Neural basis of opioid-induced respiratory depression and its rescue

Abstract

Opioid-induced respiratory depression (OIRD) causes death following an opioid overdose, yet the neurobiological mechanisms of this process are not well understood. Here, we show that neurons within the lateral parabrachial nucleus that express the µ-opioid receptor (PBLOprm1 neurons) are involved in OIRD pathogenesis. PBLOprm1 neuronal activity is tightly correlated with respiratory rate, and this correlation is abolished following morphine injection. Chemogenetic inactivation of PBLOprm1 neurons mimics OIRD in mice, whereas their chemogenetic activation following morphine injection rescues respiratory rhythms to baseline levels. We identified several excitatory G protein–coupled receptors expressed by PBLOprm1 neurons and show that agonists for these receptors restore breathing rates in mice experiencing OIRD. Thus, PBLOprm1 neurons are critical for OIRD pathogenesis, providing a promising therapeutic target for treating OIRD in patients.

Convergent, functionally independent signaling by mu and delta opioid receptors in hippocampal parvalbumin interneurons

“…In LC, reducing available surface MORs with a covalent antagonist leads to a reduction not only in the amplitude of MOR-mediated currents, but also a slowing of activation kinetics ( Williams, 2014 ). To test this hypothesis, we virally overexpressed human MOR (hMOR) with an mCherry tag in Pvalb Cre mice and probed the resulting enhanced MOR signaling with CYLE in TIPP-Psi ( Liu et al, 2021 ; Figure 4H1 ). As predicted, hMOR overexpression enhanced both the magnitude (57.5 ± 7.8 pA, n = 8 cells, p < 0.0001, unpaired t-test) and the kinetics (421.8 ± 68.7 ms, n = 8 cells, p = 0.0052, unpaired t-test) of the MOR-mediated current evoked with a strong light flash in comparison to those recorded from Pvalb Cre / Rosa26-lsl-tdTomato mice ( Figure 4I–K ).…”

Molecular ontology of the parabrachial nucleus

“…Most injection sites and implants were larger than most PB subpopulations, which intermingle extensively, so these approaches simultaneously targeted subsets of PB neurons with distinct connections and functions. Now, genetic methods allow investigators to target more specific subpopulations, including an overlapping potpourri of neurons that express Satb2, Calca , Pdyn, Cck , Oxtr1 , Htr2c , Oprm1 , or Tacr1 (Barik et al., 2021; Chiang et al., 2020; Fu et al., 2019; Garfield et al., 2014; Jarvie et al., 2021; Kaur et al., 2017; Liu et al., 2021; Norris et al., 2021; Palmiter, 2018; Park et al., 2020; Ryan et al., 2017; Yang et al., 2020). Limiting the immense potential of this approach were the lack of a framework for understanding ontological relationships between subpopulations and a lack of markers for remaining PB neurons.…”

Nucleus Tractus Solitarius Neurons Activated by Hypercapnia and Hypoxia Lack Mu Opioid Receptor Expression

“…Since Oprm1 Cre/tdT mice lose a functional copy of MOR (Liu et al, 2021 ), it was important to determine if morphine is still effective in these mice. In Oprm1 Cre/tdT mice, morphine (30 mg/kg) did cause respiratory depression compared to saline-treated controls ( n = 4/group).…”

“…All experiments were approved by the Institutional Animal Care and Use Committee at the University of Florida and were in agreement with the National Institutes of Health “Guide for the Care and Use of Laboratory Animals.” Homozygous Oprm1 Cre/Cre mice (Liu et al, 2021 ) (Jackson Labs Stock #035574) were crossed with homozygous Ai9-tdTomato Cre reporter mice (Jackson Labs Stock #007909) to generate Oprm1 Cre/tdT mice. Oprm1 Cre/tdT mice (male and female, 2–6 months old) and wild-type C57BL/6J mice (male and female, 2–7 months old) were used for all experiments.…”