Evaluation of peripheral cannabinoid receptors as a target for pain management

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ABSTRACT Chronic pain impacts 11.2% of the U.S. population, and leads to considerable disability. Current pharmacotherapies for chronic pain are largely ineffective and rely heavily on opioids. Over-prescription of opioid-based compounds for pain disorders has contributed to an opioid overdose epidemic in the U.S., highlighting the urgent need to develop safer and more effective therapeutics for pain. The endocannabinoid system, which consists of cannabinoid receptors (CB1 and CB2) and their endogenous ligands, has emerged as an alternative therapeutic target to currently available pain medications. Exogenously administered cannabinoids (CBs) display mixed outcomes in clinical trials for chronic pain suggesting the therapeutic potential of CB-based therapies in pain disorders is largely unknown. CB agonists also exhibit unwanted side- effects (e.g. tolerance and psychoactivity) largely due to central CB1R activation. Dorsal root ganglion (DRG) contain the cell bodies of primary afferents responsible transmitting peripheral nociceptive signaling to the spinal cord. Activation of peripheral CB1R receptors in DRG has been viewed as a potential means to harness the therapeutic actions of CB1Rs while circumventing unwanted CNS-related side-effects. Yet, there have been few investigations regarding antinociceptive effects of peripheral CB ligands. In the present proposal I plan to incorporate pharmacological and novel genetic-based approaches to elucidate the contributions of peripheral CB1R receptors in reducing sensory and non-reflexive components of pain in both male and female mice. The mentor's lab previously demonstrated functional differences of metabotropic glutamate receptor 2/3 receptors activity in cultured neurons derived from mouse and human dorsal root ganglion. This suggests the mechanistic basis of other pharmacological targets, such as CBs, may differ between species. Human and mouse CB1 exhibit differential signaling in hippocampal autaptic cultures. Only one report to-date investigated CB signaling in human-derived DRG and no comparative studies regarding CB receptor signaling have ever been conducted between rodent and human in this tissue. To better understand the clinical validity of targeting peripheral CB1Rs I will take advantage of an extremely unique opportunity to conduct comparative studies of CB receptor function in mouse and human DRG. These studies have potential to generate transformative data in understanding transability of preclinical findings regarding peripheral antinociceptive effects of CBs. The central hypothesis that CB1R present on nociceptors in DRG are responsible for the antinociceptive effects of peripheral CB administration observed in mice and that this mechanism will translate to humans will be evaluated in the present proposal. The data generated from the proposed experiments will greatly aid in our understanding of the underlying mechanisms in which peripheral CB1R activation promotes antinociceptive like effects in mouse and whether or not similar approaches will translate into humans; potentially leading to better approaches of utilizing CB1R signaling for the treatment of chronic pain disorders.