Endocannabinoid Targeting for Opioid Induced Respiratory Depression

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Project Summary Accidental overdoses fatalities define the opioid epidemic despite research efforts for alternative means to address Opioid Use Disorder [1] and alternative chronic pain therapies [2]. The Centers for Disease Control report over 400,000 lives lost since 1999 and more than 130 people lose their life to an accidental overdose daily [3]. This number will continue to climb with excessive utilization of prescription opioids and the presence of stronger synthetic opioids in the illicit market [4-6]. A potentially fatal opioid overdose can be successfully reversed with naloxone, mu opioid receptor antagonist, [7], but with the number of pain patients rising above heart disease and diabetes [2] and the increased presence of fentanyl in the illicit opioid market, adequate distribution of naloxone to reverse an overdose before oxygen deprivation occurs remains difficult [8]. Attempts to reduce opioid overdoses with novel opioid-like compounds have been largely unsuccessful [9]. Therefore, it is essential that unexplored therapeutic strategies to prevent opioid-induced respiratory depression be discovered. Fatal opioid overdoses are typically attributed to respiratory depression, during which neurons within the preBötzinger complex (pBc) in the brainstem that control reflexive inspiration are inhibited. Our pilot data suggest that 1) the pBc contains the components of the endocannabinoid system, including the cannabinoid receptor 2 (CB2R), 2) CB2R activation by endogenous cannabinoid system (ECBS) lipids is critical to normal respiration control, and 3) exogenous application of a CB2R agonist mitigates morphine induced respiratory depression. The current proposal will build upon these findings, using behavioral pharmacology, whole body plethysmography, imaging, molecular biology, analytical chemistry, and gene-editing to test the hypothesis that endogenous cannabinoid levels in the pBc are reduced during opioid induced respiratory depression (OIRD) and that administration of a brain penetrant CB2R agonist will mitigate OIRD. Aim 1 will test CB2R agonism as a strategy to mitigate to OIRD. Each aim contains rationally designed studies that include sex differences through inclusion of male and female mice, application to both acute and chronic use of medicinal and recreational opioids (fentanyl, oxycodone, and heroin), and multiple chemical classes of CB2R agonists to prevent and reverse OIRD. Aim 2 will determine levels of endocannabinoid lipids, enzymes, and receptors in the preBotzinger complex (pBc) during OIRD. Successful completion of proposed studies will serve to enhance our knowledge of the role of ECBS within the pBc in during normal respiration and during OIRD and validate targeting the CB2R as a safe treatment therapeutic to reduce opioid overdoses.