Persistent inflammation promotes endocannabinoid release and presynaptic cannabinoid 1 receptor desensitization

Pain therapies targeting the cannabinoid system are increasing with expansion of cannabis legalization but adaptations in the endogenous cannabinoid system during inflammatory pain could limit their efficacy. Presynaptic inhibition of GABA release mediated by cannabinoid 1 receptor (CB1R) agonists in the ventrolateral periaqueductal gray (vlPAG) is markedly reduced in male and female Sprague Dawley rats after persistent inflammation induced by Complete Freunds Adjuvant (CFA). Inflammation results in increased endocannabinoid (eCB) synthesis and desensitization of presynaptic CB1Rs that is reversed by a GRK2/3 inhibitor, Compound 101. Despite CB1R desensitization, eCB activation of CB1Rs is maintained after inflammation. Depolarization-induced suppression of inhibition (DSI) in naive animals is rapid and transient, but is prolonged in recordings after inflammation. Prolonged DSI is mediated by 2-arachidonoylglycerol (2-AG) indicating reduced monoacylglycerol lipase (MAGL) activity. These adaptations within the endogenous cannabinoid system have important implications for the development of future pain therapies targeting CB1Rs or MAGL.