

Oh, I forgot to tell you...Remeron not only blocks the 5ht3 receptor but also the 5ht2 receptor.


----------



## trbell (Nov 1, 2000)

I'd like to see the remeron diagram if you can find it, lotronexlover. I had a bad reaction to it when I tried but that was before I tried zelmac which produced some major changes. i suspect that most of of will be taking some combination of 'brain' and 'gut' pills and right now even the 'experts' don't understand the whole thing.tom


----------



## trbell (Nov 1, 2000)

I'd like to see the remeron diagram if you can find it, lotronexlover. I had a bad reaction to it when I tried but that was before I tried zelmac which produced some major changes. i suspect that most of of will be taking some combination of 'brain' and 'gut' pills and right now even the 'experts' don't understand the whole thing.tom


----------



## pdb (Jun 28, 2001)

Instead of blocking the 5HT3 receptor which is causing the digestive process to move too quickly, is it somehow possible to work on the 5HT4 receptor - sort ot increase the rate at which the 5HT4 receptor causes the gut to slow down? I'm sure someone has already thought of this. I just find this whole topic fascinating.I've been on Remeron for about 5 months now. At first it worked great, but over time its effectiveness has decreased. At this point, my symptoms are about 50% better than they were before I started taking it. I still get D about twice a week for no reason.Does anyone know if Remeron affects the gut in any other way? The reason I ask is because at higher doses (45 mgs) I seemed to experience a tightening of the muscles in my stomach. I almost wondered if the Remeron was actually increasing my D by contracting the muscles somehow. I decreased to 22.5 mgs and it's a bit better.


----------



## pdb (Jun 28, 2001)

Instead of blocking the 5HT3 receptor which is causing the digestive process to move too quickly, is it somehow possible to work on the 5HT4 receptor - sort ot increase the rate at which the 5HT4 receptor causes the gut to slow down? I'm sure someone has already thought of this. I just find this whole topic fascinating.I've been on Remeron for about 5 months now. At first it worked great, but over time its effectiveness has decreased. At this point, my symptoms are about 50% better than they were before I started taking it. I still get D about twice a week for no reason.Does anyone know if Remeron affects the gut in any other way? The reason I ask is because at higher doses (45 mgs) I seemed to experience a tightening of the muscles in my stomach. I almost wondered if the Remeron was actually increasing my D by contracting the muscles somehow. I decreased to 22.5 mgs and it's a bit better.


----------



## LotronexLover (Jan 10, 2001)

Tom, I thought you were D. Isn't Zelmac / Zelnorm for C?How many mgs did you start on? What side effects did you get...groggy, tired, jittery, low blood sugar? I had those side effects for a week or so. They tapered off little by little for me. I am still a bit tired in the morning & I still can't go to the gym without a liter of lemonade. Otherwise I am fine.I tried finding the site with the diagram on it. I thought it was on the Organon site but it is not. I will let you know if I find it elsewhere.


----------



## LotronexLover (Jan 10, 2001)

Tom, I thought you were D. Isn't Zelmac / Zelnorm for C?How many mgs did you start on? What side effects did you get...groggy, tired, jittery, low blood sugar? I had those side effects for a week or so. They tapered off little by little for me. I am still a bit tired in the morning & I still can't go to the gym without a liter of lemonade. Otherwise I am fine.I tried finding the site with the diagram on it. I thought it was on the Organon site but it is not. I will let you know if I find it elsewhere.


----------



## LotronexLover (Jan 10, 2001)

Ah ha! Found it. They changed the drawings to small colored ones with less info. Either way it has the same point...Don't laugh...Go towww.inthebedroom.comOn left click on Remeron. Once you get to that, on bottom, click on "patient information".That will give you the cute little drawing of the blocked 5ht2 & 5ht3 receptors, with an increase to the 5ht1 receptor.


----------



## LotronexLover (Jan 10, 2001)

Ah ha! Found it. They changed the drawings to small colored ones with less info. Either way it has the same point...Don't laugh...Go towww.inthebedroom.comOn left click on Remeron. Once you get to that, on bottom, click on "patient information".That will give you the cute little drawing of the blocked 5ht2 & 5ht3 receptors, with an increase to the 5ht1 receptor.


----------



## bellyknot (Jul 24, 2000)

I'm so confused! Can anyone tell me which antidepressant works best for C type? I need to be on one for panic attacks and GAD. Right now I'm on Serzone and am thinking about switching but need your imput on the C thing. Thanks all!


----------



## bellyknot (Jul 24, 2000)

I'm so confused! Can anyone tell me which antidepressant works best for C type? I need to be on one for panic attacks and GAD. Right now I'm on Serzone and am thinking about switching but need your imput on the C thing. Thanks all!


----------



## LotronexLover (Jan 10, 2001)

I am not a doctor but I have friend with C. He takes Zoloft for anxiety and for C. It blocks the 5ht4 receptor.Back to the diagram. That link worked before but the redirect is not redirecting.Try this... http://organoninc.com/remeron.html Again... click Remeron, then click "patient info" on bottom. If that doesn't work try www.organoninc.comClick Remeron, I think Consumer info, then patient info. Tell me if you got it.


----------



## LotronexLover (Jan 10, 2001)

I am not a doctor but I have friend with C. He takes Zoloft for anxiety and for C. It blocks the 5ht4 receptor.Back to the diagram. That link worked before but the redirect is not redirecting.Try this... http://organoninc.com/remeron.html Again... click Remeron, then click "patient info" on bottom. If that doesn't work try www.organoninc.comClick Remeron, I think Consumer info, then patient info. Tell me if you got it.


----------



## bonniei (Jan 25, 2001)

A diagram would be real nice to have.If you find it do put it up Lotronex lover. Tom, I think the info you may have been looking for is the following. There is all this serotonin floating around in the gut. and all these 5Ht receptors are in contact with this serotonin. These 5ht receptors connect with the autonomic circuit. The crucial thing is to maintain an equilibrium between norepinephrine(NE) and serotonin in the autonomic circuit. So your thermostat analogy is correct. the right temperature is the right equilibrium between the two. The receptors(5HT3 and 5HT4) can increase the serotonin in this circuit by absorbing serotonin from the gut into the autonomic circuit(5HT4 agonists help with that that)and decrease it by b1ocking it from being absorbed(5ht3 antagonists facilitiate that). The right balance between the two is important as they can influence the levels of dopamine [DA], acetylcholine [ACh] which affect GI contractility, muscle tone and motility"In C-IBS, a hyperadrenergic state (ie, enhanced norepinephrine) may lead to a reduction in basal 5-HT. Increased levels of norepinephrine stimulate inhibitory dopamine neurons, which leads to an inhibition of acetylcholine release that results in a reduction in GI contractility and muscle tone. On the other hand, serotonergic dominance inhibits norepinephrine, which can then lead to increased levels of acetylcholine and enhanced motility, hence D-IBS. Because physiological processes are in constant flux, with receptors up- or downregulating, 5-HT and norepinephrine may alternate in dominance, leading to clinical manifestations of alternating D-IBS and C-IBS." from http://www.medscape.com/viewarticle/418586_3 Hope that helps


----------



## bonniei (Jan 25, 2001)

A diagram would be real nice to have.If you find it do put it up Lotronex lover. Tom, I think the info you may have been looking for is the following. There is all this serotonin floating around in the gut. and all these 5Ht receptors are in contact with this serotonin. These 5ht receptors connect with the autonomic circuit. The crucial thing is to maintain an equilibrium between norepinephrine(NE) and serotonin in the autonomic circuit. So your thermostat analogy is correct. the right temperature is the right equilibrium between the two. The receptors(5HT3 and 5HT4) can increase the serotonin in this circuit by absorbing serotonin from the gut into the autonomic circuit(5HT4 agonists help with that that)and decrease it by b1ocking it from being absorbed(5ht3 antagonists facilitiate that). The right balance between the two is important as they can influence the levels of dopamine [DA], acetylcholine [ACh] which affect GI contractility, muscle tone and motility"In C-IBS, a hyperadrenergic state (ie, enhanced norepinephrine) may lead to a reduction in basal 5-HT. Increased levels of norepinephrine stimulate inhibitory dopamine neurons, which leads to an inhibition of acetylcholine release that results in a reduction in GI contractility and muscle tone. On the other hand, serotonergic dominance inhibits norepinephrine, which can then lead to increased levels of acetylcholine and enhanced motility, hence D-IBS. Because physiological processes are in constant flux, with receptors up- or downregulating, 5-HT and norepinephrine may alternate in dominance, leading to clinical manifestations of alternating D-IBS and C-IBS." from http://www.medscape.com/viewarticle/418586_3 Hope that helps


----------



## bellyknot (Jul 24, 2000)

Thank you LotronexLover. I appreciate the info. and now I'm off to v







isit with yet ANOTHER new GI.


----------



## bellyknot (Jul 24, 2000)

Thank you LotronexLover. I appreciate the info. and now I'm off to v







isit with yet ANOTHER new GI.


----------



## bonniei (Jan 25, 2001)

Looks like you and I posted at the same time Lotronex lover. Will check the link out


----------



## bonniei (Jan 25, 2001)

Looks like you and I posted at the same time Lotronex lover. Will check the link out


----------



## bonniei (Jan 25, 2001)

The first link didn't work. I did eventually find remeron and consumer info and then patient info with the second link but it didn't have any diagram. I don't know what I am doing wrong







Anyone else find it?


----------



## bonniei (Jan 25, 2001)

The first link didn't work. I did eventually find remeron and consumer info and then patient info with the second link but it didn't have any diagram. I don't know what I am doing wrong







Anyone else find it?


----------



## trbell (Nov 1, 2000)

the link for remeron from what I can tell is to organinc which sells it?I was IBS-C for many years but then took some zelmac and now I seem to have both IBS-D and C, so for my money these things are very individual at this point and what works for one wouldn't necessarily work for others.idid have a bad reaction to remeron but I think it was just me.tom


----------



## trbell (Nov 1, 2000)

the link for remeron from what I can tell is to organinc which sells it?I was IBS-C for many years but then took some zelmac and now I seem to have both IBS-D and C, so for my money these things are very individual at this point and what works for one wouldn't necessarily work for others.idid have a bad reaction to remeron but I think it was just me.tom


----------



## eric (Jul 8, 1999)

Good post Bonnie, the article you want to look for in medscape on this is by Marvin Schuster and explains all this in detail.The receptors are in the gut also.Like Bonnie's article it is the circulation regulation that is very important.One other thing, anti depressants can stop working because the synapes can become desenstized over time.


----------



## eric (Jul 8, 1999)

Good post Bonnie, the article you want to look for in medscape on this is by Marvin Schuster and explains all this in detail.The receptors are in the gut also.Like Bonnie's article it is the circulation regulation that is very important.One other thing, anti depressants can stop working because the synapes can become desenstized over time.


----------



## bonniei (Jan 25, 2001)

Thanks eric. i was beginning to wonder if I was off topic, lol


----------



## bonniei (Jan 25, 2001)

Thanks eric. i was beginning to wonder if I was off topic, lol


----------



## eric (Jul 8, 1999)

Bonnie, I cannot log into medscape for some reason.Can you pull up that article for meIts the role of serotonin in fucntional gi disorders and its by Dr Marvin Schuster. I would appreciate it, thanks.


----------



## eric (Jul 8, 1999)

Bonnie, I cannot log into medscape for some reason.Can you pull up that article for meIts the role of serotonin in fucntional gi disorders and its by Dr Marvin Schuster. I would appreciate it, thanks.


