The Role of OPRM1 in the Neonatal Autoresuscitation Reflex and Sudden Infant Death Syndrome

Opioid receptors are widely expressed throughout the brain and integral in nociception as well as homeostatic regulation of autonomic processes including respiration through modulation of respiratory rhythmogenesis and chemosensory responses. Perturbations to homeostatic mu opioid receptor (MOR) signaling via opiate overdose results in respiratory depression, aberrant breathing, and often death. With the rise of opioid use over the last two decades, many infants are being diagnosed with Neonatal Abstinence Syndrome (NAS), a congenital cardio-respiratory disorder resulting from prenatal exposure to opioids. Infants born with NAS have a fourfold increased risk for Sudden Infant Death Syndrome (SIDS). SIDS and related Sudden Unexpected Infant Death takes the lives of approximately 3,400 infants annually under the age of one and its etiology remains mostly unknown. Currently SIDS is explained via the triple risk model that proposes that SIDS occurs in a vulnerable infant during a critical developmental period when triggered by an external stressor, converging on the failure of the neonate autoresuscitation reflex in most cases. Recently a study identified an association between a mutation in the OPRM1 gene encoding MORs and SIDS cases. However, how this gene and perturbations in its native function modulates respiratory regulation are poorly understood. We hypothesize that native OPRM1 function is integral to protective neonate respiratory reflexes and that perturbation of native OPRM1 signaling negatively affects the neonatal autoresuscitation reflex. Male and female OPRM1 loss of function mice were assayed for their autoresuscitation reflex on our novel testbed, Looper. Mice were exposed to repeated bouts of anoxia and allowed to autoresuscitate until death occurred. Preliminary data suggest that loss of OPRM1 function results in a higher mortality rate on the autoresuscitation assay with OPRM1 KO mice surviving significantly less anoxic challenges compared to wild type controls. No sex differences were observed between male and female survival for all genotype groups. Results indicate that perturbation of the native function of OPRM1 produces a vulnerability to autoresuscitation dysfunction and mitigated survival. Our data demonstrate the first functional assessment of OPRM1 in neonatal cardiovascular function and autoresuscitation and reveal an important risk factor that may be implicated in perpetuating SIDS and NAS phenotypes. Additional analyses of distinct parameters from respiratory trace data for OPRM1 loss of function mice will aid in a deeper, mechanistic understanding of features implicated in autoresuscitation dysfunction. Future studies aim to characterize specific splice variants of OPRM1, known to produce neomorphic function and model the SIDS associated VUS, to further characterize the implication of OPRM1 and its variants in congenital respiratory diseases. Funding sources NIH/NHLBI R01HLN161142-01 and R01HL130249-07. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.