Intranasal Leptin Reduces Mortality from Opioid Overdose in Mice

Rationale: North America is currently facing an opioid epidemics. Over 130 Americans die every day from an opioid overdose and the COVID-19 pandemic has increased opioid usage and opioid-related deaths. Respiratory depression is the main cause of morbidity and mortality from opioids. We have previously shown that leptin acts as respiratory stimulant and prevents opioid-induced respiratory depression and upper airway obstruction without reducing analgesia. In this study, we aimed to examine if intranasal (IN) administration of leptin effectively delivers leptin to the brain and prevents opioid-related deaths. Methods: To determine leptin delivery to the brain male C57BL/6J mice, were treated with IN leptin at 1.2 mg/kg in 1% BSA (n=5) or 1% BSA (n=5) and sacrificed 20 min later. Brains were harvested, the olfactory bulbs, medullas and hypotalami were isolated, quick frozen and stored at-80°C. For leptin level measurements, brain tissue was homogenized, protease inhibitors and protein concentrations were determined and ELISA was performed. To determine the survival probability, male C57BL/6J mice, 12 weeks of age, received IN leptin (n=26) or vehicle (n=25) at 1.2 mg/kg and 30 minutes later received a bolus of intraperitoneal (IP) morphine at 400mg/kg. Mice were video monitored for 24 hours and survival time after morphine injection was recorded Results: IN leptin significantly increased leptin levels in the olfactory bulb (from 0 ng/mL to 7.53 ng/mL, p = 0.004) and medulla (from 0.008 ng/mL to 0.107 ng/mL) and presented a trend in the hypothalamus (from 0.018 ng/mL to 0.291 ng/mL, p = 0.1). Mice that received IN leptin had a higher survival rate when compared to mice that received vehicle (69% vs 92%, p = 0.044, Figure). Conclusion: We demonstrated that the intranasal route is effective for the delivery of leptin to the brain and that leptin reduced opioid-induced mortality. (Table Presented).