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

Abstract

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.

Keywords: AAV, adeno-associated virus; CDC, Centers for Disease control and prevention; CTAP, MOR agonist (D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2); DAMGO, synthetic specific MOR agonist [D-Ala2, N-MePhe4, Gly-ol]-enkephalin; DRG, dorsal respiratory group; FDA, Food and Drug Administration; GIRK, G protein-gated inwardly-rectifying potassium (K+); GPCR, G protein-coupled receptor; KCNQ, voltage-gated potassium (Kv) channels in the KCNQ (Kv7) family; KF, Kölliker-Fuse nucleus; Kölliker-Fuse nucleus and opioid-induced respiratory depression; MOR, mu opioid receptor; NADES, neonatal antidepressant exposure syndrome; NAS, neonatal abstinence syndrome; NIH, National Institutes of Health; NK-1R, neurokinin-1 receptor; NOWES, neonatal opioid withdrawal syndrome; Neonatal opioid withdrawal syndrome; Neural mediation of opioid-induced respiratory depression; OAD, opioid analgesic drug; OIRD, opioid-induced respiratory depression; PBL, lateral parabrachial; PBN, parabrachial nucleus; PRG, pontine respiratory group; Pathophysiology of opioid-induced respiratory depression; Pre-Bötzinger complex and opioid-induced respiratory depression; RD, respiratory depression; TACR1, tachykinin receptor 1; VRG, ventral respiratory group; preBötC, pre-Bötzinger complex.

Graphical abstract

Fig. 1

Changes to breathing in mice during OIRD induced by injection of morphine. (a) Breathing airflow (mL/sec) in normoxia (21% O₂, 0% CO₂) 15 min after injection of saline (black) or morphine (red). (b) Trace of the airflow from a single breath in hypercapnia after saline (black) and morphine (red) injection. Two phases, inspiration Ti and expiration Te, are seen after saline (black) whereas after morphine (red), airflow is markedly reduced and a pause, or third phase, is seen. (c) Shows the inspiration Ti, and expiration Te, time lengths. (d) Diagrammatic representation of morphine-induced change to a breath. The resultant decrease in respiratory rate is due to an extended inspiration time Ti and a pause phase which is extended to preserve tidal volume, TV. This results in breaths after morphine showing an approximately similar TV as seen with control breaths. Adapted from Bachmutsky I, Wei XP, Kish E et al (2020) Opioids depress breathing through two small brainstem sites. eLife 9:e52694 10.7554/eLife.52694, an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0).

Fig. 2

Plethysmography traces from breathing in mice (airflow in mL/sec) in hypercapnia after injection of saline or opioid into the preBötC before and after Oprm1 deletion. (a) and (b). Unlike saline, the effect on breathing by morphine was clearly depressive. (c) and (d). After Oprm1 deletion from the preBötC and Kölliker-Fuse/parabrachial nucleus (KF/PBN), breathing after morphine in mice subjected to double deletion appeared almost identical to breathing seen in control mice. (e) and (f). Traces from breathing of Oprm1^fl/fl floxed mice in normoxia after injection of a super-saturating dose of fentanyl (150 mg/kg) showing RD in Oprm1-positive floxed mice but a normal breathing pattern in mice after Oprm1 deletion from the preBötC and KF/PBN. Adapted from Bachmutsky I, Wei XP, Kish E et al (2020) Opioids depress breathing through two small brainstem sites. eLife 9:e52694 https://doi.org/10.7554/eLife.52694, an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0).

Fig. 3

Proposed speculative pathways in opioid-induced activation of the G-protein-coupled MOR triggering of (a) activation of GIRK channels and inhibition of voltage-gated Ca⁺⁺and cAMP pathways and (b) opioid-induced inhibition of respiratory circuits by opening of GIRK channels, inhibition of adenyl cyclase and recruitment of β-arrestin2. Shaded gray areas indicate pathways not known to be involved in opioid inhibition of the corresponding neuronal function. AMPA, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; βarr2, beta-arrestin2; Gα_i, G-protein α_i; Gβγ, G-protein βγ; GIRK, G-protein-gated inwardly rectifying potassium; RGS, regulators of G-protein signaling. Adapted from Montandon G, Slutsky AS. Solving the opioid crisis: Respiratory depression by opioids as critical endpoint. Chest 2019; 156: 653–8. Reproduced with permission from Elsevier.

