An endocannabinoid mechanism for stress-induced analgesia

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 stress-induced analgesia, 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-AG) and anandamide. A newly developed inhibitor of the 2-AG-deactivating enzyme, monoacylglycerol lipase, selectively increases 2-AG concentrations and, when injected into the periaqueductal grey matter, enhances stress-induced analgesia in a CB1-dependent manner. Inhibitors of the anandamide-deactivating enzyme fatty-acid amide hydrolase, 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

Ethanol Seeking by Long Evans Rats Is Not Always a Goal-Directed Behavior

Background -- Two parallel and interacting processes are said to underlie animal behavior, whereby learning and performance of a behavior is at first via conscious and deliberate (goal-directed) processes, but after initial acquisition, the behavior can become automatic and stimulus-elicited (habitual). With respect to instrumental behaviors, animal learning studies suggest that the duration of training and the action-outcome contingency are two factors involved in the emergence of habitual seeking of “natural” reinforcers (e.g., sweet solutions, food or sucrose pellets). To rigorously test whether behaviors reinforced by abused substances such as ethanol, in particular, similarly become habitual was the primary aim of this study. Methodology/Principal Findings -- Male Long Evans rats underwent extended or limited operant lever press training with 10% sucrose/10% ethanol (10S10E) reinforcement (variable interval (VI) or (VR) ratio schedule of reinforcement), or with 10% sucrose (10S) reinforcement (VI schedule only). Once training and pretesting were complete, the impact of outcome devaluation on operant behavior was evaluated after lithium chloride injections were paired with the reinforcer, or unpaired 24 hours later. After limited, but not extended instrumental training, lever pressing by groups trained under VR with 10S10E and under VI with 10S was sensitive to outcome devaluation. In contrast, responding by both the extended and limited training 10S10E VI groups was not sensitive to ethanol devaluation during the test for habitual behavior. Conclusions/Significance -- Operant behavior by rats trained to self-administer an ethanol-sucrose solution showed variable sensitivity to a change in the value of ethanol, with relative insensitivity developing sooner in animals that received time-variable ethanol reinforcement during training sessions. One important implication, with respect to substance abuse in humans, is that initial learning about the relationship between instrumental actions and the opportunity to consume ethanol-containing drinks can influence the time course for the development or expression of habitual ethanol seeking behavior.Research support was provided by awards T32AA007471, F32AA018252, and R37AA011852 from the National Institute on Alcohol and Alcohol Abuse (http://www.niaaa.nih.gov) and HRD-0703584 from the National Science Foundation (www.nsf.gov). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Pharmac

Enhancement of endocannabinoid signaling and the pharmacotherapy of depression.

Cannabinoids are well known modulators of mood and emotional behavior. Current research supports a role for endocannabinoid signaling in the treatment of depression. Changes in levels of the cannabinoid CB(1) receptor or the endogenous CB(1) receptor ligands, anandamide and 2-AG, are observed both in humans suffering from depression and in animal models of depression, and experimental manipulation of CB(1) receptor signaling has also been shown to affect emotional reactivity in rodents. Importantly, inhibitors of anandamide inactivation have demonstrated efficacy in enhancing stress-coping and mood-related behavior. This article will review these areas of research, highlighting the potential of endocannabinoid metabolism modulators as therapeutics for the treatment of depression

Enhancement of endocannabinoid signaling and the pharmacotherapy of depression.

Cannabinoids are well known modulators of mood and emotional behavior. Current research supports a role for endocannabinoid signaling in the treatment of depression. Changes in levels of the cannabinoid CB(1) receptor or the endogenous CB(1) receptor ligands, anandamide and 2-AG, are observed both in humans suffering from depression and in animal models of depression, and experimental manipulation of CB(1) receptor signaling has also been shown to affect emotional reactivity in rodents. Importantly, inhibitors of anandamide inactivation have demonstrated efficacy in enhancing stress-coping and mood-related behavior. This article will review these areas of research, highlighting the potential of endocannabinoid metabolism modulators as therapeutics for the treatment of depression

The endocannabinoid system as a target for the treatment of cannabis dependence.

