Cannabinoid-targeted pain therapies are increasing with the expansion of cannabis legalization, however, their efficacy may be limited by pain-induced adaptations in the cannabinoid system. Cannabinoid receptor subtype 1 (CB1Rs) inhibition of spontaneous, miniature and evoked GABAergic postsynaptic currents (mIPSCs and eIPSCs) in the ventrolateral periaqueductal gray (vlPAG) were compared in slices from naïve and inflamed male and female Sprague-Dawley rats. Complete Freund’s Adjuvant (CFA) injections into the hindpaw induced persistent inflammation. In naïve rats, exogenous cannabinoid agonists robustly reduce both eIPSCs and mIPSCs. After 5-7 days of inflammation, the effects of exogenous cannabinoids are significantly reduced due to CB1R desensitization via GRK2/3, as function is recovered in the presence of the GRK2/3 inhibitor, Compound 101 (Cmp101). Inhibition of GABA release by presynaptic mu opioid receptors (MORs) in the vlPAG does not desensitize with persistent inflammation. Unexpectedly, while CB1R desensitization significantly reduces inhibition produced by exogenous agonists, depolarization-induced suppression of inhibition (DSI) protocols that promote 2-AG synthesis exhibit CB1R activation after inflammation. 2-AG tone is detected in slices from CFA-treated rats when GRK2/3 is blocked suggesting an increase in 2-AG synthesis after persistent inflammation. Inhibiting 2-AG degradation with the monoacylglycerol lipase (MAGL) inhibitor JZL184 during inflammation results in desensitization of CB1Rs by eCBs that is reversed with Cmp101. Collectively, these data indicate that persistent inflammation primes CB1Rs for desensitization, and MAGL degradation of 2-AG protects CB1Rs from desensitization in inflamed rats. These adaptations with inflammation have important implications for the development of cannabinoid-based pain therapeutics targeting MAGL and CB1Rs.Presynaptic G protein-coupled receptors are resistant to desensitization. Here we find that persistent inflammation increases endocannabinoid levels, priming presynaptic cannabinoid 1 receptors for desensitization upon subsequent addition of exogenous agonists. Despite the reduced efficacy of exogenous agonists, endocannabinoids have prolonged efficacy after persistent inflammation. Endocannabinoids readily induce cannabinoid 1 receptor desensitization if their degradation is blocked, indicating that endocannabinoid concentrations are maintained at sub-desensitizing levels and that degradation is critical for maintaining endocannabinoid regulation of presynaptic GABA release in the ventrolateral periaqueductal gray during inflammatory states. These adaptations with inflammation have important implications for the development of cannabinoid-based pain therapies.