Fig. 4

Inspiratory rhythmic bursts recorded in an in vitro model of DAMGO-induced OIRD in mouse preBötC slices in the presence or absence of GIRK and KCNQ potassium channel activators and blockers. Inspiratory bursts mimicking OIRD following increasing doses of the KCNQ-specific activators (a) ICA69673 and (b) retigabine. Rescue from DAMGO-induced OIRD with increasing doses of the KCNQ-specific blockers (c) chromanol 293B and (d) XE991. Failure to rescue DAMGO-induced OIRD with increasing doses of the GIRK-specific blocker tertiapin-Q (e) and failure to mimic OIRD with increasing doses of the GIRK-specific activator ML297 (f). RTG, retigabine; TPQ, tertiapin-Q. From Wei AD, Ramirez J-M. Presynaptic mechanisms and KCNQ potassium channels modulate opioid depression of respiratory drive. Front. Physiol. 2019; 10: 1407. https://doi.org/10.3389/fphys.2019.01407, an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0).

Fig. 5

Responses to transient anoxia during autoresuscitation in a pentobarbital anesthetized rat preinjected with a clinically-relevant dose of morphine (3 mg/kg) showing respiratory flow, FCO₂ fraction, and arterial blood pressure waveforms. Left to right shows resting breathing in normal air (marked ‘eupnea’), followed by breathing anoxic air (100% nitrogen) during phase marked ‘anoxia’. Access to room air was restored at the onset of respiratory arrest. Eupnea, restored by gasping, was followed by a brief secondary apnea before the return of full eupneic breathing. During autoresuscitation, a profound cardiovascular response in the form of a marked fall in blood pressure occurred. Adapted and reproduced from Shoemaker, A., Steelman, K., Srbu, R., Bell, H.J., 2020. Disparity in the effect of morphine on eupnea and gasping in anesthetized spontaneous breathing adult rats. Am. J. Physiol. Regul. Integr. Comp. Physiol. 319, R526-540, with permission from the American Physiological Society.

Fig. 6

Maternal methadone (MM) desensitizes neonatal rats at postnatal (P) days P0 and P1 to methadone-induced respiratory depression. Ventilation was measured from P0 to P5 using whole body plethysmography. Hypoxic ventilatory responses were measured in neonates 1 h after injection of methadone 1 mg/kg i.p. At P0 and P1, frequency of methadone-induced RD and tidal volume were blunted compared to MN (maternal no injection) and MS (maternal saline injection) and MM neonates at P2 also showed blunted RD frequency compared to MN at 40 min. Maternal methadone dosage MM, black circles; maternal no treatment MN, black squares; maternal saline dosage MS, gray triangles. P, postnatal day number. *MM p < 0.05 from MN; †MM p < 0.05 from MS. Adapted and reproduced from Hocker AD, Morrison NR, Selby ML et al (2021) Maternal methadone destabilizes neonatal breathing and desensitizes neonates to opioid-induced respiratory frequency depression. Front Physiol 12:604593. https://doi.org/10.3389/fphys.2021.604593, an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY).

Fig. 7

Diagrammatic representation of raised intrasynaptic concentrations of serotonin (5-hydroxytryptamine, 5-HT) and inhibition of reuptake of 5-HT by different serotonergic drugs. Serotonin, packaged into vesicles, is released by Ca++-dependent exocytosis into the synapse where it diffuses to its receptors on the post-synaptic neuron. Reuptake of the neurotransmitter into pre-synaptic nerve terminals is effected by serotonin transporter (SERT) which ensures and maintains low 5-HT plasma levels and is important for the rapid reuptake of the neurotransmitter into pre-synaptic nerve terminals. Opioids, in particular, tramadol, dextromethorphan, pethidine, methadone, and tapentadol (but generally not morphine and other phenanthrenes), SRIs, and other serotonergic agents inhibit reuptake of serotonin by inhibiting SERT, thus increasing plasma and synaptic cleft serotonin concentrations available to bind and activate the post-synaptic 5-HT receptors. In the pre-synaptic neuron, serotonin is metabolized by monoamine oxidase (MAO) to 5-hydroxyindoleacetic acid (5-HIAA). Reproduced from Baldo, BA., Rose, MA., 2020. The anaesthetist, opioid analgesic drugs, and serotonin toxicity: a mechanistic and clinical review. Br. J. Anaesth. 124, 44–62, with permission from Elsevier,