The primary cause of death associated with opioids is opioid-induced respiratory depression (OIRD). Several lines of evidence suggest that recurrent pharyngeal obstruction and loss of airway patency during opioid exposure is an additional and major risk in OIRD. The identification and validation of new therapeutic agents- antidotes for OIRD, which would not reverse the beneficial opioid-mediated analgesia, or cause acute withdrawal symptoms, is urgently needed. We have shown that an adipocyte-produced hormone leptin, which suppresses appetite and increases metabolic rate, also up-regulates control of breathing during sleep and treats obstructive sleep apnea (OSA). While obese humans and DIO mice are resistant to metabolic effects of leptin, resistance to the respiratory effects of leptin occurs at the blood brain barrier (BBB) level and can be circumvented if leptin is administered intranasally (IN), which enables brain exposure to the hormone. Our preliminary data show that: (1) morphine inhibits hypoglossal motoneurons (HMN) and induces OIRD and OSA in mice; (2) IN leptin can reverse OIRD and OSA; (3) leptin reverses opioid-induced HMN inhibition in vitro; (4) IN leptin does not diminish analgesia. Our overall hypothesis is that OIRD can be attenuated by intranasal administration of leptin, which stimulates breathing and increases upper airway patency by restoring HMN activity without acute withdrawal while maintaining analgesia. We will test our hypothesis in lean and DIO male and female mice. Specific Aim 1 will validate the leptin pathway as a target to treat OIRD. We hypothesize that IN leptin will reverse (A) OIRD and opioid-induced OSA; (B) opioid-induced suppression of hypercapnic and hypoxic chemosensitivity; and (C) upper airway collapsibility in a dose-dependent manner. Specific Aim 2 will examine effects of IN leptin on analgesia and acute opioid withdrawal. We hypothesize that leptin will not (A) decrease analgesia nor (B) induce acute opioid withdrawal. Specific Aim 3 will compare effects of different formulations of IN leptin on OIRD. Specifically, we will test leptin prepared in (A) normal saline (NS); (B) tetradecylmaltoside (TDM); (C) sodium taurodihydrofusidate (STDHF); (D) lysophosphatidylcholine (LPC). Specific Aim 4 will examine IN leptin pharmacokinetics. We will develop pharmacokinetic/pharmacodynamics relationships that could aid in clinical translation and measure the effect of IN leptin on (A) leptin delivery to the different parts of the brain; (B) activation of the leptin signaling pathway in the different parts of the brain; and C) the time course of leptin appearance in CSF and plasma. Specific Aim 5 will examine toxicity of IN leptin by examining effects of IN leptin at 3 to 30 fold multiple of the effective dose on (A) cardiovascular system (blood pressure, heart rate); (B) endocrine system (glucose, insulin levels); (C) brain pathology; (D) immune response (anti-leptin antibody). We propose that IN leptin will b...