Intranasal Leptin Prevents Opioid-Induced Respiratory Depression in Obese, Opioid Tolerant Mice

Abstract

Opioid-induced respiratory depression (OIRD) is the primary cause of death associated with opioids and individuals with obesity are particularly susceptible due to comorbid obstructive sleep apnea (OSA). Repeated exposure to opioids, as in the case of pain management, results in diminished therapeutic effect and/or the need for higher doses to maintain the same effect. With limited means to address the negative impact of repeated exposure it is critical to develop drugs that prevent deaths induced by opioids without reducing beneficial analgesia or causing withdrawal symptoms. We have previously shown that intranasal (IN) leptin can reverse apneas, hypoventilation, and upper airway obstruction while enhancing analgesia following acute morphine administration. Here we hypothesize that OIRD as a result of chronic opioid use can be attenuated by administration of IN leptin without acute withdrawal while also maintaining analgesia in both lean mice and mice with diet-induced obesity (DIO). To test this hypothesis, an opioid tolerance protocol was developed and a model of OIRD in mice chronically receiving morphine and tolerant to morphine analgesia was established. Subsequently, sleep and breathing were recorded by barometric plethysmography following acute or chronic administration of IN leptin. Operant behavioral assays and Pavlovian conditioning procedures were used to determine the impact of IN leptin on the analgesic efficacy of morphine and opioid withdrawal symptoms. Acute administration of IN leptin significantly attenuated OIRD in DIO male mice decreasing the apnea index by 58.9% and apnea time by 60.1%. In lean mice leptin was ineffective. Chronic IN leptin induced > 50% reduction in the OIRD in morphine tolerant DIO male mice suggesting the protective effect of leptin remained after the two-week treatment. Morphine caused a complete loss of temperature aversion which was not reduced by intranasal leptin indicating IN leptin does not decrease morphine analgesia. IN leptin did not modify naloxone conditional place aversion or naloxone withdrawal symptoms, suggesting that IN treatment does not induce opioid withdrawal. We conclude that IN leptin is ineffective in lean mice but prevents OIRD in obesity by increasing hypercapnic sensitivity when leptin resistance at the BBB is present without reducing analgesia or inducing withdrawal. NIH R61HL156240; NIH R01HL128970; NIH R41DA056239 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.