----------



## bonniei (Jan 25, 2001)

My link is part of the same article. the full article is found at http://www.medscape.com/viewprogram/725


----------



## bonniei (Jan 25, 2001)

My link is part of the same article. the full article is found at http://www.medscape.com/viewprogram/725


----------



## bonniei (Jan 25, 2001)

BTW you have to register with just a user name and pass word to access these medscape articles.One question which has been bothering me- I assume the autonomic circuit in my post and in the article is the one which links the gut to the brain, eric or flux?


----------



## bonniei (Jan 25, 2001)

BTW you have to register with just a user name and pass word to access these medscape articles.One question which has been bothering me- I assume the autonomic circuit in my post and in the article is the one which links the gut to the brain, eric or flux?


----------



## eric (Jul 8, 1999)

Bonnie, your gut works autonomically and is connected to the cns so basically yes.Thanks for posting that.


----------



## eric (Jul 8, 1999)

Bonnie, your gut works autonomically and is connected to the cns so basically yes.Thanks for posting that.


----------



## trbell (Nov 1, 2000)

I think that's why gut feelings are called gut feelings?tom


----------



## trbell (Nov 1, 2000)

I think that's why gut feelings are called gut feelings?tom


----------



## bonniei (Jan 25, 2001)

yW eric. Thanks for the info


----------



## bonniei (Jan 25, 2001)

yW eric. Thanks for the info


----------



## eric (Jul 8, 1999)

Here is some more info oon this."Serotonin: A Mediator of the Brain-Gut Axis Jackie D. Wood, PhD (Ohio State University) characterized the enteric nervous system as "the little brain in the gut" and as the lower end-point of the hierarchical innervation of the GI tract. The other components are prevertebral sympathetic ganglia, central sympathetic centers in the brainstem, central parasympathetics (the dorsal-vagal complex) where the vagus nerve and the descending pathways of the spinal cord originate, and higher brain centers (e.g., prefrontal cortex, amygdala, parabrachial nucleus, and hypothalamus). The sympathetics and parasympathetics are descending pathways to the gut. The higher brain centers interact with the autonomic centers by sharing information on perceptions of GI sensations and mani- festations of psychogenic factors such as physical and emotional stress. The chemical transfer of information within this circuitry is the work of serotonin (5-hydroxytryptamine, or 5-HT), 95 percent of which is localized in the GI tract and the remainder in the brain and enteric nervous system. In the first, an action potential traveling along an axon triggers release of the neurotransmitter (neurocrine signaling) 5-HT, carrying the signal to the post-synaptic neuron. In the second, 5-HT is released by either an enteric mast cell or an enterochromaffin cell (paracrine signaling). This affects neurons by extracellular diffusion. Whether by neurocrine or paracrine release, 5-HT excites neurons by inducing rapidly activating depolarization or slowly activating depolarization of the membrane potential. The 5-HT3 receptor is involved in rapidly activating depolarization. These receptors are located on the terminals of vagal afferent sensory neurons. They are activated by triggering the release of 5-HT. The activated vagal afferent transmits information in the form of action potential codes to the central nervous system. This mechanism is the peripheral basis of nausea and vomiting and the reason for using 5-HT3 antagonists as antiemetic drugs. Similarly, 5-HT3 receptors located in spinal (splanchnic) afferents are involved in signaling the central nervous system with information on the state of the gut. If these become sensitized during inflammation, elevated postprandial 5-HT serum levels may induce an exaggerated sensory code that goes into spinal integrated circuits and may reach the level of consciousness as discomfort or pain. Mast cells execute sensitization reactions to food or infection by releasing 5-HT and other mediators such as histamine. The 5-HT1P and 5-HT4 receptors modulate hypersensitivity reactions of the gut such as hypersecretion and propulsive motor events. Presynaptic inhibition (possibly through 5-HT4 receptors) at a nicotinic synapse is an important mechanism by which 5-HT affects enteric function. In addition, the 5-HT4 receptor facilitates release of acetylcholine at nicotinic synapses. This underlies the augmented intestinal propulsion seen with some prokinetic drugs. In general, motor, sensory, and chemical stimuli precipitate the release of 5-HT, which binds with sub-types of 5-HT receptors in the vagal sensory and splanchnic nerves, producing a variety of effects on the peristaltic reflex, colonic tone (5-HT3), acceleration of pan-gut transit (5-HT4), and gastric accommodation (5-HT4 and 5-HT1A). New 5-HT agents are being used experimentally to determine the roles of 5-HT receptor sub-types in motor and sensory function in the GI tract. Tegaserod and prucalopride are 5-HT4 agonists that appear to affect propulsion, and cisapride is simultaneously a 5-HT4 agonist and 5-HT3 antagonist that improves gastric accommodation. Dogiel type II myenteric neurons have a special gating function in the enteric nervous system. Unless stimulated by 5-HT, these multipolar neurons maintain a state of low excitability. But both neurocrine and paracrine release of 5-HT transforms them to a state of high excitability. Stimulation of the 5-HT receptors on their mucosal processes spreads action potentials up toward the cell body in the myenteric plexus. Once the cell body is activated, it gates the activity to other places in the enteric nervous system setting off a variety of secretory and motor events. Like enterochromaffin cells, intestinal mast cells are a source of 5-HT. These become sensitized in food allergies and infections by specific antibodies that adhere to receptors on their cell surfaces. Reappearance of the antigen cross-links the antibodies, causing degranulation of the mast cells and release of 5-HT and a variety of other mediators. The result is a form of gut behavior that includes hypersecretion and very strong propulsive contractions with attendant symptoms of diarrhea and abdominal discomfort. This behavior is programmed by the enteric nervous system and organized to eliminate threatening agents from the bowel lumen rapidly. Involvement of 5-HT1 and 5-HT2 receptors in the dorsal vagal complex has an apparent role in the brain-gut axis and psychogenic elements of bowel disorders of function. Laboratory experiments have shown that injection of spinal fluid into the fourth ventricle to influence the dorsal vagal complex produces no motility response. Injection of 5-HT alone stimulates motility minimally. But microinjection of thyrotrophin-releasing hormone followed by 5-HT generates an accentuated motility effect and acid secretion. Michael Camilleri, MD, FACG (Mayo Medical School and Clinic) dealt with the clinical importance of serotonin in IBS and carcinoid diarrhea. He also noted that blocking 5-HT sensory reception in the vagal afferents and in the chemoreceptor trigger zone of the fourth ventricle has revolutionized the treatment of chemo- therapy- and radiotherapy-induced emesis. He also emphasized the potential need for new therapies to modulate the 5-HT4 receptor involved in peristaltic and motor function of the gut. Carcinoid diarrhea is associated with overproduction of serotonin, as well as with accelerated small bowel transit, accelerated emptying of the proximal colon, and a reduction of the volume measurement of the ascending colon due to increased colonic tone. In a clinical study, treatment in the proximal colon of a carcinoid diarrhea patient was shown to traverse content around to the rectosigmoid area in just two hours -a trip that normally takes 15 to 18 hours. This suggests that 5-HT is an important mediator of postprandial colonic tone and transit of colonic residue. Clinically administerable doses of the 5-HT3 antagonist ondansetron restores normal tone. The 5-HT3 antagonists also appear to elevate the threshold for both perception of distension and pain, probably by relaxation of the colon. Study data do not suggest an anti-nociceptive effect. Tegaserod, a 5-HT4 receptor partial agonist, has been shown to increase contractile activity along the small bowel and colon of canines. In humans with constipation-predominant IBS, ororectal transit time is significantly accelerated in response to oral administration of tegaserod compared with placebo. In addition, tegaserod enhances colonic emptying. " http://www.macmcm.com/acg/acg99_gdf.htm


----------



## eric (Jul 8, 1999)

Here is some more info oon this."Serotonin: A Mediator of the Brain-Gut Axis Jackie D. Wood, PhD (Ohio State University) characterized the enteric nervous system as "the little brain in the gut" and as the lower end-point of the hierarchical innervation of the GI tract. The other components are prevertebral sympathetic ganglia, central sympathetic centers in the brainstem, central parasympathetics (the dorsal-vagal complex) where the vagus nerve and the descending pathways of the spinal cord originate, and higher brain centers (e.g., prefrontal cortex, amygdala, parabrachial nucleus, and hypothalamus). The sympathetics and parasympathetics are descending pathways to the gut. The higher brain centers interact with the autonomic centers by sharing information on perceptions of GI sensations and mani- festations of psychogenic factors such as physical and emotional stress. The chemical transfer of information within this circuitry is the work of serotonin (5-hydroxytryptamine, or 5-HT), 95 percent of which is localized in the GI tract and the remainder in the brain and enteric nervous system. In the first, an action potential traveling along an axon triggers release of the neurotransmitter (neurocrine signaling) 5-HT, carrying the signal to the post-synaptic neuron. In the second, 5-HT is released by either an enteric mast cell or an enterochromaffin cell (paracrine signaling). This affects neurons by extracellular diffusion. Whether by neurocrine or paracrine release, 5-HT excites neurons by inducing rapidly activating depolarization or slowly activating depolarization of the membrane potential. The 5-HT3 receptor is involved in rapidly activating depolarization. These receptors are located on the terminals of vagal afferent sensory neurons. They are activated by triggering the release of 5-HT. The activated vagal afferent transmits information in the form of action potential codes to the central nervous system. This mechanism is the peripheral basis of nausea and vomiting and the reason for using 5-HT3 antagonists as antiemetic drugs. Similarly, 5-HT3 receptors located in spinal (splanchnic) afferents are involved in signaling the central nervous system with information on the state of the gut. If these become sensitized during inflammation, elevated postprandial 5-HT serum levels may induce an exaggerated sensory code that goes into spinal integrated circuits and may reach the level of consciousness as discomfort or pain. Mast cells execute sensitization reactions to food or infection by releasing 5-HT and other mediators such as histamine. The 5-HT1P and 5-HT4 receptors modulate hypersensitivity reactions of the gut such as hypersecretion and propulsive motor events. Presynaptic inhibition (possibly through 5-HT4 receptors) at a nicotinic synapse is an important mechanism by which 5-HT affects enteric function. In addition, the 5-HT4 receptor facilitates release of acetylcholine at nicotinic synapses. This underlies the augmented intestinal propulsion seen with some prokinetic drugs. In general, motor, sensory, and chemical stimuli precipitate the release of 5-HT, which binds with sub-types of 5-HT receptors in the vagal sensory and splanchnic nerves, producing a variety of effects on the peristaltic reflex, colonic tone (5-HT3), acceleration of pan-gut transit (5-HT4), and gastric accommodation (5-HT4 and 5-HT1A). New 5-HT agents are being used experimentally to determine the roles of 5-HT receptor sub-types in motor and sensory function in the GI tract. Tegaserod and prucalopride are 5-HT4 agonists that appear to affect propulsion, and cisapride is simultaneously a 5-HT4 agonist and 5-HT3 antagonist that improves gastric accommodation. Dogiel type II myenteric neurons have a special gating function in the enteric nervous system. Unless stimulated by 5-HT, these multipolar neurons maintain a state of low excitability. But both neurocrine and paracrine release of 5-HT transforms them to a state of high excitability. Stimulation of the 5-HT receptors on their mucosal processes spreads action potentials up toward the cell body in the myenteric plexus. Once the cell body is activated, it gates the activity to other places in the enteric nervous system setting off a variety of secretory and motor events. Like enterochromaffin cells, intestinal mast cells are a source of 5-HT. These become sensitized in food allergies and infections by specific antibodies that adhere to receptors on their cell surfaces. Reappearance of the antigen cross-links the antibodies, causing degranulation of the mast cells and release of 5-HT and a variety of other mediators. The result is a form of gut behavior that includes hypersecretion and very strong propulsive contractions with attendant symptoms of diarrhea and abdominal discomfort. This behavior is programmed by the enteric nervous system and organized to eliminate threatening agents from the bowel lumen rapidly. Involvement of 5-HT1 and 5-HT2 receptors in the dorsal vagal complex has an apparent role in the brain-gut axis and psychogenic elements of bowel disorders of function. Laboratory experiments have shown that injection of spinal fluid into the fourth ventricle to influence the dorsal vagal complex produces no motility response. Injection of 5-HT alone stimulates motility minimally. But microinjection of thyrotrophin-releasing hormone followed by 5-HT generates an accentuated motility effect and acid secretion. Michael Camilleri, MD, FACG (Mayo Medical School and Clinic) dealt with the clinical importance of serotonin in IBS and carcinoid diarrhea. He also noted that blocking 5-HT sensory reception in the vagal afferents and in the chemoreceptor trigger zone of the fourth ventricle has revolutionized the treatment of chemo- therapy- and radiotherapy-induced emesis. He also emphasized the potential need for new therapies to modulate the 5-HT4 receptor involved in peristaltic and motor function of the gut. Carcinoid diarrhea is associated with overproduction of serotonin, as well as with accelerated small bowel transit, accelerated emptying of the proximal colon, and a reduction of the volume measurement of the ascending colon due to increased colonic tone. In a clinical study, treatment in the proximal colon of a carcinoid diarrhea patient was shown to traverse content around to the rectosigmoid area in just two hours -a trip that normally takes 15 to 18 hours. This suggests that 5-HT is an important mediator of postprandial colonic tone and transit of colonic residue. Clinically administerable doses of the 5-HT3 antagonist ondansetron restores normal tone. The 5-HT3 antagonists also appear to elevate the threshold for both perception of distension and pain, probably by relaxation of the colon. Study data do not suggest an anti-nociceptive effect. Tegaserod, a 5-HT4 receptor partial agonist, has been shown to increase contractile activity along the small bowel and colon of canines. In humans with constipation-predominant IBS, ororectal transit time is significantly accelerated in response to oral administration of tegaserod compared with placebo. In addition, tegaserod enhances colonic emptying. " http://www.macmcm.com/acg/acg99_gdf.htm


