Leptin Receptor Agonist as a Novel Prevention of Opioid Induced Respiratory Depression

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). There is no FDA-approved OIRD prevention that maintains opioid analgesia.. Several high- risk patient groups for non-naloxone-based OIRD prevention can be identified. By far the largest group includes patients with underlying OSA, who require high doses of opioids for pain control post-surgery and/or post-injury in the hospital settings. OSA is a very common disease affecting 34% of men and 17.4% of women in the US. Greater than 50% of obese individuals have OSA and the prevalence of obesity in the US is nearly 40%, and increasing. The overarching goal of our proposal to develop a novel OIRD preventive pharmaceutical and validate it in a mouse model. We have shown that an adipocyte-produced hormone, leptin, which suppresses appetite and increases metabolic rate, also stimulates breathing during sleep. Our laboratory extensively studies sleep and breathing in mice. Leptin deficient obese ob/ob mice demonstrate hypoventilation and OSA, which can be treated with leptin. We have also shown that mice with diet-induced obesity (DIO) develop OHS and OSA, similar to obese humans, despite high plasma leptin level, indicating leptin resistance. We have shown that if leptin is administered intranasally (IN) in DIO mice, the blood-brain barrier (BBB) can be circumvented, central exposure to the hormone is facilitated, and hypoventilation and sleep apnea are abolished. We have also shown that IN leptin prevents OIRD and that IN leptin does not reverse and may even augment opioid analgesia. However, the mouse and human olfactory bulbs have significant anatomical differences and response to IN leptin may differ between species. Leptin receptor agonists engineered to penetrate the BBB are promising therapeutic candidates for OIRD. Dr. Laszlo Otvos developed such a potent agonist, E1/Aca, which is superior to leptin for weight loss and metabolic dysfunction in mice and rats. We established a collaboration with Arrevus, which holds a license on E1/Aca, and developed our STTR proposal. We hypothesize that the LEPRb agonist E1/Aca will prevent OIRD in leptin resistant DIO mice without reversing analgesia. In Aim 1, we will examine the effect of E1/Aca on fentanyl-induced OIRD using the fixed dose of E1/Aca and escalating doses of fentanyl in Subaim 1A and escalating dose of E1/Aca and a fixed dose of fentanyl in Subaim 1B. In Aim 2: we will examine the effect of E1/Aca on fentanyl analgesia. We hypothesize that the target dose of E1/Aca identified from Aim 1 for OIRD will not decrease fentanyl analgesia in DIO mice. Thus, the Phase I of our STTR will establish the efficacy of the leptin receptor agonist E1/Aca for prevention of fentanyl OIRD in a mouse model.Opioid overdose kills 130 people in the United States every day according to the CDC/NCHS National Vital Statistics System, mostly due to breathing failure, and obesity is a key risk factor. We have previously shown in a mouse model that a fat-tissue produced hormone, leptin, can prevent opioid-related death. In our proposal, we will test if leptin analog E1/Aca can prevent fentanyl-induced breathing failure in our obese mouse model without diminishing the pain-killing effects of fentanyl.