Loss of OPRM1 produces sex-specific vulnerabilities in dysfunction of the neonatal autoresuscitation reflex and cardiorespiratory function

Opioid receptors are critical for the homeostatic regulation of autonomic processes wherein modulation of mu-opioid receptors (MORs) or their signaling result in dysregulated homeostatic autonomic function, which can lead to respiratory depression and death. Opioid use over the last few decades has significantly increased, resulting in a concomitant increase in infants pre-exposed to exogenous opioids during fetal development and diagnoses of Neonatal Opioid Withdrawal Syndrome (NOWS), a congenital exposure disorder characterized by cardiorespiratory dysfunction. Infants diagnosed with NOWS have a fourfold increased risk for Sudden Infant Death Syndrome (SIDS), the leading cause of infant death with unknown etiology. Postmortem genetic studies aimed at identifying the cause of death have identified several potential targets for intervention. Specifically, the Klintschar lab identified an association between a mutation in the OPRM1 gene encoding MORs and SIDS cases. However, it is difficult to understand the implications of this mutation because the role of OPRM1 perturbation in native signaling and subsequent physiological effects on the cardiorespiratory system are understudied. A prominent hypothesis in the field proposes that a SIDS outcome results when an intrinsic vulnerability is stressed by an external factor during a critical developmental period, with many cases predicted to result from the failure of the neonate autoresuscitation reflex. We hypothesize that native OPRM1 function is essential for the autoresuscitation reflex and that perturbations result in the dysfunction of this reflex. Male and female OPRM1 loss of function mice were assayed for their autoresuscitation reflex on our novel automated phenotyping pipeline, Looper, where mice were exposed to repeated bouts of anoxia followed by a recovery period where the animal is forced to autoresuscitate. This cycle is repeated until autoresuscitation is not successful. Data reveal sex-specific cardiorespiratory dysfunction and alterations in gasping dynamics following anoxic challenges in a subset of OPRM1 -/- and OPRM1 +/- mice. These dynamics may underlie a higher mortality rate in these mice than in OPRM1 +/+ sibling controls. Our results demonstrate the first functional assessment of OPRM1 in neonatal cardiorespiratory function and autoresuscitation, revealing an important risk factor that may be implicated in perpetuating SIDS and NOWS phenotypes. Future studies aim to characterize specific splice variants of OPRM1 known to produce neomorphic variants and to model the SIDS-associated variant of unknown significance identified by Klintschar. We will also assess the physiological effects of prenatal exposure to opioids during development to further characterize the implication of OPRM1 activation in congenital cardiorespiratory diseases. Funding sources NIH/NHLBI NRSA 1F32HL170536-01A1, NIH/NHLBI R01HLN161142-01, and R01HL130249-07. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.