Serotonin receptor 2B induces visceral hyperalgesia in rat model and patients with diarrhea-predominant irritable bowel syndrome

Abstract

Background: Serotonin receptor 2B (5-HT_2B receptor) plays a critical role in many chronic pain conditions. The possible involvement of the 5-HT_2B receptor in the altered gut sensation of irritable bowel syndrome with diarrhea (IBS-D) was investigated in the present study.

Aim: To investigate the possible involvement of 5-HT_2B receptor in the altered gut sensation in rat model and patients with IBS-D.

Methods: Rectosigmoid biopsies were collected from 18 patients with IBS-D and 10 patients with irritable bowel syndrome with constipation who fulfilled the Rome IV criteria and 15 healthy controls. The expression level of the 5-HT_2B receptor in colon tissue was measured using an enzyme-linked immunosorbent assay and correlated with abdominal pain scores. The IBS-D rat model was induced by intracolonic instillation of acetic acid and wrap restraint. Alterations in visceral sensitivity and 5-HT_2B receptor and transient receptor potential vanilloid type 1 (TRPV1) expression were examined following 5-HT_2B receptor antagonist administration. Changes in visceral sensitivity after administration of the TRPV1 antagonist were recorded.

Results: Here, we observed greater expression of the 5-HT_2B receptor in the colonic mucosa of patients with IBS-D than in that of controls, which was correlated with abdominal pain scores. Intracolonic instillation of acetic acid and wrap restraint induced obvious chronic visceral hypersensitivity and increased fecal weight and fecal water content. Exogenous 5-HT_2B receptor agonist administration increased visceral hypersensitivity, which was alleviated by successive administration of a TRPV1 antagonist. IBS-D rats receiving the 5-HT_2B receptor antagonist exhibited inhibited visceral hyperalgesia.Moreover, the percentage of 5-HT_2B receptor-immunoreactive (IR) cells surrounded by TRPV1-positive cells (5-HT_2B receptor I⁺) and total 5-HT_2B receptor IR cells (5-HT_2B receptor I_T) in IBS-D rats was significantly reduced by the administration of a 5-HT_2B receptor antagonist.

Conclusion: Our finding that increased expression of the 5-HT_2B receptor contributes to visceral hyperalgesia by inducing TRPV1 expression in IBS-D patients provides important insights into the potential mechanisms underlying IBS-D-associated visceral hyperalgesia.

Keywords: Abdominal pain; Diarrhea-predominant irritable bowel syndrome; Serotonin receptor 2B; Transient receptor potential vanilloid type-1; Visceral hypersensitivity.