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

Although anecdotal reports suggest that cannabis may be used to alleviate symptoms of depression, the psychotropic effects and abuse liability of this drug prevent its therapeutic application. The active constituent of cannabis, Delta(9)-tetrahydrocannabinol, acts by binding to brain CB, cannabinoid receptors, but an alternative approach might be to develop agents that amplify the actions of endogenous cannabinoids by blocking their deactivation. Here, we show that URB597, a selective inhibitor of the enzyme fatty-acid amide hydrolase, which catalyzes the intracellular hydrolysis of the endocannabinoid anandamide, exerts potent antidepressant-like effects in the mouse tail-suspension test and the rat forced-swim test. Moreover, URB597 increases firing activity of serotonergic neurons in the dorsal raphe nucleus and noradrenergic neurons in the nucleus locus ceruleus. These actions are prevented by the CB, antagonist rimonabant, are accompanied by increased brain anandamide levels, and are maintained upon repeated URB597 administration. Unlike direct CB, agonists, URB597 does not exert rewarding effects in the conditioned place preference test or produce generalization to the discriminative effects of Delta(9)-tetrahydrocannabinol in rats. The findings support a role for anandamide in mood regulation and point to fatty-acid amide hydrolase as a previously uncharacterized target for antidepressant drugs

Background:The endocannabinoid anandamide may be involved in the regulation of emotional reactivity. In particular, it has been shown that pharmacological inhibition of the enzyme fatty acid amide hydrolase (FAAH), which catalyzes the intracellular hydrolysis of anandamide, elicits anxiolytic-like and antidepressant-like effects in rodents.

Activation of group I metabotropic glutamate (mGlu) receptors drives the endocannabinoid system to cause both shortand long-term changes of synaptic strength in the striatum, hippocampus, and other brain areas. Although there is strong electrophysiological evidence for a role of endocannabinoid release in mGlu receptor-dependent plasticity, the identity of the endocannabinoid transmitter mediating this phenomenon remains undefined. In this study, we show that activation of group I mGlu receptors triggers the biosynthesis of the endocannabinoid 2-arachidonoylglycerol (2-AG), but not anandamide, in primary cultures of corticostriatal and hippocampal slices prepared from early postnatal rat brain.Pharmacological studies suggest that 2-AG biosynthesis is initiated by activation of mGlu5 receptors, is catalyzed by phospholipase C (PLC) and 1,2-diacylglycerol lipase (DGL) activities, and is dependent on intracellular Ca 2ϩ ions. Realtime polymerase chain reaction and immunostaining analyses indicate that DGL-␤ is the predominant DGL isoform expressed in corticostriatal and hippocampal slices and that this enzyme is highly expressed in striatal neurons, where it is colocalized with PLC-␤1. The results suggest that 2-AG is a primary endocannabinoid mediator of mGlu receptor-dependent neuronal plasticity.