Review Article: Intestinal Serotonin Signalling in Irritable Bowel Syndrome

G. M. Mawe; M. D. Coates; P. L. Moses

Disclosures

Aliment Pharmacol Ther. 2006;23(8):1067-1076. 

In This Article

The Relationship Between Serotonin Receptor Drugs and the Pathophysiology of IBS

Receptors that have been identified for 5-HT include the following: 5-HT1A-E, P, 5-HT2A,B,C, 5-HT3, 5-HT4, 5-HT5, 5-HT6 and 5-HT7. Of these, 5-HT1A, 5-HT1P, 5-HT2, 5-HT3, 5-HT4 and 5-HT7 receptors have been identified in the gut, with 5-HT2 receptors being located primarily on muscle and epithelium, and the others being located primarily on nerves.[49]

Treatment strategies for IBS involving 5-HT-related compounds are currently directed at the predominant symptoms, and 5-HT3 and 5-HT4 receptors have been the targets of choice. The 5-HT3 receptor is a ligand-gated ion channel,[50] whereas the 5-HT4 receptor is a seven-transmembrane domain, G-protein-coupled receptor.[51] The 5-HT4 receptor is linked to GS, and activation of this receptor leads to an increase in cyclic AMP. While both types of receptors can undergo desensitization, 5-HT3 receptors exhibit rapid desensitization upon sustained exposure to an agonist.[52] This property of 5-HT3 receptors bring into question clinical potential of 5-HT3 agonists, particularly those with full agonist properties, and would make 5-HT3 receptors particularly susceptible to increased availability of 5-HT when SERT is decreased.

In IBS-D, the 5-HT3 receptor antagonists such as alosetron are thought to work primarily by inhibiting the activation of 5-HT3 receptors located on the mucosal processes of intrinsic and extrinsic primary afferents. Inhibiting 5-HT3 receptors located on intrinsic sensory neurones can diminish motor and secretory reflex activity, and decreasing the activation of extrinsic sensory neurones, which transmit signals to the CNS, inhibits sensory signals leading to pain and discomfort.[53]

5-HT4 receptor agonists such as tegaserod are used as a treatment for IBS-C. It is not yet clear whether 5-HT4 receptors are located on the mucosal processes of intrinsic and extrinsic sensory neurones, but if these receptors are present at this location, 5-HT4 agonists would augment the activation of motor and secretory reflex activity. Electrophysiological and anatomical studies have demonstrated that 5-HT4 receptors are located on nerve terminals throughout the ENS that mediate excitatory synaptic transmission.[54,55,56] Activation of these presynaptic 5-HT4 receptors leads to an increase in the amount of transmitters, such as acetylcholine, that are released from these terminals, and therefore enhances reflex responses.

It is not understood whether 5-HT3 antagonists and/or 5-HT4 agonists have an effect on the 5-HT signalling anomalies that have been detected in IBS, or whether their mechanisms of action simply involve increasing or decreasing reflex activity at sites further downstream in the circuitry. It is possible that increased 5-HT availability contributes to the symptoms of IBS-D, and if this is the case, an antagonist working at the site of 5-HT signalling between EC cells and sensory nerves would be operating at the site of disrupted 5-HT signalling. Conversely, if 5-HT4 receptors are also located on mucosal projections of afferent nerves, as some data suggest,[57] 5-HT4 agonists may promote the activation of enteric reflexes at the site of disrupted 5-HT signalling, and thereby relieve constipation. The presynaptic action of 5-HT4 agonists on nerve terminals in enteric neural circuitry is downstream from the site of disrupted mucosal 5-HT signalling. In an intriguing report by Tonini et al., 5-HT7 receptors were found to mediate intestinal smooth muscle relaxation and accommodation. Endogenous 5-HT was involved in smooth muscle accommodation in the preparatory phase of peristalsis by direct activation of 5-HT7 receptors. The authors suggest that abnormal stimulation of the 5-HT7 receptor may contribute to certain clinical syndromes like IBS and that the 5-HT7 receptor may be a reasonable candidate for therapeutic intervention in some patients.[58]

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