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Attenuation of fear‐conditioned analgesia in rats by monoacylglycerol lipase inhibition in the anterior cingulate cortex: Potential role for CB 2 receptors
Author(s) -
Corcoran Louise,
Mattimoe Darragh,
Roche Michelle,
Finn David P.
Publication year - 2020
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.14976
Subject(s) - am251 , monoacylglycerol lipase , endocannabinoid system , pharmacology , chemistry , cannabinoid receptor , nociception , diacylglycerol lipase , receptor , antagonist , medicine , biochemistry
Background and Purpose 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. Experimental Approach 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 catabolizing 2‐AG), AM630 (CB 2 receptor antagonist), AM251 (CB 1 receptor antagonist) or MJN110 + AM630 on FCA were assessed. Key Results 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 CB 1 and CB 2 receptors was detectable in the ACC of formalin‐injected rats and unchanged in those expressing FCA. Conclusion and Implications These results suggest that an MGL substrate in the ACC, likely 2‐AG, modulates FCA and that within the ACC, 2‐AG‐CB 2 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 co‐morbidity.