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Intranasal Leptin Prevents Opioid-induced Sleep-disordered Breathing in Obese Mice.

ABSTRACT: 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.

SUBMITTER: Freire C

PROVIDER: S-EPMC7528928 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ObjectiveTo examine the association between sleep-disordered breathing and stroke outcomes, and determine the contribution of sleep-disordered breathing to outcome disparities in Mexican Americans.MethodsIschemic stroke patients (n = 995), identified from the population-based Brain Attack Surveillance in Corpus Christi Project (2010-2015), were offered participation in a sleep-disordered breathing study including a home sleep apnea test (ApneaLink Plus). Sleep-disordered breathing (respiratory event index ≥10) was determined soon after stroke. Neurologic, functional, cognitive, and quality of life outcomes were assessed at 90 days poststroke. Regression models were used to assess associations between sleep-disordered breathing and outcomes, adjusted for sociodemographics, prestroke function and cognition, health-risk behaviors, stroke severity, and vascular risk factors.ResultsMedian age was 67 years (interquartile range [IQR] = 59-78); 62.1% were Mexican American. Median respiratory event index was 14 (IQR = 6-25); 62.8% had sleep-disordered breathing. Sleep-disordered breathing was associated with worse functional outcome (mean difference in activities of daily living/instrumental activities of daily living score = 0.15, 95% confidence interval [CI] = 0.01-0.28) and cognitive outcome (mean difference in modified Mini-Mental State Examination = -2.66, 95% CI = -4.85 to -0.47) but not neurologic or quality of life outcomes. Sleep-disordered breathing accounted for 9 to 10% of ethnic differences in functional and cognitive outcome and was associated with cognitive outcome more strongly for Mexican Americans (β = -3.97, 95% CI = -6.63 to -1.31) than non-Hispanic whites (β = -0.40, 95% CI = -4.18 to 3.39, p-interaction = 0.15).InterpretationSleep-disordered breathing is associated with worse functional and cognitive function at 90 days poststroke. These outcomes are reasonable endpoints for future trials of sleep-disordered breathing treatment in stroke. If effective, sleep-disordered breathing treatment may somewhat lessen ethnic stroke outcome disparities. ANN NEUROL 2019;86:241-250.

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Intranasal Leptin Prevents Opioid-induced Sleep-disordered Breathing in Obese Mice.

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