The 5-HT3 receptor antagonist alosetron inhibits the colorectal distention induced depressor response and spinal c-fos expression in the anaesthetised rat

Abstract

Background-Noxious intestinal distention elicits a reflex depressor response in the sodium pentobarbitone anaesthetised rat, which can be used as an index of visceral nociception. 5-HT 3 receptor antagonists inhibit this reflex. Repeated colorectal distention (CRD) induces Fos like immunoreactivity (Fos-LI) in the rat spinal cord. Aims-To examine the eVect of the 5-HT 3 receptor antagonist alosetron on the depressor response to CRD, and on Fos expression in the lumbosacral spinal cord. Methods-Male rats were anaesthetised with sodium pentobarbitone, and mean arterial blood pressure monitored during repeated colorectal balloon inflation before and after treatment with alosetron or saline. Rats anaesthetised with urethane and treated with alosetron or saline underwent a repeated CRD paradigm, after which the lumbosacral spinal cord was removed and processed for visualisation of Fos-LI. Results-CRD elicited reproducible, volume dependent falls in arterial blood pressure, and repeated distention-eVect curves were constructed. Alosetron (1-100 µg/kg intravenously) inhibited the depressor response to CRD in a dose related manner, with an ID 50 value of 3.0 µg/kg. Following repeated CRD, numbers of Fos-LI neurones were significantly increased to 1246 (total in 12 sections at 120 µm intervals from L6 to S1) compared with 49 in sham distended animals. Pretreatment with alosetron (100 µg/kg) significantly reduced numbers of Fos-LI neurones to 479.8. Conclusion-The 5-HT 3 receptor antagonist alosetron inhibits the depressor response to CRD in a potent and dose dependent manner. It also inhibits CRD induced Fos-LI in the spinal cord. These results suggest that 5-HT 3 receptors are involved in visceral nociceptive transmission, perhaps located on primary aVerent or spinal neurones. (Gut 2000;46:474-480)

TRPV1 Function in Mouse Colon Sensory Neurons Is Enhanced by Metabotropic 5-Hydroxytryptamine Receptor Activation

“…Interestingly, several recent studies have reported an increased number of enteroendocrine cells in IBS patients (Bearcroft et al, 1998;Spiller et al, 2000;Houghton et al, 2003). Furthermore, the peripherally acting 5-HT 3 receptor antagonist alosetron blunts visceral sensation in animal models and humans and has been used clinically in the treatment of IBS (Kozlowski et al, 2000;Camilleri et al, 2001). Although circumstantial in nature, these data raise the question whether and how 5-HT affects visceral sensation and contributes to the development of visceral hypersensitivity.…”

“…Spinal 5-HT receptors also play important roles in descending modulation of pain, including visceral pain (Urban and Gebhart, 1999), and drugs that cross the blood brain barrier may exert both peripheral and central effects. The peripherally acting 5-HT 3 receptor antagonist alosetron blunts responses to colorectal distension in experimental animals and improves discomfort and pain in a subgroup of patients with functional bowel disorders (Camilleri et al, 1999;Kozlowski et al, 2000). Interestingly, other 5-HT 3 receptor antagonists do not consistently affect visceral pain in experimental animals or humans (Langlois et al, 1996;Kim and Camilleri, 2000).…”

Serotonin receptor modulators in the treatment of irritable bowel syndrome

“…This refl ex depressor response can be used as a measure of visceral nociception. Alosetron has been shown to inhibit this vasodepressor response to colorectal distension by blocking the 5HT3 receptors (Kozlowski et al 2000). In functional brain imaging studies, alosetron has been shown to decrease brain activity in bilateral frontotemporal cortex and various limbic structures in response to colorectal distension .…”

Neuropathophysiology of functional gastrointestinal disorders

“…This excitatory action on intestinal sensory nerves is mediated by the 5-HT3 receptor subtype and is blocked by selective 5-HT3 receptor antagonists (e.g. alosetron) [75] . Intramural terminals of both spinal and vagal sensory nerves express 5-HT3 receptors.…”

“…alosetron) [74,75] . Intramural terminals of both spinal and vagal sensory nerves express 5-HT3 receptors.…”