----------



## LotronexLover (Jan 10, 2001)

OK, I just wrote down step by step how to get the cartoon thingy for Remeron.Go to www.remeron.comClick on USA VisitorClick on bottom "Patient Information"The cartoon should pop up


----------



## LotronexLover (Jan 10, 2001)

OK, I just wrote down step by step how to get the cartoon thingy for Remeron.Go to www.remeron.comClick on USA VisitorClick on bottom "Patient Information"The cartoon should pop up


----------



## LotronexLover (Jan 10, 2001)

When I switched from 30 mg. to 45 mg. I had diahreah episodes for about 2 weeks. Then it went away. I have heard this happen to another person too. I don't know if it is the body adjusting or not.I still get D once in a while when I am stressed. I have a bottle of perscription Immodium, called Loporamide. It is the same thing as immodium but saves me money to buy by the bottle through insurance.


----------



## LotronexLover (Jan 10, 2001)

When I switched from 30 mg. to 45 mg. I had diahreah episodes for about 2 weeks. Then it went away. I have heard this happen to another person too. I don't know if it is the body adjusting or not.I still get D once in a while when I am stressed. I have a bottle of perscription Immodium, called Loporamide. It is the same thing as immodium but saves me money to buy by the bottle through insurance.


----------



## trbell (Nov 1, 2000)

got the remeron info but couldn't get the cartoon. Actually it's a good explanation i thought - not a lot of claims and they were careful to say that it's all theory.tom


----------



## trbell (Nov 1, 2000)

got the remeron info but couldn't get the cartoon. Actually it's a good explanation i thought - not a lot of claims and they were careful to say that it's all theory.tom


----------



## dhove (Apr 1, 2002)

Very Informative Reading. If, however, you wish to eliminate (sorry about the pun, but for those of us who suffer, or have suffered in the past, we find humor whever we can) anyway, if you want to stop the problem instead of just the symptoms, buy a bottle of "ImmunoLin" from swansonvitamins.comor Schiff, or the retailer of your choice, take it for a month, with or without current drugs you are taking, it doesn't matter, at least it didn't for me. Diarhea and constipation and leakage are things that happen once a year, instead of once a day! This stuff just plain works!!! I didn't know much about it when I started taking it, still don't, but I have learned it has immunogloulins and mitogenic growth factors in it. IGF-1 for one, and this is one factor that is decreased in those who suffer from IBS and Fibromyalgia. I know they said it couldn't be done, but I am slowly learning.Best of luck !


----------



## dhove (Apr 1, 2002)

Very Informative Reading. If, however, you wish to eliminate (sorry about the pun, but for those of us who suffer, or have suffered in the past, we find humor whever we can) anyway, if you want to stop the problem instead of just the symptoms, buy a bottle of "ImmunoLin" from swansonvitamins.comor Schiff, or the retailer of your choice, take it for a month, with or without current drugs you are taking, it doesn't matter, at least it didn't for me. Diarhea and constipation and leakage are things that happen once a year, instead of once a day! This stuff just plain works!!! I didn't know much about it when I started taking it, still don't, but I have learned it has immunogloulins and mitogenic growth factors in it. IGF-1 for one, and this is one factor that is decreased in those who suffer from IBS and Fibromyalgia. I know they said it couldn't be done, but I am slowly learning.Best of luck !


----------



## trbell (Nov 1, 2000)

dhove, glad it worked for you, but with all the advances, anybody selling anything should be able to say what it does for who and why?tom


----------



## trbell (Nov 1, 2000)

dhove, glad it worked for you, but with all the advances, anybody selling anything should be able to say what it does for who and why?tom


----------



## loon (Dec 10, 2001)

dhove -I appreciate the fact that you believe that you have found the "miracle cure" for your IBS but we have all heard it before for one product or another. There is no "one pill cures all" in IBS - no matter what you say.I personally do not want to ingest "bovine serum" which is the main ingredient in the product you are pushing. None of the web sites that sell the product adequately reveal what this mysterious product is (I think it has something to do with the human growth hormone which has gotten such bad press lately). I even called and talked to the company that produces the product wholesale for the manufacturers and they could not or would not tell me what it is.Therefore, I suggest that until you know what it is and why it "works" and can share that with the bb you keep the advertisements to a minimum level.Continued good health to you and for those of us choosing other paths to wellness.loon


----------



## loon (Dec 10, 2001)

dhove -I appreciate the fact that you believe that you have found the "miracle cure" for your IBS but we have all heard it before for one product or another. There is no "one pill cures all" in IBS - no matter what you say.I personally do not want to ingest "bovine serum" which is the main ingredient in the product you are pushing. None of the web sites that sell the product adequately reveal what this mysterious product is (I think it has something to do with the human growth hormone which has gotten such bad press lately). I even called and talked to the company that produces the product wholesale for the manufacturers and they could not or would not tell me what it is.Therefore, I suggest that until you know what it is and why it "works" and can share that with the bb you keep the advertisements to a minimum level.Continued good health to you and for those of us choosing other paths to wellness.loon


----------



## mxwe (Apr 7, 2002)

How does Paxil and Wellbutrin work on 5ht?I have panic dirrahea and nothing really works for that except Xanax and lomomtil-


----------



## mxwe (Apr 7, 2002)

How does Paxil and Wellbutrin work on 5ht?I have panic dirrahea and nothing really works for that except Xanax and lomomtil-


----------



## eric (Jul 8, 1999)

Serotonin and IBS"How do the new serotonergically active drugs currently being developed for the treatment of irritable bowel syndrome (IBS) differ from the selective serotonin reuptake inhibitor (SSRI) class of drugs [e.g., fluoxetine (Prozac), paroxetine (Paxil), sertraline (Zoloft)]? The SSRIs have been specifically developed as antidepressant drugs. Serotonin is found in both the brain and the gut, but it is now widely understood that 95% of the serotonin in the body resides in the gut." http://www.aboutibs.org/Publications/serotonin.html


----------



## eric (Jul 8, 1999)

Serotonin and IBS"How do the new serotonergically active drugs currently being developed for the treatment of irritable bowel syndrome (IBS) differ from the selective serotonin reuptake inhibitor (SSRI) class of drugs [e.g., fluoxetine (Prozac), paroxetine (Paxil), sertraline (Zoloft)]? The SSRIs have been specifically developed as antidepressant drugs. Serotonin is found in both the brain and the gut, but it is now widely understood that 95% of the serotonin in the body resides in the gut." http://www.aboutibs.org/Publications/serotonin.html


----------



## bonniei (Jan 25, 2001)

I have edited the postJust realized pdb's questions were perhaps not answered


> quote:But Remeron is also a 5HT-3 antagonist. Does this mean that it is reducing the amount of that type of serotonin in my body, while boosting levels of other types of serotonin?


An antagonist blocks action, an agonist facilitates action. A 5HT3 anatagonist will block action at the 5HT3 receptor site - the action being to absorb serotonin . So it is reducing the amount of serotonin in the autonomic circuit connected to these receptor sites leading to a norepinephrine dominance in the circuit Stimulation of the site would lead to the release of substance P and acetylcholine, which are excitatory neurotransmitters for GI smooth muscle. An antagonist will work in the opposite way. Anyway that is the way I understand it. There is only one type of serotonin. The important thing is the location of the serotonin


----------



## bonniei (Jan 25, 2001)

I have edited the postJust realized pdb's questions were perhaps not answered


> quote:But Remeron is also a 5HT-3 antagonist. Does this mean that it is reducing the amount of that type of serotonin in my body, while boosting levels of other types of serotonin?


An antagonist blocks action, an agonist facilitates action. A 5HT3 anatagonist will block action at the 5HT3 receptor site - the action being to absorb serotonin . So it is reducing the amount of serotonin in the autonomic circuit connected to these receptor sites leading to a norepinephrine dominance in the circuit Stimulation of the site would lead to the release of substance P and acetylcholine, which are excitatory neurotransmitters for GI smooth muscle. An antagonist will work in the opposite way. Anyway that is the way I understand it. There is only one type of serotonin. The important thing is the location of the serotonin


----------



## LotronexLover (Jan 10, 2001)

We sound like a bunch of scientists or doctors not IBS sufferers, but it is great how informed we are. I will try to look into your wellbutrin question. I am not sure which 5ht they effect.


----------



## LotronexLover (Jan 10, 2001)

We sound like a bunch of scientists or doctors not IBS sufferers, but it is great how informed we are. I will try to look into your wellbutrin question. I am not sure which 5ht they effect.


