i81 VISCERAL PERCEPTION Gut: first published as 10.1136/gut.51.suppl_1.i81 on 1 July 2002. Downloaded from Serotonergic modulation of visceral sensation: lower gut M Camilleri ............................................................................................................................. Gut 2002;51(Suppl I):i81–i86 The role of 5-HT agents in the modulation of lower receptors with several subclasses that can be dif- gastrointestinal function is discussed. Selective serotonin ferentiated on the basis of structure, molecular mechanisms, and functions. Importantly, 5-HT reuptake inhibitors are of potential benefit in functional reuptake is a mechanism that is relevant in the gastrointestinal diseases although formal evidence is digestive tract as well as in the central nervous lacking. Novel pharmacological approaches include system (CNS). Thus the actions of intrinsic primary afferent neurones activated by mucosal 5-HT3 antagonists and 5-HT4 agonists. These stroking are enhanced by SSRIs. pharmacological classes have shown beneficial effects Figure 1 shows a submucosal neurone acti- on a global efficacy end point, and ameliorated more vated by mucosal stroking, as shown by fluores- cence of the neurone. This activation was than one symptom of lower gut function in clinical trials. enhanced in the presence of the SSRI fluoxetine, They offer promise for the development of novel suggesting that SSRIs may influence digestive therapies for the treatment and control of irritable bowel function.2 syndrome. PSYCHOTROPHIC AGENTS INCLUDING .......................................................................... SSRIs To date, psychotrophic agents have probably been SUMMARY best reserved for those patients with symptoms of Serotonin (5-HT) is a biogenic amine that diarrhoea and pain associated with IBS.3 How- functions as a neurotransmitter of sensorimotor ever, there is increasing interest in the potential functions in the digestive tract. This paper application of SSRIs, which are the most widely addresses the role of 5-HT agents in the modula- used antidepressants, and tend not to cause con- tion of lower gastrointestinal function. Selective stipation or induce diarrhoea in all patients. One serotonin reuptake inhibitors (SSRIs) are of uncontrolled study supports the efficacy of SSRIs 4 potential benefit in functional gastrointestinal in treating patients with IBS. SSRIs, which http://gut.bmj.com/ diseases although formal evidence is lacking. sometimes cause diarrhoea,5 are currently being Apart from central effects, they may have periph- assessed in prospective studies. There is an initial eral actions, as has been shown with paroxetine understanding of the effects on gastrointestinal in the small bowel and citalopram in the colon. functions of individual agents in this class, Novel pharmacological approaches include 5-HT3 specifically buspirone, paroxetine, and citalo- antagonists such as alosetron and cilansetron, pram. and 5-HT4 agonists such as tegaserod and pruca- on September 27, 2021 by guest. Protected copyright. lopride. These pharmacological classes have had Pharmacology and pharmacodynamic beneficial effects on a global efficacy end point, effects of SSRIs and novel psychotropics on and ameliorated more than one symptom of lower gastrointestinal function in health gut function in clinical trials. They offer promise Buspirone is a non-benzodiazepine anxiolytic for the treatment of female patients with symp- drug with demonstrated efficacy in the treatment toms of diarrhoea or constipation predominant of generalised anxiety disorder. Preliminary stud- irritable bowel syndrome (IBS), respectively. ies have suggested that buspirone may be useful in the treatment of a variety of other psychiatric INTRODUCTION conditions.6 Although the exact mechanism of This paper addresses the role of 5-HT and action is not known, buspirone has a high affinity serotonergic agents in the modulation of small for 5-HT1A receptors. The active metabolite of bus- bowel and colon functions. The first section deals pirone, 1-pyrimidinylpiperazine, functions as an with antidepressants, including the evidence for 7 alpha2 adrenoceptor antagonist. In animal mod- the effect of SSRIs. The second section deals with els, buspirone has been shown to suppress stress the evidence for the various novel serotonergic induced caecal motor responses through 5-HT1A 8 approaches based on modulation of 5-HT3 and receptors. There is no further understanding of ....................... 