Luminal serotonin time-dependently modulates vagal afferent driven antinociception in response to colorectal distention in rats

Abstract

Background: Compelling evidence shows that vagal afferents mediate antinociception in response to visceral insults. Our recent findings implied that luminal serotonin (5-hydroxytryptamine, 5-HT) might mediate chronic food allergen sensitized visceral hyperalgesia, in which vagal afferents might be implicated. Here, to test this hypothesis, we investigated the effects of luminal infused 5-HT on visceral nociception and the involvement of vagal antinociceptive pathway.Methods: The vagus-intact or vagotomized rats were given acute intraluminally or intraperitoneally administered 5-HT, or chronic luminal infusion of 5-HT. The visceromotor response (VMR) to colorectal distension (CRD) was electrophysiologically recorded.Key Results: Acute intraluminal infusion of 5-HT (10 or 100 nmol) significantly attenuated VMR to CRD, while systemic administered 5-HT at similar doses resulted in markedly augmented nociception. Pretreatment with luminal application of granisetron or lidocaine, or pharmacological depletion of endogenous 5-HT with injection of p-chlorophenylalanine, a 5-HT synthesis inhibitor, and subdiaphragmatic vagotomy or functional deafferentation with capsaicin abolished the effect of luminal (but not systemic) 5-HT. Chronic infusion of 5-HT (10 nmol d-1for 5 days) produced gradual augmentation of baseline VMR. And, the VMR to CRD after 5-HT infusion decreased on day 1 and 2, then gradually increased from day 3. Surgical vagotomy or daily preperfusion with granisetron canceled these time-dependent patterns.Conclusions & Inferences: Luminal 5-HT time-dependently modulates vagal afferent driven antinociception. Acute infusion of 5-HT attenuates visceral nociception via activation of vagal afferent 5-HT type 3 receptors (5-HT3Rs)within intestinal mucosa; while chronic luminal 5-HT caused gradually developed visceral hyperalgesia, which may also involve vagal 5-HT3Rs. © 2010 Blackwell Publishing Ltd.