----------



## eric (Jul 8, 1999)

FYIIntroductionNearly 7 of 10 adults are affected by one or more functional gastrointestinal (GI) disorders, such as irritable bowel syndrome (IBS), gastroesophageal reflux disease (GERD), and functional dyspepsia (FD).[1] Because of the prevalence of these GI disorders, The Johns Hopkins University School of Medicine sponsored an expert-led symposium on October 15, 1999, in Phoenix, Ariz, to explore the current state of the field. This article highlights the presentations on basic science and clinical implications that were delivered during this meeting.Gastrointestinal disorders such as IBS, GERD, and FD have been referred to collectively as "functional GI disorders." However, this label is suggestive of psychosomatic mechanisms, and, as you will gather from this presentation, the role of serotonin (5-HT) in the pathophysiology of these disorders provides supporting evidence for underlying biophysiologic mechanisms. Hence, in this forum, we use the term "GI disorders of function" (GIDF) to avoid the biases and pejorative misconceptions that may be associated with traditional concepts of functional disorders.To facilitate a better understanding of the pathophysiological mechanisms relating to the clinical symptoms of GIDF and to broaden our perspective of the current developments in the clinical pharmacology of the gut, both a basic scientist and a clinician contributed to the content of the 3 topics discussed. Overall, the presentations highlight the overlapping symptoms in IBS, GERD, and FD; examine the role of 5-HT; and review the therapeutic potential of 5-HT pharmacology in GIDF.Overlapping Symptoms of Gastrointestinal Disorders of FunctionUnderlying PhysiologyThe GI tract is the only organ with an intrinsic nervous system that consists of more than 100 million neurons. Of these, the neurons of the enteric ganglia and interstitial cells of Cajal (ICC) are central modulators of GI function. There are 3 types of enteric neurons: afferent, motor, and regulatory.[2] The normal human intestine contains an excessive number of inhibitory neurons, more than are necessary for the complete relaxation of the visceral musculature. In some GI motility disorders, the amount of intrinsic motor inhibitory innervation is inadequate to provide complete relaxation. Decreased numbers of inhibitory motor neurons and/or decreased production of nitric oxide (which, because of its smooth muscle-relaxing properties, plays a key role in mediating GI motility[3]) in inhibitory motoneurons have been demonstrated in achalasia, gastric stasis and hypertrophic pyloric stenosis, chronic intestinal pseudo-obstruction, and megacolon or Hirschsprung's disease.[3]A significant recent advance in the enteric sciences has been the identification of the ICC as generators of the pacemaker potential in the stomach and small and large intestines, as elements that amplify neurotransmission from nerve to smooth muscle and as elements that may be stretch receptors.[4,5] In severe constipation and chronic intestinal pseudo-obstruction, the surface area of the ICC network is considerably less than that found in tissues from healthy subjects, and structural anomalies are apparent in the existing cells.[6] The decrease in surface area of the "pacemaker" cells profoundly compromises smooth muscle contractility.Natural History and Clinical PresentationThe symptoms of GIDF are quite common, and collectively these disorders are responsible for 17 million physician visits per year. These symptoms are manifestations of aberrations in motor function[7] and visceral sensitivity[8] that in turn may reflect changes in normal neurophysiologic processes at the molecular, genetic, or cellular level. Approximately 20% of the population experience heartburn, and this is fairly consistent among studies performed in the United States and Europe. The prevalence of IBS is approximately 15%, and the average prevalence of FD based on recent studies is approximately 27%.The frequency with which overlapping symptoms in IBS, GERD, and FD occur is consistent with the neurobiology of the gut. Among individuals with IBS, 42% have reflux symptoms and 45% have dyspepsia; among those with heartburn, 38% have dyspepsia and 25% have IBS; and of those with dyspepsia, 55% have reflux symptoms and 38% have IBS (Locke and colleagues; submitted for publication). Studies have shown that patients also can experience transitions between disorders, during which they may have the symptoms of one disorder replaced by the symptoms of another years later. Hence, symptoms not only come and go, but they also change over time.[9]Approach to ManagementThe management of IBS, GERD, and FD is typically symptom-based, involves minimal testing, and often emphasizes lifestyle modification. Frequently, the same agents are used to treat multiple conditions:Acid inhibitors are commonly used in the treatment of GERD and dyspepsia.Prokinetics are often used to treat GERD, dyspepsia, and constipation.Anticholinergics are used in the management of dyspepsia and IBS.Tricyclic antidepressants are often prescribed to treat multiple functional disorders.During the past decade, we have seen that GIDF are common and that there has been a great emphasis on splitting them into separate categories, eg, IBS, GERD, and FD. In part, this practice has been useful for creating homogeneous populations for research. However, a significant body of research currently provides evidence that IBS, GERD, and FD have considerable overlap and transitions and may well be part of a broader GI disorder, representing variations in the presentation of an irritable gut.[9]


----------



## eric (Jul 8, 1999)

FYIIntroductionNearly 7 of 10 adults are affected by one or more functional gastrointestinal (GI) disorders, such as irritable bowel syndrome (IBS), gastroesophageal reflux disease (GERD), and functional dyspepsia (FD).[1] Because of the prevalence of these GI disorders, The Johns Hopkins University School of Medicine sponsored an expert-led symposium on October 15, 1999, in Phoenix, Ariz, to explore the current state of the field. This article highlights the presentations on basic science and clinical implications that were delivered during this meeting.Gastrointestinal disorders such as IBS, GERD, and FD have been referred to collectively as "functional GI disorders." However, this label is suggestive of psychosomatic mechanisms, and, as you will gather from this presentation, the role of serotonin (5-HT) in the pathophysiology of these disorders provides supporting evidence for underlying biophysiologic mechanisms. Hence, in this forum, we use the term "GI disorders of function" (GIDF) to avoid the biases and pejorative misconceptions that may be associated with traditional concepts of functional disorders.To facilitate a better understanding of the pathophysiological mechanisms relating to the clinical symptoms of GIDF and to broaden our perspective of the current developments in the clinical pharmacology of the gut, both a basic scientist and a clinician contributed to the content of the 3 topics discussed. Overall, the presentations highlight the overlapping symptoms in IBS, GERD, and FD; examine the role of 5-HT; and review the therapeutic potential of 5-HT pharmacology in GIDF.Overlapping Symptoms of Gastrointestinal Disorders of FunctionUnderlying PhysiologyThe GI tract is the only organ with an intrinsic nervous system that consists of more than 100 million neurons. Of these, the neurons of the enteric ganglia and interstitial cells of Cajal (ICC) are central modulators of GI function. There are 3 types of enteric neurons: afferent, motor, and regulatory.[2] The normal human intestine contains an excessive number of inhibitory neurons, more than are necessary for the complete relaxation of the visceral musculature. In some GI motility disorders, the amount of intrinsic motor inhibitory innervation is inadequate to provide complete relaxation. Decreased numbers of inhibitory motor neurons and/or decreased production of nitric oxide (which, because of its smooth muscle-relaxing properties, plays a key role in mediating GI motility[3]) in inhibitory motoneurons have been demonstrated in achalasia, gastric stasis and hypertrophic pyloric stenosis, chronic intestinal pseudo-obstruction, and megacolon or Hirschsprung's disease.[3]A significant recent advance in the enteric sciences has been the identification of the ICC as generators of the pacemaker potential in the stomach and small and large intestines, as elements that amplify neurotransmission from nerve to smooth muscle and as elements that may be stretch receptors.[4,5] In severe constipation and chronic intestinal pseudo-obstruction, the surface area of the ICC network is considerably less than that found in tissues from healthy subjects, and structural anomalies are apparent in the existing cells.[6] The decrease in surface area of the "pacemaker" cells profoundly compromises smooth muscle contractility.Natural History and Clinical PresentationThe symptoms of GIDF are quite common, and collectively these disorders are responsible for 17 million physician visits per year. These symptoms are manifestations of aberrations in motor function[7] and visceral sensitivity[8] that in turn may reflect changes in normal neurophysiologic processes at the molecular, genetic, or cellular level. Approximately 20% of the population experience heartburn, and this is fairly consistent among studies performed in the United States and Europe. The prevalence of IBS is approximately 15%, and the average prevalence of FD based on recent studies is approximately 27%.The frequency with which overlapping symptoms in IBS, GERD, and FD occur is consistent with the neurobiology of the gut. Among individuals with IBS, 42% have reflux symptoms and 45% have dyspepsia; among those with heartburn, 38% have dyspepsia and 25% have IBS; and of those with dyspepsia, 55% have reflux symptoms and 38% have IBS (Locke and colleagues; submitted for publication). Studies have shown that patients also can experience transitions between disorders, during which they may have the symptoms of one disorder replaced by the symptoms of another years later. Hence, symptoms not only come and go, but they also change over time.[9]Approach to ManagementThe management of IBS, GERD, and FD is typically symptom-based, involves minimal testing, and often emphasizes lifestyle modification. Frequently, the same agents are used to treat multiple conditions:Acid inhibitors are commonly used in the treatment of GERD and dyspepsia.Prokinetics are often used to treat GERD, dyspepsia, and constipation.Anticholinergics are used in the management of dyspepsia and IBS.Tricyclic antidepressants are often prescribed to treat multiple functional disorders.During the past decade, we have seen that GIDF are common and that there has been a great emphasis on splitting them into separate categories, eg, IBS, GERD, and FD. In part, this practice has been useful for creating homogeneous populations for research. However, a significant body of research currently provides evidence that IBS, GERD, and FD have considerable overlap and transitions and may well be part of a broader GI disorder, representing variations in the presentation of an irritable gut.[9]


