An endocannabinoid mechanism for stress-induced analgesia

Abstract

Acute stress suppresses pain by activating brain pathways that engage opioid or non-opioid mechanisms. Here we show that an opioid-independent form of this phenomenon, termed stressinduced analgesia 1 , is mediated by the release of endogenous marijuana-like (cannabinoid) compounds in the brain. Blockade of cannabinoid CB 1 receptors in the periaqueductal grey matter of the midbrain prevents non-opioid stress-induced analgesia. In this region, stress elicits the rapid formation of two endogenous cannabinoids, the lipids 2-arachidonoylglycerol 2 (2-AG) and anandamide 3 . A newly developed inhibitor of the 2-AG-deactivating enzyme, monoacylglycerol lipase 4,5 , selectively increases 2-AG concentrations and, when injected into the periaqueductal grey matter, enhances stress-induced analgesia in a CB 1 -dependent manner. Inhibitors of the anandamide-deactivating enzyme fatty-acid amide hydrolase 6 , which selectively elevate anandamide concentrations, exert similar effects. Our results indicate that the coordinated release of 2-AG and anandamide in the periaqueductal grey matter might mediate opioid-independent stress-induced analgesia. These studies also identify monoacylglycerol lipase as a previously unrecognized therapeutic target.Stress activates neural systems that inhibit pain sensation. This adaptive response, referred to as stress-induced analgesia (SIA), depends on the recruitment of brain pathways that project from the amygdala to the midbrain periaqueductal grey matter (PAG) and descend to the brainstem rostroventromedial medulla and dorsal horn of the spinal cord 7 . Endogenous opioid peptides have key functions in this process 1,8 , but other as yet unidentified neurotransmitters are also known to be involved 1 . We proposed that endocannabinoids might be implicated in stress analgesia for two reasons. First, agonists of CB 1 receptors-the predominant cannabinoid receptor subtype present in the brain 9,10 -exert profound antinociceptive effects 7 and suppress activity in nociceptive neurons 11-14 . Second, CB 1 antagonists increase the activity of nociceptive rostroventromedial medulla neurons 14 and enhance sensitivity to noxious stimuli 15 , indicating that an intrinsic endocannabinoid tone might regulate descending antinociceptive pathways 7 . To study non-opioid SIA we delivered brief, continuous electric foot shock to rats and quantified their sensitivity to pain after stress by using the tail-flick test. As demonstrated previously 1,16 , this stimulation protocol caused a profound antinociceptive effect that was not affected by intraperitoneal (i.p.) injection of the opiate antagonist naltrexone (14 mg kg 21 ) (Fig. 1a). However, the response was almost abolished by administration of the CB 1 antagonist rimonabant (SR141617A, 5 mg kg

Increase of brain endocannabinoid anandamide levels by FAAH inhibition and alcohol abuse behaviours in the rat

“…Several reports indicate that in rodents, increases of brain anandamide levels following reuptake inhibition or metabolic degradation result in a significant anxiolytic-like response and analgesia (Bortolato et al 2006;Kathuria et al 2003;Hohmann et al 2005;Piomelli et al 2006). Consistent with this finding, our results show that URB597 prevents anxiety-like responses elicited by an acute IP injection of a high alcohol dose.…”

A neuroscientist's guide to lipidomics

“…Facing DGlα, on the opposite side of the synaptic cleft, are both CB 1 rs 63 and monoacylglycerol lipase 67 , a presynaptic enzyme that cleaves 2-AG to terminate its actions 32,61,68 . We do not know precisely how 2-AG crosses the water-filled cleft to reach CB 1 r-containing terminals, but its amphipathic nature and/or its association with extracellular lipid-binding proteins 69,70 are likely to be important.…”

Anxiolytic-Like Properties of the Anandamide Transport Inhibitor AM404

“…Moreover, the hypoalgesic phenotype of FAAH-deficient mice (Cravatt et al, 2001) and the ability of FAAH inhibitors to alleviate pain, anxiety, and depression in rodent models (Kathuria et al, 2003;Lichtman et al, 2004;Hohmann et al, 2005;Gobbi et al, 2005) suggest that anandamide modulates the activity of neural circuits involved in the control of nociception, stress and emotion. These findings raise two clinically relevant questions.…”