5‐HT 3 Receptor Signaling in a Rat Model of Sex Specific Visceral Hypersensitivity

Abstract

Background Irritable bowel syndrome (IBS) is a functional gastrointestinal motor and visceral sensation disorder that is more prominent in women compared to men. 5-Hydroxytryptamine (5-HT, serotonin) signaling is disrupted in some IBS patients possibly due to polymorphic variations in the gene encoding the serotonin transporter (SERT) which result in increased extracellular 5-HT availability. Female SERT knockout (KO) rats exhibit visceral hypersensitivity to colonic distention that mimics colonic hypersensitivity known to occur in female IBS patients. Objective. We tested the hypothesis that 5-HT action at 5-HT3 receptors contributes to visceral hypersensitivity. Methods. We examined the effects of acute administration of morphine and the 5-HT3 receptor antagonists alosetron, granisetron, and ondansetron on visceral sensitivity in SERT KO and wild type (WT) rats. We measured the visceromotor response (VMR) to colorectal distension (CRD). Results. Ondansetron (0.1 mg/kg, s.c) did not affect visceral sensitivity, while alosetron (0.1 mg/kg, s.c.) increased the VMR to CRD in SERT KO female rats and WT male rats. Granisetron (0.1 mg/kg, s.c.) increased VMR to CRD in SERT KO female rats only. Morphine (3 mg/kg s.c.) suppressed the VMR to CRD in all rats. Conclusions The results suggest that acute peripheral administration of some 5-HT3 receptor antagonists causes a paradoxical increase in the VMR to CRD. 5-HT3 receptor antagonists may interact with ascending pain pathways and descending pain inhibitory pathways. Supported by: 5R21NS075841