----------



## eric (Jul 8, 1999)

5-HT as a Mediator of the Brain-Gut ConnectionThe hierarchic neural control of the digestive tract includes 5 basic levels of integrative organization[2]:Level 1 is in the enteric nervous system.Level 2 is in sympathetic ganglia.Levels 3 and 4 are parasympathetic and sympathetic centers within the medulla oblongata that represent pathways for information transfer from the central nervous system to the gut.Level 5 includes higher brain centers that provide descending information from the central nervous system regarding the perception of GI sensations and manifestations of psychogenic factors such as physical and emotional stress.Serotonin mediates the chemical transfer of information (ie, functions as a signal substance) within the neural circuitry of most of the integrative levels of the hierarchy. Ninety-five percent of 5-HT is localized in the gut. The two important paracrine sources of 5-HT in the GI tract are the enterochromaffin cells and the enteric mast cells.[10] Whether released from neurons (neurocrine) or nonneuronal (paracrine) cells, 5-HT is excitatory to neurons by triggering either a rapidly activating depolarization through an inotropic receptor (eg, 5-HT3) or a slowly activating depolarization of the membrane potential through a metabotropic receptor (eg, 5-HT1P).[11]Mechanism of ActionThe amount of 5-HT released in the gut increases after a meal. Serotonin activates splanchnic afferents, which then transmit the signals to the central nervous system, likely bypassing levels of consciousness. However, in cases of inflammation, the afferents become sensitized and 5-HT release leads to an exaggerated sensory cascade that involves spinal integrated circuits; this kind of information reaches levels of consciousness manifested as discomfort or pain. Mast cells induce sensitization reactions to food or infection by releasing 5-HT. The 5-HT1P and 5-HT4 receptors modulate hypersensitivity reactions of the gut, such as hypersecretion and propulsive motor events.Presynaptic inhibition (possibly mediated through 5-HT4 receptors) at nicotinic synapses is an important mechanism by which 5-HT affects enteric function. In vitro neurophysiologic studies[12] suggest that serotonin may act presynaptically to suppress acetylcholine release. Presynaptic inhibition functions as a brake to control a cascade of excitatory signals, keeping "runaway" excitation under control. In addition, the 5-HT4 receptor facilitates nicotinic synaptic transmission, which is believed to underlie the augmented intestinal propulsion seen in animal studies.At the level of the dorsal vagal complex in the brain stem (level 4), an injection of minute quantities of 5- HT elicits minimal effect on gastric motility and acid secretion. However, this effect is accentuated when microapplication of thyrotropin-releasing hormone (TRH) precedes the injection of 5-HT, suggesting that 5-HT and TRH are released in variable proportions to mediate changes in digestive function appropriate to differing states of the individual.[13]Role of 5-HT in Motor and Sensory ProcessesSerotonin affects several GI motor and sensory functions in response to noxious mechanical or inflammatory stimuli. Motor, sensory, or chemical stimuli may precipitate the release of 5-HT, which binds to 5-HT receptors localized on vagal and spinal afferents and leads to a cascade of events that may affect the modulation of colonic tone (5-HT3), acceleration of gastric emptying, pan-gut transit (5- HT4), or gastric accommodation (5-HT4, 5-HT1A).[10]The carcinoid syndrome provides a better understanding of the putative role of 5-HT in the pathophysiology of GIDF. Excessive 5-HT is secreted by carcinoid tumors. Using isotopes as a noninvasive means of tracking transit in the stomach, small bowel, and colon, it was shown that patients with carcinoid diarrhea exhibited accelerated emptying of the proximal colon and a reduction in its volume. This volume reduction of the colon is associated with an increased colonic tone, suggesting that 5-HT controls postprandial tone.[14]The increasing evidence that 5-HT receptors affect both sensory and motor processes in the gut indicates that they are promising targets for novel 5-HT pharmacotherapeutic agents. In fact, a number of 5-HT agents are currently under development for motility disorders. Tegaserod, a 5-HT4 partial agonist, has been shown to increase contractile activity along the small bowel and colon of canines, ie, animals given tegaserod demonstrated an accelerated movement of isotope through the proximal and distal colon in a dose-dependent fashion, at least in the first 30 minutes after intravenous administration of the agent.[15] Likewise, in humans with constipation-predominant IBS, colonic filling (a surrogate for orocecal transit time) is accelerated in response to oral administration of tegaserod relative to placebo. In the same experiments, acceleration of colonic emptying was demonstrated, as indicated by the larger proportion of isotope reaching the distal colon at 48 hours after administration of tegaserod relative to pretreatment transit.[16]Studies of 5-HT3 antagonists indicate that this pharmacological class may be useful in delaying colonic transit and modulating GI tone. However, preliminary findings do not provide compelling evidence for an antinociceptive effect of 5-HT3 antagonists, seen in a study by Delvaux and colleagues.[17] This study also showed that the 5-HT3 antagonist alosetron increased the threshold for the sensation of first perception and pain, possibly related to changes in colonic compliance. Although these data do not indicate an antinociceptive effect, the change in GI tone allows a larger volume to be accommodated in the colon.The Therapeutic Potential of 5-HT in GIDFThe evolution of mechanistic hypotheses underlying IBS began with a focus on motor abnormalities in the 1950s, shifted to visceral hypersensitivity around the 1970s, and then moved to brain-gut connectivity in the 1980s. In the 1990s, the role of 5-HT in the pathophysiology of IBS is the primary focus of clinical research.The 5-HT Drugs: Mechanisms of ActionEnterochromaffin cells act as sensory transducers and respond to mechanical and chemical stimuli by releasing 5-HT. Extrinsic primary afferent neurons (from the vagus), peripheral endings of the intrinsic primary afferent neurons, myenteric interneurons, and secretomotor neurons are sites containing 5-HT3 receptors; 5-HT4 receptors are localized in the distal ends of intrinsic primary afferent neurons within the myenteric plexus, nerve endings of excitatory motoneurons terminating in longitudinal and circular muscles, nerve endings of cholinergic interneurons, and secretomotor neurons in the submucosal plexus.[10,18]The 5-HT1 receptors are G protein-linked and couple to several intracellular signaling pathways. Sumatriptan and buspirone are 5-HT1/ receptor agonists. Impaired gastric fundus accommodation to a meal, a symptom associated with FD, induces early satiety. Studies in animals have shown that sumatriptan selectively excites a population of nitric oxide inhibitory motoneurons. Nitric oxide facilitates the fundic relaxation (ie, relaxation of longitudinal and circular smooth muscle layers), which increases gastric accommodation. As many as 40% of patients with FD have impaired accommodation.[19] Clinical studies show that sumatriptan reduces symptom scores for dysmotility-like FD; similar findings were reported with buspirone.[19,20]The 5-HT3 receptors are ligand-gated ion channels. They mediate GI reflexes and secretion, which blunt the visceral perception, leading to therapeutic efficacy in the inhibition of emesis and treatment of functional motility disorders. Because 5-HT3 antagonists may blunt visceral perception, reduce colonic compliance and postprandial gastro-colonic response, and slow colonic transit, the utility of this class of agents (eg, ondansetron and alosetron) for the treatment of diarrhea-predominant IBS is under investigation. Current analyses of the 5-HT3 receptor is unraveling a more complex molecular structure (ie, existence of multiple subunits) and paving the way for the development of more specific pharmacotherapeutic agents.The 5-HT4 receptors are located in the smooth muscle layers and nerve terminals of the myenteric plexus. These G protein-linked receptors mediate muscle relaxation and acetylcholine release, which lowers the peristaltic threshold and enhances peristaltic efficiency. The 5-HT4 receptors selectively couple to the stimulatory G protein, Gs. Activation of Gs leads to a cascade of events, including activation of adenylate cyclase, increased intracellular cyclic AMP, and activation of protein kinase A. Protein kinase A mediates the excitatory effects of 5-HT4 receptor stimulation. Mosapride and cisapride are both 5-HT4 agonists. Cisapride is widely used in treating GI motility disorders such as GERD. However, it can adversely affect cardiac function. In comparing electrocardiograms of rabbits given mosapride and cisapride, Carlsson and coworkers[21] showed that mosapride had little or no effect on rabbit electrophysiological features, whereas cisapride prolonged the Q-T interval in a population of rabbits, suggesting that the lengthening of the Q-T interval by cisapride is not mediated by the 5-HT4 receptor.Cisapride, prucalopride, and tegaserod are examples of 5-HT4 receptor agonists in this class.[22]Cisapride, which is both a 5-HT3 antagonist and 5-HT4 agonist, is effective in the treatment of FD but less effective for the treatment of constipation and IBS. Cisapride enhances gastric accommodation and emptying but appears to enhance gastric perception in the fasting state.[21]Prucalopride is a selective 5-HT4 receptor agonist that induces a potent dose-dependent acceleration of colonic transit; it also increases stool frequency. This agent may be useful for chronic constipation and slow transit constipation.[23]Tegaserod is a 5-HT4 receptor partial agonist. An earlier dose-ranging, placebo-controlled study using 1, 4, 12, and 24 mg of tegaserod showed that both 4- and 12-mg doses increased colonic transit. Recent phase 3 data[24] from patients with constipation-predominant IBS confirmed these findings and indicated that the 12-mg dose produced a significant increase in bowel movements compared with placebo. Using subjective global assessment of relief (overall GI symptoms, abdominal pain and discomfort, and constipation), near-maximum results were produced by tegaserod in week 1 compared with placebo.[25] Tegaserod was well tolerated, and the incidence of adverse effects was similar to placebo.Concluding RemarksThe ubiquity of 5-HT and its receptors in the gastrointestinal tract is indicative of the importance of this messenger molecule in modulating gut function. Molecular and pharmacological studies continue to reveal different classes of 5-HT receptors (eg, 5-HT7) that are potential targets of new agents for the treatment of GIDF. http://www.medscape.com/viewprogram/613


