Respiratory depression (RD) is the primary cause of death due to
opioids.
Opioids bind to mu (µ)-
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-Bötzinger complex (preBötC) and the pontine Kölliker-Fuse nucleus (KF) contribute equally to OIRD but RD was not totally eliminated.
Morphine showed a differential influence on preBötC and KF neurons - low doses attenuated RD following deletion of MORs from preBötC neurons and an increase in
apneas after high doses whereas deletion of MORs from KF neurons but not the preBötC attenuated RD at both high and low doses. In other KO mice studies,
morphine administration after deletion of Oprm1 from both the preBötC and the KF/PBN neurons, led to the conclusion that both respiratory centres contribute to OIRD but the preBötC predominates. MOR-mediated post-synaptic activation of
GIRK potassium channels has been implicated as a cause of OIRD. A complementary mechanism in the preBötC 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 preBötC neurons.
Methadone, administered to alleviate symptoms of neonatal
opioid withdrawal syndrome (NOWES), desensitized rats to OIRD. Protection lost between postnatal days 1 and 2 coincides with the preBötC 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.