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.