----------



## eric (Jul 8, 1999)

5-HT as a Mediator of the Brain-Gut ConnectionThe hierarchic neural control of the digestive tract includes 5 basic levels of integrative organization[2]:Level 1 is in the enteric nervous system.Level 2 is in sympathetic ganglia.Levels 3 and 4 are parasympathetic and sympathetic centers within the medulla oblongata that represent pathways for information transfer from the central nervous system to the gut.Level 5 includes higher brain centers that provide descending information from the central nervous system regarding the perception of GI sensations and manifestations of psychogenic factors such as physical and emotional stress.Serotonin mediates the chemical transfer of information (ie, functions as a signal substance) within the neural circuitry of most of the integrative levels of the hierarchy. Ninety-five percent of 5-HT is localized in the gut. The two important paracrine sources of 5-HT in the GI tract are the enterochromaffin cells and the enteric mast cells.[10] Whether released from neurons (neurocrine) or nonneuronal (paracrine) cells, 5-HT is excitatory to neurons by triggering either a rapidly activating depolarization through an inotropic receptor (eg, 5-HT3) or a slowly activating depolarization of the membrane potential through a metabotropic receptor (eg, 5-HT1P).[11]Mechanism of ActionThe amount of 5-HT released in the gut increases after a meal. Serotonin activates splanchnic afferents, which then transmit the signals to the central nervous system, likely bypassing levels of consciousness. However, in cases of inflammation, the afferents become sensitized and 5-HT release leads to an exaggerated sensory cascade that involves spinal integrated circuits; this kind of information reaches levels of consciousness manifested as discomfort or pain. Mast cells induce sensitization reactions to food or infection by releasing 5-HT. The 5-HT1P and 5-HT4 receptors modulate hypersensitivity reactions of the gut, such as hypersecretion and propulsive motor events.Presynaptic inhibition (possibly mediated through 5-HT4 receptors) at nicotinic synapses is an important mechanism by which 5-HT affects enteric function. In vitro neurophysiologic studies[12] suggest that serotonin may act presynaptically to suppress acetylcholine release. Presynaptic inhibition functions as a brake to control a cascade of excitatory signals, keeping "runaway" excitation under control. In addition, the 5-HT4 receptor facilitates nicotinic synaptic transmission, which is believed to underlie the augmented intestinal propulsion seen in animal studies.At the level of the dorsal vagal complex in the brain stem (level 4), an injection of minute quantities of 5- HT elicits minimal effect on gastric motility and acid secretion. However, this effect is accentuated when microapplication of thyrotropin-releasing hormone (TRH) precedes the injection of 5-HT, suggesting that 5-HT and TRH are released in variable proportions to mediate changes in digestive function appropriate to differing states of the individual.[13]Role of 5-HT in Motor and Sensory ProcessesSerotonin affects several GI motor and sensory functions in response to noxious mechanical or inflammatory stimuli. Motor, sensory, or chemical stimuli may precipitate the release of 5-HT, which binds to 5-HT receptors localized on vagal and spinal afferents and leads to a cascade of events that may affect the modulation of colonic tone (5-HT3), acceleration of gastric emptying, pan-gut transit (5- HT4), or gastric accommodation (5-HT4, 5-HT1A).[10]The carcinoid syndrome provides a better understanding of the putative role of 5-HT in the pathophysiology of GIDF. Excessive 5-HT is secreted by carcinoid tumors. Using isotopes as a noninvasive means of tracking transit in the stomach, small bowel, and colon, it was shown that patients with carcinoid diarrhea exhibited accelerated emptying of the proximal colon and a reduction in its volume. This volume reduction of the colon is associated with an increased colonic tone, suggesting that 5-HT controls postprandial tone.[14]The increasing evidence that 5-HT receptors affect both sensory and motor processes in the gut indicates that they are promising targets for novel 5-HT pharmacotherapeutic agents. In fact, a number of 5-HT agents are currently under development for motility disorders. Tegaserod, a 5-HT4 partial agonist, has been shown to increase contractile activity along the small bowel and colon of canines, ie, animals given tegaserod demonstrated an accelerated movement of isotope through the proximal and distal colon in a dose-dependent fashion, at least in the first 30 minutes after intravenous administration of the agent.[15] Likewise, in humans with constipation-predominant IBS, colonic filling (a surrogate for orocecal transit time) is accelerated in response to oral administration of tegaserod relative to placebo. In the same experiments, acceleration of colonic emptying was demonstrated, as indicated by the larger proportion of isotope reaching the distal colon at 48 hours after administration of tegaserod relative to pretreatment transit.[16]Studies of 5-HT3 antagonists indicate that this pharmacological class may be useful in delaying colonic transit and modulating GI tone. However, preliminary findings do not provide compelling evidence for an antinociceptive effect of 5-HT3 antagonists, seen in a study by Delvaux and colleagues.[17] This study also showed that the 5-HT3 antagonist alosetron increased the threshold for the sensation of first perception and pain, possibly related to changes in colonic compliance. Although these data do not indicate an antinociceptive effect, the change in GI tone allows a larger volume to be accommodated in the colon.The Therapeutic Potential of 5-HT in GIDFThe evolution of mechanistic hypotheses underlying IBS began with a focus on motor abnormalities in the 1950s, shifted to visceral hypersensitivity around the 1970s, and then moved to brain-gut connectivity in the 1980s. In the 1990s, the role of 5-HT in the pathophysiology of IBS is the primary focus of clinical research.The 5-HT Drugs: Mechanisms of ActionEnterochromaffin cells act as sensory transducers and respond to mechanical and chemical stimuli by releasing 5-HT. Extrinsic primary afferent neurons (from the vagus), peripheral endings of the intrinsic primary afferent neurons, myenteric interneurons, and secretomotor neurons are sites containing 5-HT3 receptors; 5-HT4 receptors are localized in the distal ends of intrinsic primary afferent neurons within the myenteric plexus, nerve endings of excitatory motoneurons terminating in longitudinal and circular muscles, nerve endings of cholinergic interneurons, and secretomotor neurons in the submucosal plexus.[10,18]The 5-HT1 receptors are G protein-linked and couple to several intracellular signaling pathways. Sumatriptan and buspirone are 5-HT1/ receptor agonists. Impaired gastric fundus accommodation to a meal, a symptom associated with FD, induces early satiety. Studies in animals have shown that sumatriptan selectively excites a population of nitric oxide inhibitory motoneurons. Nitric oxide facilitates the fundic relaxation (ie, relaxation of longitudinal and circular smooth muscle layers), which increases gastric accommodation. As many as 40% of patients with FD have impaired accommodation.[19] Clinical studies show that sumatriptan reduces symptom scores for dysmotility-like FD; similar findings were reported with buspirone.[19,20]The 5-HT3 receptors are ligand-gated ion channels. They mediate GI reflexes and secretion, which blunt the visceral perception, leading to therapeutic efficacy in the inhibition of emesis and treatment of functional motility disorders. Because 5-HT3 antagonists may blunt visceral perception, reduce colonic compliance and postprandial gastro-colonic response, and slow colonic transit, the utility of this class of agents (eg, ondansetron and alosetron) for the treatment of diarrhea-predominant IBS is under investigation. Current analyses of the 5-HT3 receptor is unraveling a more complex molecular structure (ie, existence of multiple subunits) and paving the way for the development of more specific pharmacotherapeutic agents.The 5-HT4 receptors are located in the smooth muscle layers and nerve terminals of the myenteric plexus. These G protein-linked receptors mediate muscle relaxation and acetylcholine release, which lowers the peristaltic threshold and enhances peristaltic efficiency. The 5-HT4 receptors selectively couple to the stimulatory G protein, Gs. Activation of Gs leads to a cascade of events, including activation of adenylate cyclase, increased intracellular cyclic AMP, and activation of protein kinase A. Protein kinase A mediates the excitatory effects of 5-HT4 receptor stimulation. Mosapride and cisapride are both 5-HT4 agonists. Cisapride is widely used in treating GI motility disorders such as GERD. However, it can adversely affect cardiac function. In comparing electrocardiograms of rabbits given mosapride and cisapride, Carlsson and coworkers[21] showed that mosapride had little or no effect on rabbit electrophysiological features, whereas cisapride prolonged the Q-T interval in a population of rabbits, suggesting that the lengthening of the Q-T interval by cisapride is not mediated by the 5-HT4 receptor.Cisapride, prucalopride, and tegaserod are examples of 5-HT4 receptor agonists in this class.[22]Cisapride, which is both a 5-HT3 antagonist and 5-HT4 agonist, is effective in the treatment of FD but less effective for the treatment of constipation and IBS. Cisapride enhances gastric accommodation and emptying but appears to enhance gastric perception in the fasting state.[21]Prucalopride is a selective 5-HT4 receptor agonist that induces a potent dose-dependent acceleration of colonic transit; it also increases stool frequency. This agent may be useful for chronic constipation and slow transit constipation.[23]Tegaserod is a 5-HT4 receptor partial agonist. An earlier dose-ranging, placebo-controlled study using 1, 4, 12, and 24 mg of tegaserod showed that both 4- and 12-mg doses increased colonic transit. Recent phase 3 data[24] from patients with constipation-predominant IBS confirmed these findings and indicated that the 12-mg dose produced a significant increase in bowel movements compared with placebo. Using subjective global assessment of relief (overall GI symptoms, abdominal pain and discomfort, and constipation), near-maximum results were produced by tegaserod in week 1 compared with placebo.[25] Tegaserod was well tolerated, and the incidence of adverse effects was similar to placebo.Concluding RemarksThe ubiquity of 5-HT and its receptors in the gastrointestinal tract is indicative of the importance of this messenger molecule in modulating gut function. Molecular and pharmacological studies continue to reveal different classes of 5-HT receptors (eg, 5-HT7) that are potential targets of new agents for the treatment of GIDF. http://www.medscape.com/viewprogram/613


----------



## bonniei (Jan 25, 2001)

I edited my last post. pdb please read it again.


----------



## bonniei (Jan 25, 2001)

I edited my last post. pdb please read it again.


----------



## trbell (Nov 1, 2000)

so it's really a gut brain connection?tom


----------



## trbell (Nov 1, 2000)

so it's really a gut brain connection?tom


----------



## eric (Jul 8, 1999)

yes, yes and yes.


----------



## eric (Jul 8, 1999)

yes, yes and yes.


----------



## pdb (Jun 28, 2001)

thanks everyone for the responses. I've learned so much from this site. if only my doctor was as knowledgable.







by the way, I've decided to go off the Remeron completely. there is still a lot to be learned about these drugs and I think it was affecting me in other ways besides just decreasing my D. I'd rather try to treat myself with CBT.


----------



## pdb (Jun 28, 2001)

thanks everyone for the responses. I've learned so much from this site. if only my doctor was as knowledgable.







by the way, I've decided to go off the Remeron completely. there is still a lot to be learned about these drugs and I think it was affecting me in other ways besides just decreasing my D. I'd rather try to treat myself with CBT.


----------



## bonniei (Jan 25, 2001)

yes tom there really is a brain gut connection, lol. Like eric hasn't driven the point in often enough







Of particular interest to you and other IBS-C's, one last bit of info on the brain gut connection and this topic:"Also, stimulation of 5-HT4 receptor sites leads to the release of various neurotransmitters and the peristaltic reflex in vitro, suggesting that 5-HT4 receptor agonists may be beneficial in treating patients with constipation-predominant IBS "pdb, glad to be of service if my info helped. Antidepressants are very complex drugs and have all kinds of undesired effects. So I can understand you wanting to get off it


----------



## bonniei (Jan 25, 2001)

yes tom there really is a brain gut connection, lol. Like eric hasn't driven the point in often enough







Of particular interest to you and other IBS-C's, one last bit of info on the brain gut connection and this topic:"Also, stimulation of 5-HT4 receptor sites leads to the release of various neurotransmitters and the peristaltic reflex in vitro, suggesting that 5-HT4 receptor agonists may be beneficial in treating patients with constipation-predominant IBS "pdb, glad to be of service if my info helped. Antidepressants are very complex drugs and have all kinds of undesired effects. So I can understand you wanting to get off it


----------



## pdb (Jun 28, 2001)

bonniei (or anyone else) -I now understand about the 5HT-3 receptor, and how it acts to speed up the digestive process. So in effect, blocking it with an antagonist slows things down and helps diarrhea.However, I'm still a bit confused about the 5HT-4 receptor. There seems to be some differeing information out there. I've read that the 5HT-4 receptor is in charge of slowing things down, so wouldn't it take an antagonist to block the receptor and speed things up to help relieve constipation? Conversely, wouldn't an agonist slow things down even more and make C even worse? I had asked a similar question about 5HT-4 agonists possibly helping D but didn't get an answer.


----------



## pdb (Jun 28, 2001)

bonniei (or anyone else) -I now understand about the 5HT-3 receptor, and how it acts to speed up the digestive process. So in effect, blocking it with an antagonist slows things down and helps diarrhea.However, I'm still a bit confused about the 5HT-4 receptor. There seems to be some differeing information out there. I've read that the 5HT-4 receptor is in charge of slowing things down, so wouldn't it take an antagonist to block the receptor and speed things up to help relieve constipation? Conversely, wouldn't an agonist slow things down even more and make C even worse? I had asked a similar question about 5HT-4 agonists possibly helping D but didn't get an answer.


----------



## bonniei (Jan 25, 2001)

I think your info is not correct. Stimulation of 5-HT4 receptor sites leads to the release of various neurotransmitters and the peristaltic reflex which leads to a BM. So you need an agonist to facilitate this action and speed things up even more rather than an antagonist to block it and kill the peristaltic reflex


----------



## bonniei (Jan 25, 2001)

I think your info is not correct. Stimulation of 5-HT4 receptor sites leads to the release of various neurotransmitters and the peristaltic reflex which leads to a BM. So you need an agonist to facilitate this action and speed things up even more rather than an antagonist to block it and kill the peristaltic reflex


----------



## eric (Jul 8, 1999)

PDB, just to make sure we weren't posting at the same time, but I posted a lot on this on page 1 of the thread. "The 5-HT4 receptors are located in the smooth muscle layers and nerve terminals of the myenteric plexus. These G protein-linked receptors mediate muscle relaxation and acetylcholine release, which lowers the peristaltic threshold and enhances peristaltic efficiency. The 5-HT4 receptors selectively couple to the stimulatory G protein, Gs. Activation of Gs leads to a cascade of events, including activation of adenylate cyclase, increased intracellular cyclic AMP, and activation of protein kinase A. Protein kinase A mediates the excitatory effects of 5-HT4 receptor stimulation. Mosapride and cisapride are both 5-HT4 agonists. Cisapride is widely used in treating GI motility disorders such as GERD. However, it can adversely affect cardiac function. In comparing electrocardiograms of rabbits given mosapride and cisapride, Carlsson and coworkers[21] showed that mosapride had little or no effect on rabbit electrophysiological features, whereas cisapride prolonged the Q-T interval in a population of rabbits, suggesting that the lengthening of the Q-T interval by cisapride is not mediated by the 5-HT4 receptor. Cisapride, prucalopride, and tegaserod are examples of 5-HT4 receptor agonists in this class.[22] Cisapride, which is both a 5-HT3 antagonist and 5-HT4 agonist, is effective in the treatment of FD but less effective for the treatment of constipation and IBS. Cisapride enhances gastric accommodation and emptying but appears to enhance gastric perception in the fasting state.[21] Prucalopride is a selective 5-HT4 receptor agonist that induces a potent dose-dependent acceleration of colonic transit; it also increases stool frequency. This agent may be useful for chronic constipation and slow transit constipation.[23] Tegaserod is a 5-HT4 receptor partial agonist. An earlier dose-ranging, placebo-controlled study using 1, 4, 12, and 24 mg of tegaserod showed that both 4- and 12-mg doses increased colonic transit. Recent phase 3 data[24] from patients with constipation-predominant IBS confirmed these findings and indicated that the 12-mg dose produced a significant increase in bowel movements compared with placebo. Using subjective global assessment of relief (overall GI symptoms, abdominal pain and discomfort, and constipation), near-maximum results were produced by tegaserod in week 1 compared with placebo.[25] Tegaserod was well tolerated, and the incidence of adverse effects was similar to placebo."


