5-HT3 receptors mediate the time-dependent vagal afferent modulation of nociception during chronic food allergen-sensitized visceral hyperalgesia in rats

P>Converging lines of evidence demonstrate a vagally mediated antinociceptive pathway in animals undergoing acute visceral insults, the contribution of this system to visceral pain following chronic noxious stimuli is unknown. 5-HT3 receptor (5-HT(3)Rs) on spinal afferents are crucially involved in nociceptive processing, the role of 5-HT(3)Rs on vagal afferents is unclear. The aim of the present study was to determine the contribution of vagal afferents to visceral nociception in rats undergoing chronic luminal allergen stimulation and whether it involves vagal 5-HT(3)Rs. Sensitized rats received chicken egg albumin (EA, 1 mg mL-1) in drinking water for 2 weeks (day 1-14). Visceromotor response (VMR) to colorectal distension [colorectal distension (CRD), 60 mmHg] and the levels of mRNA encoding 5-HT3R (including 3A and 3B subunits) in the nodose ganglia (NG) were evaluated on day 2, 4, 8 and 15. Chronic EA challenge induced gradually increased visceral nociception, with a peak on day 15. Subdiaphragmatic vagotomy or functional deafferentation with capsaicin abolished this time-dependent manner, inducing hyperalgesia from day 2, lasting to day 15. Intraluminal infusion of a 5-HT3R antagonist (granisetron), whether alone or infused after local mucosa anaesthetic with 1% lidocaine, mimicked the effects of vagotomy. The mRNA levels for 5-HT3B or 5-HT3A subunit in the NG showed an opposite time-course to that of visceral pain, which increased from day 2, then decreased gradually to levels lower than those of controls. Our results demonstrate a time-dependent vagal afferent modulation of chronic allergen-sensitized visceral hyperalgesia, which may involve a 5-HT3R pathway.