Intranasal Leptin Prevents Opioid Induced Sleep Disordered Breathing in Obese Mice

Respiratory depression is the main cause of morbidity and mortality associated with opioids. Obesity increases opioid-related mortality, which is mostly related to co-morbid obstructive sleep apnea. Naloxone, a μ-opioid receptor blocker, is an effective antidote, but it reverses analgesia. Similar to obese humans, diet-induced obese mice hypoventilate during sleep and develop obstructive sleep apnea, which can be treated with intranasal leptin. We hypothesized that intranasal leptin reverses opioid-induced sleep disordered breathing in obese mice without decreasing analgesia. To test this hypothesis, diet-induced obese 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. Excitatory post-synaptic currents were recorded in vitro from hypoglossal motor neurons following application of the μ opioid receptor agonist [D-Ala2, N-MePhe4, Gly-ol]-enkephalin (DAMGO) and leptin. Morphine dramatically increased the frequency of apneas and greatly increased severity of hypoventilation and obstructive sleep apnea. Leptin decreased the frequency of apneas, improved obstructive sleep apnea and completely reversed hypoventilation, whereas morphine analgesia was enhanced. Our in vitro studies demonstrated that DAMGO reduced the frequency of excitatory post-synaptic currents in hypoglossal motoneurons and that application of leptin restored excitatory synaptic neurotransmission. Our findings suggest that intranasal leptin may prevent opioid respiratory depression during sleep in obese patients receiving opioids without reducing analgesia.

Keywords: Hypoventilation; Leptin; Morphine; Opioid reversal agents; Sleep apnea syndromes.