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

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.