Despite their abuse potential, opioids remain a gold standard analgesic. One of the lesser discussed effects of chronic opioid use is opioid induced hyperalgesia (OIH), or increased pain sensitivity in some users. OIH persists for a longer duration than opioid withdrawal and may contribute to drug seeking and relapse in people with substance use disorders. The physiological causes of OIH are caused by (1) repeated µ opioid activation and desensitization, and (2) activation of inflammatory pathways by morphine binding to Toll-like receptor 4. Cannabinoids have well established analgesic and anti-inflammatory properties. Endogenous cannabinoids (i.e., endocannabinoids) have anti-inflammatory effects with limited intoxicating effects, as compared with exogenous cannabinoids. The proposed study will use an experimental animal model of repeated morphine exposure, followed by paw incision injury. Our goal is to test the hypothesis that inhibition of the endocannabinoid catabolic enzyme monoacylglycerol lipase (MAGL) decreases pain and inflammation caused by repeated morphine treatment. Male and female mice will be repeatedly administered morphine or vehicle, in the presence of increased endocannabinoid tone, for four days. Endocannabinoid tone will be increased by either chemical inhibition of MAGL, or genetic deletion of MAGL globally or on neurons only. Then, a small incision will be made and sutured closed in the plantar surface of one hindpaw, to model postoperative hyperalgesia. Mice will be tested repeatedly for pain- induced, pain-suppressed, and pain conditioning behavioral models. Endocannabinoid receptor mechanism will be determined using selective CB1 and CB2 cannabinoid receptor antagonists. Paw tissue will be collected to quantify proinflammatory cytokine levels, and individual cytokine levels will be correlated with pain-related behaviors. The anti-inflammatory mechanisms of endocannabinoid modulation will be further probed in vitro, using isolated macrophages/monocytes. Extant studies of preclinical OIH models have used male animals almost exclusively. Because women may be at increased risk for developing OIH, we will include sufficient numbers of both female and male mice to investigate Sex as a Biological Variable. In addition to increasing basic understanding of the underlying neural and immunological mechanisms that contribute to opioid-induced hyperalgesia, our translational research goal is to develop treatments for substance abuse disorders.