The rostral ventromedial medulla (RVM) is a relay in the descending pain modulatory system and an important site of endocannabinoid modulation of pain. Endocannabinoids inhibit GABA release in the RVM but it is not known if this effect persists in chronic pain states. In the present studies, persistent inflammation induced by complete Freund's adjuvant (CFA) increased GABAergic miniature inhibitory postsynaptic currents (mIPSCs). Endocannabinoid activation of cannabinoid (CB1) receptors known to inhibit presynaptic GABA release was significantly reduced in the RVM of CFA‐treated rats compared to naïve rats. The reduction in CFA‐treated rats correlated with decreased CB1 receptor protein expression and function in the RVM. Paradoxically, the non‐selective CB1/CB2 receptor agonist WIN55,212 inhibited GABAergic mIPSCs in both naïve and CFA‐treated rats. However, WIN55,212 inhibition was reversed by the CB1 receptor antagonist rimonabant in naïve rats but not in CFA‐treated rats. WIN55,212‐mediated inhibition in CFA‐treated rats was blocked by the CB2 receptor‐selective antagonist SR144528 indicating that CB2 receptor function in the RVM is increased during persistent inflammation. Consistent with these results, CB2 receptor agonists, AM1241 and GW405833 inhibited GABAergic mIPSC frequency only in CFA‐treated rats and the inhibition was reversed with SR144258. When administered alone, SR144528 and another CB2 receptor‐selective antagonist AM630 increased mIPSC frequency in the RVM of CFA‐treated rats indicating that CB2 receptors are tonically activated by endocannabinoids. Our data provide evidence that CB2 receptor function emerges in the RVM in persistent inflammation and that selective CB2 receptor agonists may be useful for treatment of persistent inflammatory pain.Support or Funding InformationThese studies were supported by the grants from NIH (DA035316 and R56NS093894), and America Heart Association (13SDG14590005, MH.L.).