Cannabinoid 1 receptor colocalizes with substance P and 5‐HT in the ferret brainstem

Cannabinoids (CB) exert their anti‐emetic effect through an action at CB1 receptors (CB1r) in the dorsal vagal complex in the brainstem. Evidence has been presented that shows that endocannabinoids may activate these receptors to limit the degree of emesis under physiological conditions. Other transmitter systems involved in the regulation of emesis include substance P (SP, acting at NK1 receptors) and 5‐HT (acting at 5‐HT3 receptors). The anatomic relationships of these transmitter systems have not been determined. Our aim was to determine if CB1r is present in terminals that also express 5‐HT or SP. We examined CB1r with 5‐HT and SP by immunohistochemistry and confocal microscopic imaging. CB1r was shown in dense punctate immunoreactivity in the dorsal motor nucleus of the vagus and immunoreactivity for 5‐HT and SP was sparse in comparison, with relatively little overlap, as shown by low Pearson correlation coefficients. Colocalization was shown between CB1r and 5‐HT as well as CB1r and SP in terminals around some neurons as shown by coincident peaks of fluorescent intensity in histograms. In conclusion, in ferret CB1r was expressed on terminals in the brainstem containing SP or 5‐HT, providing an anatomical substrate for endogenous cannabinoids to inhibit their release in order to limit emesis.