Targeting Leptin Pathway to Treat Opioid-Induced Respiratory Depression

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PROJECT SUMMARY Opioid overdose kills 130 people in the United States every day according to the CDC/NCHS National Vital Statistics System. The primary cause of death associated with opioids is opioid-induced respiratory depression (OIRD). Opioids act on μ-opioid receptors (MOR) within the brainstem, including the preBőtzinger complex and the ventral respiratory group to decrease respiratory rate. 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. Thus, OIRD is a heterogeneous condition, which includes two independent respiratory phenotypes, impaired control of breathing manifested by decreased respiratory rate, and upper airway obstruction (UAO) similar to obstructive sleep apnea. Understanding both of these two major respiratory phenotypes of OIRD is critical for drug development. Naloxone is a competitive antagonist of MORs and other opioid receptors. Naloxone has been used for decades to reverse OIRD. It has a rapid onset and it is available in the intranasal formulation. However, naloxone reverses opioid-induced analgesia and may cause acute withdrawal symptoms. In addition, it has short half-life. Therefore, the identification and validation of new long lasting therapeutic agents-antidotes for OIRD, which would not reverse the beneficial MOR mediated analgesia, or cause acute withdrawal symptoms, is urgently needed. Our overarching hypothesis is that leptin may serve as a novel treatment for OIRD. Systemic (subcutaneous and intraperitoneal) leptin administration stimulates breathing and upper airway function in lean and leptin deficient ob/ob mice. While obese humans and diet-induced obese (DIO) mice are resistant to leptin, resistance to the respiratory effects of leptin occurs at the blood brain barrier level and can be circumvented if leptin is administered intranasally (IN). Our Preliminary data show that: (1) morphine inhibits hypoglossal motoneurons (HMN) and induce OIRD in mice; (2) IN leptin can reverse OIRD; (3) leptin reverses opioid-induced HMN inhibition in vitro; (4) The respiratory effects of IN leptin last greater than 6 hours, which is substantially longer than naloxone; (5) IN leptin does not diminish, but rather facilitates, MOR analgesia. Our overall hypothesis is that OIRD can be treated by intranasal administration of leptin, which stimulates breathing and increases upper airway patency by restoring HMN activity while maintaining MOR-mediated analgesia. We will evaluate the leptin pathway as a potential target to treat OIRD using both in vivo and in vitro models. Specific Aim 1 will examine if IN leptin alone (A) or in combination with naloxone (B) treats OIRD and UAO in DIO and lean male and female mice. Specific Aim 2 will examine the neurobiological mechanisms by which leptin treats opioid-induced decreases in the activity of HMNs in vitro. The proposal will validate leptin as a novel target to treat OIRD and will develop and validate novel in vivo and in vitro assays for OIRD in response to the NIH RFA-DA-20-025.