Serotonergic modulation of visceral sensation: lower gut. (Visceral Perception).

The role of 5-HT agents in the modulation of lower gastrointestinal function is discussed. Selective serotonin reuptake inhibitors are of potential benefit in functional gastrointestinal diseases although formal evidence is lacking. Novel pharmacological approaches include [5-HT.sub.3] antagonists and [5-HT.sub.4] agonists. These pharmacological classes have shown beneficial effects on a global efficacy end point, and ameliorated more than one symptom of lower gut function in clinical trials. They offer promise for the development of novel therapies for the treatment and control of irritable bowel syndrome.

SUMMARY

Scrotonin (5-HT) is a biogenic amine that functions as a neurotransmitter of sensorimotor functions in the digestive tract. This paper addresses the role of 5-HT agents in the modulation of lower gastrointestinal function. Selective serotonin reuptake inhibitors (SSRIs) are of potential benefit in functional gastrointestinal diseases although formal evidence is lacking. Apart from central effects, they may have peripheral actions, as has been shown with paroxetine in the small bowel and citalopram in the colon. Novel pharmacological approaches include [5-HT.sub.3] antagonists such as alosetron and cilansetron, and [5-HT.sub.4] agonists such as tegaserod and prucalopride. These pharmacological classes have had beneficial effects on a global efficacy end point, and ameliorated more than one symptom of lower gut function in clinical trials. They offer promise for the treatment of female patients with symptoms of diarrhoea or constipation predominant irritable bowel syndrome (IBS), respectively.

INTRODUCTION

This paper addresses the role of 5-NT and serotonergic agents in the modulation of small bowel and colon functions. The first section deals with antidepressants, including the evidence for the effect of SSRIs. The second section deals with the evidence for the various novel serotonergic approaches based on modulation of [5-HT.sub.3] and [5-HT.sub.4] receptors. Projected use of novel therapies is also discussed.

5-HT: A NEUROTRANSMITTER IN SENSORIMOTOR FUNCTIONS OF THE DIGESTIVE TRACT

5-HT is a biogenic amine that functions as a neurotransmittcr of sensorimotor functions in the digestive tract. Its actions have been reviewed elsewhere. There are seven main classes of 5-HT receptors with several subclasses that can be differentiated on the basis of structure, molecular mechanisms, and functions. Importantly, 5-HT reuptake is a mechanism that is relevant in the digestive tract as well as in the central nervous system (CNS). Thus the actions of intrinsic primary afferent neurones activated by mucosal stroking are enhanced by SSRIs.

Figure 1 shows a submucosal neurone activated by mucosal stroking, as shown by fluorescence of the neurone. This activation was enhanced in the presence of the SSRI fluoxetine, suggesting that SSRIs may influence digestive function. (2)

PSYCHOTROPHIC AGENTS INCLUDING SSRIs

To date, psychotrophic agents have probably been best reserved for those patients with symptoms of diarrhoea and pain associated with IBS. (3) However, there is increasing interest in the potential application of SSRIs, which are the most widely used antidepressants, and tend not to cause constipation or induce diarrhoea in all patients. One uncontrolled study supports the efficacy of SSRIs in treating patients with IBS. (4) SSRIs, which sometimes cause diarrhoea, (5) are currently being assessed in prospective studies. There is an initial understanding of the effects on gastrointestinal functions of individual agents in this class, specifically buspirone, paroxetine, and citalopram.

Pharmacology and pharmacodynamic effects of SSRIs and novel psychotropics on gastrointestinal function in health

Buspirone is a non-benzodiazepine anxiolytic drug with demonstrated efficacy in the treatment of generalised anxiety disorder. Preliminary studies have suggested that buspirone may be useful in the treatment of a variety of other psychiatric conditions. (6) Although the exact mechanism of action is not known, buspirone has a high affinity for [5-HT.sub.1A] receptors. The active metabolite of buspirone, 1-pyrimidinylpiperazine, functions as an…