Current research in pathophysiology of opioid-induced respiratory depression, neonatal opioid withdrawal syndrome, and neonatal antidepressant exposure syndrome

Respiratory depression (RD) is the primary cause of death due to opioids. Opioids bind to mu (mu)-opioid receptors (MORs) encoded by the MOR gene Oprm1, widely expressed in the central and peripheral nervous systems including centers that modulate breathing. Respiratory centers are located throughout the brainstem. Experiments with Oprm1-deleted knockout (KO) mice undertaken to determine which sites are necessary for the induction of opioid-induced respiratory depression (OIRD) showed that the pre-Bo center dot tzinger complex (preBo center dot tC) and the pontine Ko center dot lliker-Fuse nucleus (KF) contribute equally to OIRD but RD was not totally eliminated. Morphine showed a differential influence on preBo center dot tC and KF neurons - low doses attenuated RD following deletion of MORs from preBo center dot tC neurons and an increase in apneas after high doses whereas deletion of MORs from KF neurons but not the preBo center dot tC attenuated RD at both high and low doses. In other KO mice studies, morphine administration after deletion of Oprm1 from both the preBo center dot tC and the KF/PBN neurons, led to the conclusion that both respiratory centres contribute to OIRD but the preBo center dot tC predominates. MOR-mediated post-synaptic activation of GIRK potassium channels has been implicated as a cause of OIRD. A complementary mechanism in the preBo center dot tC involving KCNQ potassium channels independent of MOR signaling has been described. Recent experiments in rats showing that morphine depresses normal, but not gasping breathing, cast doubt on the belief that eupnea, sighs, and gasps, are under the control of preBo center dot tC neurons. Methadone, administered to alleviate symptoms of neonatal opioid withdrawal syndrome (NOWS), desensitized rats to OIRD. Protection lost between postnatal days 1 and 2 coincides with the preBo center dot tC becoming the dominant generator of respiratory rhythm. Neonatal antidepressant exposure syndrome (NADES) and serotonin toxicity (ST) show similarities including RD. Enzyme CYP2D6 involved in opioid detoxification is polymorphic. Individuals of different CYP2D6 genotype may show increased, decreased, or no enzyme activity, contributing to the variability of patient responses to different opioids and OIRD.