Intranasal Leptin Prevents Opioid Induced Respiratory Depression in Obesity

Abstract

IntroductionNorth America is currently facing obesity and opioid epidemics. Respiratory depression is the main cause of morbidity and mortality from opioids. Obese individuals with Obstructive Sleep Apnea have a higher risk of opioid induced respiratory depression (OIRD). Leptin acts as respiratory stimulant augmenting control of breathing and improving upper airway patency. We have previously shown that obesity‐induced leptin resistance can be circumvented by intranasal administration of leptin. In this study, we aimed to examine if intranasal administration of leptin prevents OIRD.MethodsMale diet‐induced obese C57BL/6J mice (n=8) were instrumented with headmount containing EEG and EMG leads under 1–2% isoflurane anesthesia. After recovery period polysomnograms were performed in a crossover manner with 1 week interval between studies. Mice received intranasal (IN) leptin or vehicle (BSA) at 0.4 mg/kg and 30 minutes later received a bolus of intraperitoneal (IP) morphine at 10 mg/kg followed by implantation of a subcutaneous osmotic pump delivering morphine at 2 mg/kg/h for the duration of the study (11am–5pm). The control group received IN vehicle, IP saline and a sham osmotic pump filled with saline. Minute ventilation (VE) was recorded through sleep/wake states and upper airway obstruction was defined by the presence of inspiratory flow limitation (IFL). Apneas were scored when flow was absent for two or more respiratory cycles. Excitatory post‐synaptic currents (EPSCs) were recorded in‐vitro from hypoglossal motor neurons (HGNs) and changes in EPSC amplitude and frequency were examined following application of the μ opioid receptor agonist (DAMGO) and leptin.ResultsMorphine induced severe inspiratory flow limitation and apneas during NREM sleep. Morphine increased IFL breath frequency (from 12% to 57% of all breaths, p<0.001) and apneas (from 13.5±3.5/h to 91.5±20.0/h, p<0.01) and decreased maximal inspiratory flow (VImax) during IFL breaths (from 3.4±0.4 to 2.3±0.4 mL/s, p<0.05) and VE (from 1.1±0.1 to 0.7±0.2 mL/min/g, p<0.05). Leptin attenuated effects of morphine. IN Leptin decreased IFL breath frequency (from 57% to 45%, p<0.005) and reduced the number of apneas (from 91.5±20.0/h to 34.3±7.0/h, p<0.01). Leptin reduced the severity of upper airway obstruction increasing VImax (from 2.3±0.4 to 2.8±0.4, p<0.05) and minute ventilation (from 0.7±0.2 to 1.0±0.2, p<0.05) during IFL breathing. Furthermore, in vitro studies showed that administration of DAMGO reduced EPSC frequency (but not EPSC amplitude) in HGNs that was reversed by application of leptin.ConclusionMorphine caused respiratory suppression and upper airway obstruction during sleep in DIO mice and decreased EPSC frequency in HGNs. Leptin relieved morphine‐induced hypoventilation and Obstructive Sleep Apnea and reversed the opioid induced depression of excitatory synaptic neurotransmission to HGNs. We conclude that intranasal leptin may prevent OIRD in obesity.Support or Funding InformationR01HL 128970, R01HL 138932, FAPESP 2018/08758‐3