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Endocannabinoid modulation by FAAH and monoacylglycerol lipase within the analgesic circuitry of the periaqueductal grey
Author(s) -
Lau Benjamin K,
Drew Geoffrey M,
Mitchell Vanessa A,
Vaughan Christopher W
Publication year - 2014
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.12839
Subject(s) - endocannabinoid system , fatty acid amide hydrolase , monoacylglycerol lipase , anandamide , chemistry , pharmacology , am251 , cannabinoid receptor , cannabinoid , periaqueductal gray , neurotransmission , neuroscience , agonist , biochemistry , biology , receptor , central nervous system , midbrain
Background and Purpose Endogenous cannabinoids (endocannabinoids) in the periaqueductal grey ( PAG ) play a vital role in mediating stress‐induced analgesia. This analgesic effect of endocannabinoids is enhanced by pharmacological inhibition of their degradative enzymes. However, the specific effects of endocannabinoids and the inhibitors of their degradation are largely unknown within this pain‐modulating region. Experimental Approach In vitro electrophysiological recordings were conducted from PAG neurons in rat midbrain slices. The effects of the major endocannabinoids and their degradation inhibitors on inhibitory GABA ergic synaptic transmission were examined. Key Results Exogenous application of the endocannabinoid, anandamide ( AEA ), but not 2‐arachidonoylglycerol (2‐ AG ), produced a reduction in inhibitory GABA ergic transmission in PAG neurons. This AEA ‐induced suppression of inhibition was enhanced by the fatty acid amide hydrolase ( FAAH ) inhibitor, URB 597, whereas a 2‐AG‐induced suppression of inhibition was unmasked by the monoacylglycerol lipase (MGL) inhibitor, JZL184. In addition, application of the CB 1 receptor antagonist, AM 251, facilitated the basal GABA ergic transmission in the presence of URB 597 and JZL 184, which was further enhanced by the dual FAAH / MGL inhibitor, JZL 195. Conclusions and Implications Our results indicate that AEA and 2‐ AG act via disinhibition within the PAG , a cellular action consistent with analgesia. These actions of AEA and 2‐ AG are tightly regulated by their respective degradative enzymes, FAAH and MGL . Furthermore, individual or combined inhibition of FAAH and/or MGL enhanced tonic disinhibition within the PAG . Therefore, the current findings support the therapeutic potential of FAAH and MGL inhibitors as a novel pharmacotherapy for pain.