Introduction The intestinal hormone cholecystokinin (CCK) inhibits food intake via stimulation of vagal afferent neurons (VAN). In fasted rats, there is increased synthesis of the endocannabinoid anandamide (AEA) in the small intestine, and of its receptor (CB1) in VAN. Peripheral AEA stimulates food intake via VAN and endogenous CCK inhibits expression of CB1. The aim of the present studies was to characterise CB1 expression in VAN and to determine the functional significance of stimulation of these receptors.
Methods Nodose ganglion neurons expressing CB1 were detected by immunohistochemistry or in situ hybridisation in rats following dietary manipulation or administration of drugs and hormones ip. Similar approaches were used for MCH1 and Y2 receptor expression.
Results Expression of CB1 in rat VAN was detectable within 6 h and increased to a maximum after 24 h of fasting when approximately 50% of neurons in the mid- and caudal regions expressed the receptor. In contrast, MCH1R, which is also associated with orexigenic signalling, showed a delayed increase in expression compared with CB1 while Y2R, associated with satiety signalling, exhibited decreased expression with fasting. Administration of CCK8s (10 nmol) to fasted rats decreased expression of CB1 and MCH-1 but the t1/2 for loss of CB1 was approximately 1 h compared with 3 h for MCH-1. The action of CCK was inhibited by ghrelin and orexin-A. The CB1 agonist AEA (10 mg) had ghrelin-like actions in reversing the effect of CCK on CB1, MCH1 and Y2 receptor expression. In contrast, in rats fasted for 18 h, administration of a CB1 antagonist/inverse agonist (AM281, 0.25 mg) downregulated CB1 expression and increased Y2 receptor expression.
Conclusion Activation of CB1 on vagal afferent neurons determines the pattern of expression of receptors in these neurons indicating a new and hitherto unrecognised role for endocannabinoids in gut-brain signalling.
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