The endocannabinoid system modulates neurotransmission at inhibitory and excitatory synapses in brain regions relevant to the regulation of pain, emotion, motivation, and cognition. This signaling system is engaged by the active component of cannabis, Delta9-tetrahydrocannabinol (Delta9-THC), which exerts its pharmacological effects by activation of G protein-coupled type-1 (CB1) and type-2 (CB2) cannabinoid receptors. During frequent cannabis use a series of poorly understood neuroplastic changes occur, which lead to the development of dependence. Abstinence in cannabinoid-dependent individuals elicits withdrawal symptoms that promote relapse into drug use, suggesting that pharmacological strategies aimed at alleviating cannabis withdrawal might prevent relapse and reduce dependence. Cannabinoid replacement therapy and CB1 receptor antagonism are two potential treatments for cannabis dependence that are currently under investigation. However, abuse liability and adverse side-effects may limit the scope of each of these approaches. A potential alternative stems from the recognition that (i) frequent cannabis use may cause an adaptive down-regulation of brain endocannabinoid signaling, and (ii) that genetic traits that favor hyperactivity of the endocannabinoid system in humans may decrease susceptibility to cannabis dependence. These findings suggest in turn that pharmacological agents that elevate brain levels of the endocannabinoid neurotransmitters, anandamide and 2-arachidonoylglycerol (2-AG), might alleviate cannabis withdrawal and dependence. One such agent, the fatty-acid amide hydrolase (FAAH) inhibitor URB597, selectively increases anandamide levels in the brain of rodents and primates. Preclinical studies show that URB597 produces analgesic, anxiolytic-like and antidepressant-like effects in rodents, which are not accompanied by overt signs of abuse liability. In this article, we review evidence suggesting that (i) cannabis influences brain endocannabinoid signaling and (ii) FAAH inhibitors such as URB597 might offer a possible therapeutic avenue for the treatment of cannabis withdrawal

The endocannabinoid system as a target for the treatment of cannabis dependence.

The endocannabinoid system modulates neurotransmission at inhibitory and excitatory synapses in brain regions relevant to the regulation of pain, emotion, motivation, and cognition. This signaling system is engaged by the active component of cannabis, Delta9-tetrahydrocannabinol (Delta9-THC), which exerts its pharmacological effects by activation of G protein-coupled type-1 (CB1) and type-2 (CB2) cannabinoid receptors. During frequent cannabis use a series of poorly understood neuroplastic changes occur, which lead to the development of dependence. Abstinence in cannabinoid-dependent individuals elicits withdrawal symptoms that promote relapse into drug use, suggesting that pharmacological strategies aimed at alleviating cannabis withdrawal might prevent relapse and reduce dependence. Cannabinoid replacement therapy and CB1 receptor antagonism are two potential treatments for cannabis dependence that are currently under investigation. However, abuse liability and adverse side-effects may limit the scope of each of these approaches. A potential alternative stems from the recognition that (i) frequent cannabis use may cause an adaptive down-regulation of brain endocannabinoid signaling, and (ii) that genetic traits that favor hyperactivity of the endocannabinoid system in humans may decrease susceptibility to cannabis dependence. These findings suggest in turn that pharmacological agents that elevate brain levels of the endocannabinoid neurotransmitters, anandamide and 2-arachidonoylglycerol (2-AG), might alleviate cannabis withdrawal and dependence. One such agent, the fatty-acid amide hydrolase (FAAH) inhibitor URB597, selectively increases anandamide levels in the brain of rodents and primates. Preclinical studies show that URB597 produces analgesic, anxiolytic-like and antidepressant-like effects in rodents, which are not accompanied by overt signs of abuse liability. In this article, we review evidence suggesting that (i) cannabis influences brain endocannabinoid signaling and (ii) FAAH inhibitors such as URB597 might offer a possible therapeutic avenue for the treatment of cannabis withdrawal