Role of CB1 Receptors in Opioid Tolerance During Pain

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PROJECT SUMMARY The goal of this research is to characterize the interaction between the mu-opioid and CB1-cannabinoid receptors during pain. The analgesic properties of opioids are well known, and because of the recent legalization of medicinal cannabis in many US states, cannabis is increasingly being utilized as an analgesic. A growing body of evidence suggests that the cannabinoid and opioid systems interact in several ways that could be of significant therapeutic utility. However, the mechanisms of cannabinoid/opioid interactions, and the abuse potential of combined cannabinoid/opioid administration have yet to be elucidated. Therefore, we propose to characterize the interaction between opioids and cannabinoids in conditions during which these drugs might be used for their analgesic properties; specifically, in inflammatory and neuropathic pain. This five-year, Pathway to Independence project has three Specific Aims. The first Aim, to characterize pain- induced adaptations in the CB1 receptor system, was addressed during the mentored phase of this award. The independent Aims (during the R00 phase) characterized the effects of vaporized low-THC whole-plant cannabis extract (WPE). We found that WPE is not able to reverse hypersensitivity in animals with neuropathic pain, it does not attenuate morphine tolerance, however it does reduce the abuse liability of opioids. Although the modulation of opioid reward is a promising finding, vaporized WPE lacks clinical utility in the context of chronic pain, given its lack of efficacy for anti-hyperalgesia. Based upon our previous findings, we hypothesize that unlike low-THC, high-THC whole-plant cannabis extract (THC-WPE) will reduce pain and morphine tolerance in animals with neuropathic pain, while simultaneously reducing the abuse liability of opioids. The proposed studies have immense clinical relevance, given the prevalence of THC consumption by chronic pain patients. The studies in this Supplement do not deviate from those proposed in the original Application. The completion of the proposed studies will allow me to accomplish my immediate goals of further characterizing opioid/cannabinoid interactions, and focus on therapeutic protocols which have the greatest clinical implications. In doing so, my work will more directly benefit human health, which is in line with my long-term goal of identifying novel therapies that maximize analgesia while minimizing negative side effects. These studies represent a critical stepping-stone whereby I might engage in collaborative clinical studies that are informed by my findings at the bench. As a single mother and the primary caregiver of an 8-year old child, this Supplement will also provide bridge funding at a critical and vulnerable time of my career, as I compete for my first R01 funding. The proposed studies will undoubtedly result in peer-reviewed publications which will help me re-gain momentum lost due to caregiving responsibilities during the COVID-19 pandemic.