Endocannabinoid mechanisms of stress-induced analgesia and their sites of action
Suplita, Richard Lee
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Recent work in our laboratory has identified a role for endogenous cannabinoids in non-opioid stress-induced analgesia (SIA) induced by brief continuous foot shock. Cannabinoid SIA is mediated by the mobilization of the endogenous cannabinoids 2-arachidonoylglycerol (2-AG) and anandamide, albeit with markedly distinct time courses (Hohmann et al., 2005). Whereas 2-AG is preferentially degraded by monoacylglycerol lipase (MGL), anandamide is metabolized primarily by fatty-acid amide hydrolase (FAAH). The present studies were conducted to examine the role of the endocannabinoids 2-AG and anandamide at CB1 receptors in the midbrain dorsolateral periaqueductal gray (dPAG), the brainstem rostral ventromedial medulla (RVM) and the lumbar spinal cord in cannabinoid SIA. Pharmacological blockade of vanilloid TRPV1 receptors with capsazepine administered systemically did not alter cannabinoid SIA, suggesting that cannabinoid SIA is not dependent upon TRPV1. By contrast, systemic administration of either palmitoyltrifluoromethylketone, a potent inhibitor of FAAH and phospholipase A2 activity, or the FAAH inhibitor AA-5-HT enhanced SIA in a CB1-dependent manner. Microinjection of the CB1 antagonist/inverse agonist SR141716A (rimonabant) into either the dPAG or RVM suppressed stress antinociception in this model. By contrast, microinjection of AA-5-HT into either the dPAG or RVM enhanced SIA via a CB1 mechanism. Time-dependent enhancements in levels of 2-AG, but not anandamide, were observed in lumbar spinal cord extracts derived from shocked relative to non-shocked rats, although accumulation of 2-AG was of smaller magnitude than that observed previously in the dorsal midbrain following foot shock (Hohmann et al., 2005).Spinal administration of rimonabant failed to suppress SIA at a dose that virtually eliminated SIA following microinjection into the dPAG (Hohmann et al., 2005), providing additional evidence that endocannabinoid SIA is primarily mediated by supraspinal CB1 activation. Nonetheless, intrathecal administration of the MGL inhibitor URB602, at a dose that selectively inhibits the hydrolysis of 2-AG in the dPAG (Hohmann et al., 2005), enhanced SIA through a CB1 mechanism. Despite the absence of detectable changes in post-shock levels of anandamide, spinal administration of either AA-5-HT or URB597 also enhanced SIA through CB1, presumably by increasing the accumulation of tonically released anandamide. These data provide evidence of a descending cannabinergic neural system that is activated by environmental stressors to modulate pain sensitivity in a CB1-dependent manner and suggest that endocannabinoids in the spinal cord regulate, but do not mediate, cannabinoid SIA.