O'Mahony, SM; Bulmer, DC; Coelho, AM; Fitzgerald, P; Bongiovanni, C; Lee, K; Winchester, W; Dinan, TG; Cryan, JF;

2010

January

Neurogastroenterology and Motility

5-HT2B receptors modulate visceral hypersensitivity in a stress-sensitive animal model of brain-gut axis dysfunction

Published

()

brain-gut axis 5-HT2B receptors stress visceral hypersensitivity Wistar Kyoto IRRITABLE-BOWEL-SYNDROME WISTAR-KYOTO RATS IMPAIRED GASTRIC ACCOMMODATION DEPRESSIVE BEHAVIOR RECTAL DISTENSION DRUG DEVELOPMENT PARTIAL AGONIST NERVOUS-SYSTEM HIGH-AFFINITY IN-VITRO

22

573

BackgroundIrritable bowel syndrome (IBS) is associated with an enhanced perception to visceral stimuli and exaggerated stress response. The serotonergic neurotransmitter system has been strongly implicated as a key player in the manifestation of IBS symptomatology including visceral hypersensitivity. However the role of 5-HT2B receptors in visceral pain, although speculated, is currently unclear. Thus we assessed the impact of a selective 5-HT2B receptor antagonist, RS-127445, on visceral hypersensitivity in a model of brain gut axis dysfunction the Wistar Kyoto (WKY) rat.MethodsColorectal distension (CRD) was used to assess the visceral sensitivity of the WKY rat compared to normosensitive Sprague Dawley (SD) rats. Once we verified the visceral sensitivity of the WKY rat we assessed the efficacy of RS-127445 in pain signalling from the colorectum. We administered the compound peripherally (i.p.) and centrally (i.c.v.) in order to ascertain the site of action of RS 127445. Behavioural responses to colorectal distention were then monitored.Key ResultsThe WKY rats were more viscerally hypersensitive than the SD as previously shown. RS-127445 (5 mg kg-1, i.p.) significantly reversed visceral hypersensitivity in WKY animals. Moreover, when administered intracerebroventricularly RS-127445 (100 nM) also decreased the number of pain behaviours during noxious CRD in the WKY animals.Conclusions & InferencesTaken together, blockade of 5-HT2B receptors offers an exciting novel therapeutic target for pain relief in stress-related gastrointestinal disorders such as IBS.

DOI 10.1111/j.1365-2982.2009.01432.x