----------



## eric (Jul 8, 1999)

PDB, just to make sure we weren't posting at the same time, but I posted a lot on this on page 1 of the thread. "The 5-HT4 receptors are located in the smooth muscle layers and nerve terminals of the myenteric plexus. These G protein-linked receptors mediate muscle relaxation and acetylcholine release, which lowers the peristaltic threshold and enhances peristaltic efficiency. The 5-HT4 receptors selectively couple to the stimulatory G protein, Gs. Activation of Gs leads to a cascade of events, including activation of adenylate cyclase, increased intracellular cyclic AMP, and activation of protein kinase A. Protein kinase A mediates the excitatory effects of 5-HT4 receptor stimulation. Mosapride and cisapride are both 5-HT4 agonists. Cisapride is widely used in treating GI motility disorders such as GERD. However, it can adversely affect cardiac function. In comparing electrocardiograms of rabbits given mosapride and cisapride, Carlsson and coworkers[21] showed that mosapride had little or no effect on rabbit electrophysiological features, whereas cisapride prolonged the Q-T interval in a population of rabbits, suggesting that the lengthening of the Q-T interval by cisapride is not mediated by the 5-HT4 receptor. Cisapride, prucalopride, and tegaserod are examples of 5-HT4 receptor agonists in this class.[22] Cisapride, which is both a 5-HT3 antagonist and 5-HT4 agonist, is effective in the treatment of FD but less effective for the treatment of constipation and IBS. Cisapride enhances gastric accommodation and emptying but appears to enhance gastric perception in the fasting state.[21] Prucalopride is a selective 5-HT4 receptor agonist that induces a potent dose-dependent acceleration of colonic transit; it also increases stool frequency. This agent may be useful for chronic constipation and slow transit constipation.[23] Tegaserod is a 5-HT4 receptor partial agonist. An earlier dose-ranging, placebo-controlled study using 1, 4, 12, and 24 mg of tegaserod showed that both 4- and 12-mg doses increased colonic transit. Recent phase 3 data[24] from patients with constipation-predominant IBS confirmed these findings and indicated that the 12-mg dose produced a significant increase in bowel movements compared with placebo. Using subjective global assessment of relief (overall GI symptoms, abdominal pain and discomfort, and constipation), near-maximum results were produced by tegaserod in week 1 compared with placebo.[25] Tegaserod was well tolerated, and the incidence of adverse effects was similar to placebo."


----------



## pdb (Jun 28, 2001)

so then a 5HT-4 antagonist could also in theory help D, much like a 5HT-3 antagonist?could a 5HT-3 agonist also help C?or is there just no such thing as 5HT-4 antagonist and a 5HT-3 agonist?


----------



## pdb (Jun 28, 2001)

so then a 5HT-4 antagonist could also in theory help D, much like a 5HT-3 antagonist?could a 5HT-3 agonist also help C?or is there just no such thing as 5HT-4 antagonist and a 5HT-3 agonist?


----------



## bonniei (Jan 25, 2001)

I am not an expert on this but maybe we should read eric's info and it might have more clues.. What you say makes sense. Maybe the key difference is stimulation of 5ht3 affects *motility*and stimulation of 5ht4 affects *peristaltic reflex*. Don't know if these two words make a difference. In other words maybe if you have enhanced motility and no peristalltic reflex you can still have diarrhea. Don't know. will have to read eric's info or hopefully flux will see this thread and be a good samaritan


----------



## bonniei (Jan 25, 2001)

I am not an expert on this but maybe we should read eric's info and it might have more clues.. What you say makes sense. Maybe the key difference is stimulation of 5ht3 affects *motility*and stimulation of 5ht4 affects *peristaltic reflex*. Don't know if these two words make a difference. In other words maybe if you have enhanced motility and no peristalltic reflex you can still have diarrhea. Don't know. will have to read eric's info or hopefully flux will see this thread and be a good samaritan


----------



## trbell (Nov 1, 2000)

just remember to ask your doctor. all of this is pretty new and complicated and speculative. for example, these are two of about 30 receptors they have found and safety of these new serotonin ibs drugs will be discussed at the FDA meeting in Washington next week.tom


----------



## trbell (Nov 1, 2000)

just remember to ask your doctor. all of this is pretty new and complicated and speculative. for example, these are two of about 30 receptors they have found and safety of these new serotonin ibs drugs will be discussed at the FDA meeting in Washington next week.tom


----------



## pdb (Jun 28, 2001)

yeah - what's frustrating though is I feel my doctor knows even less than I do!


----------



## pdb (Jun 28, 2001)

yeah - what's frustrating though is I feel my doctor knows even less than I do!


----------



## LotronexLover (Jan 10, 2001)

I think each 5ht receptor does a different thing. Meaning to block it - you are eleviating the reaction. If the 5ht4 receptors job is to slow things down, and the 5ht3 is to speed things up...I don't know if regulating the amount of seratonin would help.Strange Example: I would think of it being like an acid. Acid burns no matter if its a drop or a bucket full. Why only some of us have problems with processing seratonin - I don't know? My guess is maybe our intestines are somewhat seratonin intolerant? Who knows but the whole seratonin factor is very interesting no matter how you look at it. All I know is next time I visit my doctor I am going to ask her more seratonin / 5ht questions. The 5ht3 receptor ( I think ) controls sleep, sex drive, GI mobility, and a few other things. I will have to find the site on what each one does besides mess around with our GI tracts.


----------



## LotronexLover (Jan 10, 2001)

I think each 5ht receptor does a different thing. Meaning to block it - you are eleviating the reaction. If the 5ht4 receptors job is to slow things down, and the 5ht3 is to speed things up...I don't know if regulating the amount of seratonin would help.Strange Example: I would think of it being like an acid. Acid burns no matter if its a drop or a bucket full. Why only some of us have problems with processing seratonin - I don't know? My guess is maybe our intestines are somewhat seratonin intolerant? Who knows but the whole seratonin factor is very interesting no matter how you look at it. All I know is next time I visit my doctor I am going to ask her more seratonin / 5ht questions. The 5ht3 receptor ( I think ) controls sleep, sex drive, GI mobility, and a few other things. I will have to find the site on what each one does besides mess around with our GI tracts.


----------



## bonniei (Jan 25, 2001)

Another thought on this: note 5HT3 agonist would cause diarrhea I think but 5HT4 agonist only brings about a normal BM. So maybe you don't want to prescribe 5HT3 agonists for people with constipation as they would get diarrhea instead of a normal BM.The goal is to strive for normalcy.


----------



## bonniei (Jan 25, 2001)

Another thought on this: note 5HT3 agonist would cause diarrhea I think but 5HT4 agonist only brings about a normal BM. So maybe you don't want to prescribe 5HT3 agonists for people with constipation as they would get diarrhea instead of a normal BM.The goal is to strive for normalcy.


----------



## flux (Dec 13, 1998)

> quote:Instead of blocking the 5HT3 receptor which is causing the digestive process to move too quickly,


It doesnï¿½t directly. It induces diarrhea by mainly altering water flow across the small bowel wall and by decreasing mixing motions of the colon.


> quote: is it somehow possible to work on the 5HT4 receptor - sort ot increase the rate at which the 5HT4 receptor causes the gut to slow down?


4HT4 triggers the peristatlic reflex and hence moves this forward.


> quote:He takes Zoloft for anxiety and for C. It blocks the 5ht4 receptor.


This is *false* It has no direct effect on any of the serotonin receptors as far as I know. I believe this second time you posted this misinformation









> quote:I assume the autonomic circuit in my post and in the article is the one which links the gut to the brain, eric or flux


Yes.


> quote:How does Paxil and Wellbutrin work on 5ht?


It is probably safe to say to they they at least do something to its behavior at synapses, but what exactly is probably not 100% clear.


> quote:A 5HT3 anatagonist will block action at the 5HT3 receptor site - the action being to absorb serotonin


This is *false*. Reuptake transporters absorb serotonin. The 5HT3 receptor on the receiiving neuron takes ï¿½actionsï¿½ in response to binding to serotonin. Usually, I think, it is for it is to send excitatory impuluses to other neurons utilizing acetylcholine.


> quote:So in effect, blocking it with an antagonist slows things down and helps diarrhea.


It helps with diarrhea but mainly by altering water movement across the small bowel wall and stimulating mixing movements.


> quote:I've read that the 5HT-4 receptor is in charge of slowing things down, so wouldn't it take an antagonist to block the receptor and speed things up to help relieve constipation? Conversely, wouldn't an agonist slow things down even more and make C even worse?


4HT4 triggers the peristatlic reflex and hence moves this forward. So an agonist would move things forward and therefor help with slow-transit constipation.


> quote:so then a 5HT-4 antagonist could also in theory help D, much like a 5HT-3 antagonist?


Yes, that makes sense.


> quote:could a 5HT-3 agonist also help C?


Yes, that makes sense.


> quoter is there just no such thing as 5HT-4 antagonist and a 5HT-3 agonist?


Piboserod is an example of a 5HT-4 antagonist. Lintopride is another.1-benzyl-piperazine is apparently an example of a 5hT-3 agonist.


----------



## flux (Dec 13, 1998)

> quote:Instead of blocking the 5HT3 receptor which is causing the digestive process to move too quickly,


It doesnï¿½t directly. It induces diarrhea by mainly altering water flow across the small bowel wall and by decreasing mixing motions of the colon.


> quote: is it somehow possible to work on the 5HT4 receptor - sort ot increase the rate at which the 5HT4 receptor causes the gut to slow down?


4HT4 triggers the peristatlic reflex and hence moves this forward.


> quote:He takes Zoloft for anxiety and for C. It blocks the 5ht4 receptor.


This is *false* It has no direct effect on any of the serotonin receptors as far as I know. I believe this second time you posted this misinformation









> quote:I assume the autonomic circuit in my post and in the article is the one which links the gut to the brain, eric or flux


Yes.


> quote:How does Paxil and Wellbutrin work on 5ht?


It is probably safe to say to they they at least do something to its behavior at synapses, but what exactly is probably not 100% clear.


> quote:A 5HT3 anatagonist will block action at the 5HT3 receptor site - the action being to absorb serotonin


This is *false*. Reuptake transporters absorb serotonin. The 5HT3 receptor on the receiiving neuron takes ï¿½actionsï¿½ in response to binding to serotonin. Usually, I think, it is for it is to send excitatory impuluses to other neurons utilizing acetylcholine.


> quote:So in effect, blocking it with an antagonist slows things down and helps diarrhea.


It helps with diarrhea but mainly by altering water movement across the small bowel wall and stimulating mixing movements.