5-HT4 receptors. Projected use of novel therapies is the effects of buspirone on the lower bowel of also discussed. humans. Correspondence to: Paroxetine is a potent SSRI used in the Dr M Camilleri, Enteric 5-HT: A NEUROTRANSMITTER IN Neuroscience Program, treatment of a variety of psychiatric Gastroenterology Research SENSORIMOTOR FUNCTIONS OF THE Unit, Charlton 7-154, DIGESTIVE TRACT Mayo Clinic, 200 First St, 5-HT is a biogenic amine that functions as a neu- ................................................. SW Rochester, MN rotransmitter of sensorimotor functions in the 55905, USA; Abbreviations: CNS, central nervous system; IBS, [email protected] digestive tract. Its actions have been reviewed irritable bowel syndrome; SSRI, selective serotonin ....................... elsewhere.1 There are seven main classes of 5-HT reuptake inhibitor; 5-HT, serotonin. www.gutjnl.com i82 Camilleri 240 Control 200 Stimulated Gut: first published as 10.1136/gut.51.suppl_1.i81 on 1 July 2002. Downloaded from 160 120 80 40 FM2-10 labelled neurones 0 0 0.01 1.0 Fluoxetine (µM) Figure 1 Evidence of stimulation of 5-HT containing submucosal neurones by stroking the small bowel mucosa. Uptake of FM2-10 was quantified on control and mucosally stimulated sides of preparations in the absence or presence of two concentrations of fluoxetine. Reproduced with permission from Chen and colleagues.2 conditions.910Published studies of the effect of paroxetine on significant effects on oesophageal and rectal sensory thresh- the gastrointestinal tract have demonstrated stimulation of olds or compliance in healthy subjects.16 Similarly, in upper the small intestine. One study of paroxetine showed decreased functional gastrointestinal disorders, clinical benefit was migrating motor complex periodicity and increased propaga- associated with better sleep rather than changes in gastric tion velocity of phase III contractions within the small sensitivity.17 intestine.11 A decrease in orocaecal transit time following Neuromodulatory effects may occur sooner and with lower administration of paroxetine has also been demonstrated,12 dosages of tricyclic agents in IBS patients than the dosages suggesting prokinetic activity, but the method used in this ini- used in the treatment of depression (for example, 10–25 mg tial study does not allow differentiation of the effects on gas- amitriptyline or 50 mg desipramine). Because antidepressants tric versus small bowel transit. Results of these studies suggest must be used on a continual rather than on an as needed basis, that paroxetine may be useful in the treatment of dyspepsia they are generally reserved for patients with frequently recur- with delayed upper gastrointestinal transit or in symptoms of rent or continual symptoms. A 2–3 month trial is usually constipation IBS, but more formal evaluation of the effects in needed before abandoning this therapeutic approach.4 the colon are required. Tricyclic agents have varying magnitudes of effects on 5-HT Clinical effects of psychotropic agents in the treatment mechanisms and are discussed briefly. This class of agents (for of IBS example, amitriptyline, imipramine, and doxepin) are now Placebo controlled trials of antidepressants in IBS have been frequently used to treat patients with IBS, particularly those summarised elsewhere.1 Trimipramine has been shown to http://gut.bmj.com/ with more severe or refractory symptoms, impaired daily decrease abdominal pain, nausea, and depression but does not function, and associated somatisation, depression, or panic alter stool frequency.18 19 The beneficial effect seems to be attacks. Initially their use was based on the fact that a high greater in those with abdominal pain and diarrhoea. For proportion of patients with IBS reported significant example, desipramine improved abdominal pain and depression.4 13–15 Antidepressants have neuromodulatory and diarrhoea20 but in an earlier study that combined patients with analgesic properties which may benefit patients independ- either diarrhoea or constipation there was no significant ben- 13 21 ently of the psychotrophic effects of the medications. It efit for desipramine over placebo. In other studies nortriptyl- on September 27, 2021 by guest. Protected copyright. appears that the clinical effects of agents such as amitriptyline ine, in combination with fluphenazine, has been shown to result from their central actions. Thus amitriptyline had no reduce abdominal pain and diarrhoea.15 22 60 A 4 B 50 * * * * * * * * * 40 * 3 *** *** *** ****** *** ****** *** *** *** *** * 30 20 2 Alosetron Alosetron Placebo Stool consistency score Placebo 10 Treatment Follow up Treatment Follow up Proportion of patients with adequate relief (%) 0 0 0 1 2 3 4 5 6 7 8 9 10111213141516 0 1 2 3 4 5 6 7 8 9 10111213141516 Week Week Figure 2 Effect of alosetron 1 mg twice daily and placebo on adequate relief of pain (A) and stool consistency (B) in female patients with symptoms of diarrhoea. Note the improvement in symptoms and the abrupt change in symptoms with cessation