Persistent Inflammation Induces Desensitization of the Presynaptic Cannabinoid 1 Receptor in the Ventrolateral Periaqueductal Gray.

The cannabinoid system is highly plastic and sensitive to environmental perturbations, often leading to downregulation of the cannabinoid 1 receptor (CB1R). Here, we investigate adaptations in CB1R regulation after persistent inflammation using patch clamp electrophysiology and radioligand binding. Under basal conditions, activation of the presynaptic CB1R with the cannabinoid receptor agonists WIN-55,212-2 or CP-55,940 suppress GABA release. This suppression is reversed by the CB1R-selective antagonists SR141716A (rimonabant) or AM251. After 5-7 days of inflammation induced by intraplantar injection of Complete Freund's Adjuvant (CFA), CB1R function is significantly reduced. Interestingly, radioligand binding assays indicate that the receptor binding is not different between naïve and CFA-treated animals. Our data indicate that in the ventrolateral periaqueductal gray, persistent inflammation causes desensitization, as opposed to downregulation, of the CB1R in both male and female Sprague Dawley rats. Further, we find that persistent inflammation increases endocannabinoid levels, potentially leading to prolonged activation of the CB1R and desensitization. These data highlight an important regulatory mechanism for the CB1R in response to persistent inflammation.