Attenuation of fear-conditioned analgesia in rats by monoacylglycerol lipase inhibition in the anterior cingulate cortex: potential role for CB2 receptors.

Improved understanding of brain mechanisms regulating endogenous analgesia is important from a fundamental physiological perspective and for identification of novel therapeutic strategies for pain. The endocannabinoid system plays a key role in stress-induced analgesia, including fear-conditioned analgesia (FCA), a potent form of endogenous analgesia. Here we studied the role of the endocannabinoid 2-arachidonoyl glycerol (2-AG) within the anterior cingulate cortex (ACC; a brain region implicated in the affective component of pain) in FCA in rats. FCA was modelled in male Lister-hooded rats by assessing formalin-evoked nociceptive behaviour in an arena previously paired with footshock. The effects of intra-ACC administration of MJN110 (inhibitor of monoacylglycerol lipase [MGL], the primary enzyme catabolising 2-AG), AM630 (CB2 receptor antagonist), AM251 (CB1 receptor antagonist), or MJN110+AM630 on FCA were assessed. MJN110 attenuated FCA when microinjected into the ACC, an effect associated with increased levels of 2-AG in the ACC. This effect of MJN110 on FCA was unaltered by co-administration of AM251 but was blocked by AM630, which alone reduced nociceptive behaviour in non-fear-conditioned rats. RT-qPCR confirmed that mRNA encoding CB1 and CB2 receptors was detectable in the ACC of formalin-injected rats, and unchanged in those expressing FCA. These results suggest that a MGL substrate in the ACC, likely 2-AG, modulates FCA, and that within the ACC, 2-AG-CB2 receptor signalling may suppress this form of endogenous analgesia. These results may facilitate increased understanding and improved treatment of, pain- and fear-related disorders and their comorbidity.