> quote:I've read that the 5HT-4 receptor is in charge of slowing things down, so wouldn't it take an antagonist to block the receptor and speed things up to help relieve constipation? Conversely, wouldn't an agonist slow things down even more and make C even worse?


4HT4 triggers the peristatlic reflex and hence moves this forward. So an agonist would move things forward and therefor help with slow-transit constipation.


> quote:so then a 5HT-4 antagonist could also in theory help D, much like a 5HT-3 antagonist?


Yes, that makes sense.


> quote:could a 5HT-3 agonist also help C?


Yes, that makes sense.


> quoter is there just no such thing as 5HT-4 antagonist and a 5HT-3 agonist?


Piboserod is an example of a 5HT-4 antagonist. Lintopride is another.1-benzyl-piperazine is apparently an example of a 5hT-3 agonist.


----------



## trbell (Nov 1, 2000)

it would be great if all this was written out someplace tom


----------



## trbell (Nov 1, 2000)

it would be great if all this was written out someplace tom


----------



## bonniei (Jan 25, 2001)

THANKS flux for a much needed review of this thread but did the *false* have to be so bold? Do you think you could tone it down just a wee bit next time? Just kidding.







It is very generous of you to spend so much time on this.







And here I thought you were not going to answer.Must get over my fear of that.









> quote:This is *false*. Reuptake transporters absorb serotonin. The 5HT3 receptor on the receiving neuron takes "actions" in response to binding to serotonin.


I guess you are objecting to my using the word absorb.I admit I was being a wee bit simplistic. I didn't want to overhelm them with too many details. Besides I wouldn't know how to begin.Thanks again


----------



## bonniei (Jan 25, 2001)

THANKS flux for a much needed review of this thread but did the *false* have to be so bold? Do you think you could tone it down just a wee bit next time? Just kidding.







It is very generous of you to spend so much time on this.







And here I thought you were not going to answer.Must get over my fear of that.









> quote:This is *false*. Reuptake transporters absorb serotonin. The 5HT3 receptor on the receiving neuron takes "actions" in response to binding to serotonin.


I guess you are objecting to my using the word absorb.I admit I was being a wee bit simplistic. I didn't want to overhelm them with too many details. Besides I wouldn't know how to begin.Thanks again


----------



## Guest (Apr 14, 2002)

Geeze, but this is complicated. Just trying to take it all in is overwhelming for me.All I know is that when I've taken antidepressants, my IBS has gotten significantly worse.Guess I'll have to plead both ignorance of this topic and go by my standard, which is: All things are good in moderation.I am sure I will be flogged for this, but do we really think that God intended for our lives to be this complicated?


----------



## Guest (Apr 14, 2002)

Geeze, but this is complicated. Just trying to take it all in is overwhelming for me.All I know is that when I've taken antidepressants, my IBS has gotten significantly worse.Guess I'll have to plead both ignorance of this topic and go by my standard, which is: All things are good in moderation.I am sure I will be flogged for this, but do we really think that God intended for our lives to be this complicated?


----------



## bonniei (Jan 25, 2001)

Art Spirit, LOL. You had to be following the thread from the beginning to understand it. It was much more handleable in bits and pieces.


> quote:A 5HT3 anatagonist will block action at the 5HT3 receptor site - the action being to absorb serotonin


Just a clarification in the context of flux saying that serotonin is not absorbed but it "binds" to the receptor and triggers other actions like utilizing acetylcholine. So it affects the neurotransmitter dependence- i.e between serotonin, norepinephrine, dopamine and acetylcholine-which I had written in my first post and leads to stopping the Dflux, if you are still following the thread, does this statement pass your approval? Or could you please link it up to the neurotransmitter dependence? Please







? Or is it not linked to that at all? My info that the neurotransmitter dependence is important in IBS is from an article from Oct 2000


----------



## bonniei (Jan 25, 2001)

Art Spirit, LOL. You had to be following the thread from the beginning to understand it. It was much more handleable in bits and pieces.


> quote:A 5HT3 anatagonist will block action at the 5HT3 receptor site - the action being to absorb serotonin


Just a clarification in the context of flux saying that serotonin is not absorbed but it "binds" to the receptor and triggers other actions like utilizing acetylcholine. So it affects the neurotransmitter dependence- i.e between serotonin, norepinephrine, dopamine and acetylcholine-which I had written in my first post and leads to stopping the Dflux, if you are still following the thread, does this statement pass your approval? Or could you please link it up to the neurotransmitter dependence? Please







? Or is it not linked to that at all? My info that the neurotransmitter dependence is important in IBS is from an article from Oct 2000


----------



## flux (Dec 13, 1998)

> quote:There are 5 receptors in your brain that release seratonin. 5ht1, 5ht2, 5ht3, 5ht4 ,& 5ht5


No receptor releases serotonin. It is released by presynaptic vesicles in the presynaptic neuron. There are subtypes of the recepctors above and there are also 5HT-6 and 5HT-7 receptors, although I donï¿½t know if they are in the brain.


> quote:If you block the 5ht4 receptor, ex. Zoloft or Zelnorm, that one controls gut mobility also. The 5ht4 receptor slows down gut mobility causing constipation.


Once again, *HUGE ERRORS*. Zoloft does not affect the 5HT4 receptor and Zelnorm does *not* block it, but instead triggers it. And the 5HT4 receptor triggers the peristaltic reflex which increases gut motility and could lead to diarrhea.


> quote:Therefor, why try to block the rest of the receptors?


The other receptors also may play roles in motility and sensation. We probably need more information about them.


> quote:My doctor tries to teach me about the drugs I take & what they do


If your doctor is feeding the misinformation above, take these posts to him/her.









> quote:So it affects the neurotransmitter dependence


Make that inter-dependence


----------



## flux (Dec 13, 1998)

> quote:There are 5 receptors in your brain that release seratonin. 5ht1, 5ht2, 5ht3, 5ht4 ,& 5ht5


No receptor releases serotonin. It is released by presynaptic vesicles in the presynaptic neuron. There are subtypes of the recepctors above and there are also 5HT-6 and 5HT-7 receptors, although I donï¿½t know if they are in the brain.


> quote:If you block the 5ht4 receptor, ex. Zoloft or Zelnorm, that one controls gut mobility also. The 5ht4 receptor slows down gut mobility causing constipation.


Once again, *HUGE ERRORS*. Zoloft does not affect the 5HT4 receptor and Zelnorm does *not* block it, but instead triggers it. And the 5HT4 receptor triggers the peristaltic reflex which increases gut motility and could lead to diarrhea.


> quote:Therefor, why try to block the rest of the receptors?


The other receptors also may play roles in motility and sensation. We probably need more information about them.


> quote:My doctor tries to teach me about the drugs I take & what they do


If your doctor is feeding the misinformation above, take these posts to him/her.









> quote:So it affects the neurotransmitter dependence


Make that inter-dependence


----------



## bonniei (Jan 25, 2001)

> quote:Make that interdependence


*Picky, picky!*Thanks Mr Picky!


----------



## bonniei (Jan 25, 2001)

> quote:Make that interdependence


*Picky, picky!*Thanks Mr Picky!


----------



## bonniei (Jan 25, 2001)

I hope you realize I am kidding flux. I perhaps should have put a







graemlin in my last post . You are, of course, right using dependence changes the meaning of that sentence.Anyone looking for a really simple explanation of agonists and antagonists without you being overwhelmed might want to check this site out. http://www.ptd.neu.edu/Neuroanatomy/Cyberc...Antagonists.htm


----------



## bonniei (Jan 25, 2001)

I hope you realize I am kidding flux. I perhaps should have put a







graemlin in my last post . You are, of course, right using dependence changes the meaning of that sentence.Anyone looking for a really simple explanation of agonists and antagonists without you being overwhelmed might want to check this site out. http://www.ptd.neu.edu/Neuroanatomy/Cyberc...Antagonists.htm


----------



## trbell (Nov 1, 2000)

flux or eric or k, I think it would be helpful if someone were to write this all out and publish it in print or on the web somewhere. Most of the info out only covers half the story and it is very confusing.tom


----------



## trbell (Nov 1, 2000)

flux or eric or k, I think it would be helpful if someone were to write this all out and publish it in print or on the web somewhere. Most of the info out only covers half the story and it is very confusing.tom


----------



## bonniei (Jan 25, 2001)

Yes flux- write an editorial for the IBS community.







BTW where is the other editorial on SIBO? We haven't forgotten about it


----------



## bonniei (Jan 25, 2001)

Yes flux- write an editorial for the IBS community.







BTW where is the other editorial on SIBO? We haven't forgotten about it


----------



## bonniei (Jan 25, 2001)

kmottus is busy this month. She is away on field trips. Don't know if she is following this thread. Don't know about eric.


----------



## bonniei (Jan 25, 2001)

kmottus is busy this month. She is away on field trips. Don't know if she is following this thread. Don't know about eric.


----------



## eric (Jul 8, 1999)

FYI""Serotonin (5-hydroxtryptamine, or 5-HT) is a chemical neurotransmittter (a chemical in the nervous system that helps transmit messages along the nervous system). It is found in three main areas of the body: the intestinal wall, blood vessels and the central nervous system. Chemical neurotransmitters produce their effects as a consequence of interactions with appropriate receptors. In cell biology, a receptor is a structure on the surface of a cell or inside a cell that selectively receives and binds a specific substance -- such as a hormone or a neurotransmitter. Serotonin (5-HT) interacts with an array of receptors. These receptor sites are labeled 1-7. (For example, serotonin receptor site 1 is labeled 5-HT1, site 2 is 5-HT1, etc.). These 7 different receptors act on different areas of the body, such as those affecting smooth muscle relaxation, sleep regulation, cardiovascular function and gastointestinal and vascular smooth muscle contraction. An antagonist acts against and blocks an action. An agonist acts like and stimulates an action. Antagonists and agonists are key agents in the chemistry of the human body and in pharmacology -- the study and development of drugs. The new generation of drugs being evaluated to treat IBS either block or stimulate the action of serotonin at specific receptor sites that affect the GI tract."


----------



## eric (Jul 8, 1999)

FYI""Serotonin (5-hydroxtryptamine, or 5-HT) is a chemical neurotransmittter (a chemical in the nervous system that helps transmit messages along the nervous system). It is found in three main areas of the body: the intestinal wall, blood vessels and the central nervous system. Chemical neurotransmitters produce their effects as a consequence of interactions with appropriate receptors. In cell biology, a receptor is a structure on the surface of a cell or inside a cell that selectively receives and binds a specific substance -- such as a hormone or a neurotransmitter. Serotonin (5-HT) interacts with an array of receptors. These receptor sites are labeled 1-7. (For example, serotonin receptor site 1 is labeled 5-HT1, site 2 is 5-HT1, etc.). These 7 different receptors act on different areas of the body, such as those affecting smooth muscle relaxation, sleep regulation, cardiovascular function and gastointestinal and vascular smooth muscle contraction. An antagonist acts against and blocks an action. An agonist acts like and stimulates an action. Antagonists and agonists are key agents in the chemistry of the human body and in pharmacology -- the study and development of drugs.  The new generation of drugs being evaluated to treat IBS either block or stimulate the action of serotonin at specific receptor sites that affect the GI tract."


----------



## mxwe (Apr 7, 2002)

How does Wellbutrin affect serotonin?


----------



## mxwe (Apr 7, 2002)

How does Wellbutrin affect serotonin?


----------

