Intranasal leptin prevents opioid-induced respiratory depression

Abstract

Opioid-induced respiratory depression (OIRD) is the main cause of death from an opioid overdose. Obesity increases opioid-related mortality, which is mostly related to co-morbid obstructive sleep apnea (OSA). Naloxone, a μ-opioid receptor (MOR) blocker, is an effective antidote, but it reverses analgesia. Similar to obese humans, diet-induced obese (DIO) mice hypoventilate during sleep and develop OSA, which can be treated with intranasal leptin. We hypothesized that leptin reverses OIRD in DIO mice without decreasing analgesia. DIO mice were treated with morphine at 10 mg/kg subcutaneously and with leptin vs placebo intranasally. Sleep and breathing were recorded by barometric plethysmography and pain sensitivity was measured by the tail flick test. Morphine dramatically increased the frequency of apneas and greatly increased severity of hypoventilation and OSA. Leptin decreased the frequency of apneas (Fig. 1), improved OSA and completely reversed hypoventilation, whereas morphine analgesia was enhanced. Our in vitro studies demonstrated that a MOR agonist [D-Ala2, N-MePhe4, Gly-ol]-enkephalin (DAMGO) reduced excitatory post-synaptic currents in hypoglossal motoneurons (HMNs) and that application of leptin restored excitatory synaptic neurotransmission to HMNs. Our findings suggest that intranasal leptin may prevent OIRD in obese patients receiving opioids without reducing analgesia.