Respiratory depression is the main cause of morbidity and mortality associated with opioids. Obesity increases opioid-related mortality, which is mostly related to comorbid obstructive sleep apnea. Naloxone, a μ-opioid receptor blocker, is an effective antidote, but it reverses analgesia. Like humans with obesity, mice with diet-induced obesity 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, mice with diet-induced obesity were treated with morphine at 10 mg/kg subcutaneously and with leptin or placebo intranasally. Sleep and breathing were recorded by barometric plethysmography, and pain sensitivity was measured by the tail-flick test. Excitatory postsynaptic currents were recorded in vitro from hypoglossal motor neurons after the application of the μ-opioid receptor agonist [D-Ala², N-MePhe⁴, Gly-ol]-enkephalin and leptin. Morphine dramatically increased the frequency of apneas and greatly increased the 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 [D-Ala², N-MePhe⁴, Gly-ol]-enkephalin reduced the frequency of excitatory postsynaptic 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 patients with obesity receiving opioids without reducing analgesia.

呼吸抑制是与阿片类药物相关的发病率和死亡率的主要原因。肥胖会增加与阿片类药物相关的死亡率，这主要与合并阻塞性睡眠呼吸暂停有关。纳洛酮是一种 μ-阿片受体阻滞剂，是一种有效的解毒剂，但它可以逆转镇痛。与肥胖的人类一样，饮食引起的肥胖小鼠在睡眠期间通气不足并出现阻塞性睡眠呼吸暂停，这可以用鼻内瘦素治疗。我们假设鼻内瘦素可以在不降低镇痛作用的情况下逆转肥胖小鼠阿片类药物引起的睡眠障碍呼吸。为了验证这一假设，饮食诱导肥胖的小鼠接受了 10 mg/kg 吗啡皮下注射和瘦素或安慰剂鼻内注射。通过气压体积描记法记录睡眠和呼吸，并且通过甩尾测试测量疼痛敏感性。记录兴奋性突触后电流在应用 μ-阿片受体激动剂 [D-Ala ²、N-MePhe ⁴、Gly-ol]-脑啡肽和瘦素后，从舌下运动神经元体外提取。吗啡显着增加了呼吸暂停的频率，并大大增加了换气不足和阻塞性睡眠呼吸暂停的严重程度。瘦素降低了呼吸暂停的频率，改善了阻塞性睡眠呼吸暂停，并完全逆转了换气不足，而吗啡镇痛作用增强。我们的体外研究表明 [D-Ala ² , N-MePhe ⁴, Gly-ol]-脑啡肽降低了舌下运动神经元中兴奋性突触后电流的频率，并且瘦素的应用恢复了兴奋性突触神经传递。我们的研究结果表明，鼻内瘦素可以预防接受阿片类药物治疗的肥胖患者睡眠期间的阿片类药物呼吸抑制，而不会降低镇痛效果。