Finding inspiration in opioid‐induced respiratory depression

Opioids are a class of psychoactive drugs that serve like a double-edged sword. While they are effective analgesic agents, the opioids’ highly addictive nature enhances the likelihood for abuse. In the USA alone, nearly 1.7 million people suffer from substance use disorders related to prescription opioids and are therefore at an increased risk for opioid overdose. Despite this risk, far less progress has been made towards understanding the physiological basis for the hallmark of opioid overdose, respiratory depression, as compared to the physiology underlying opioid-based analgesia and addiction. While it is well-accepted that opioids act centrally through μ-opioid receptors (MORs) to cause respiratory depression, these receptors are widely distributed throughout neural networks largely responsible for the central control of breathing. For example, MORs are expressed in both the preBötzinger complex, the putative site of inspiratory rhythmogenesis (Smith et al. 1991), and the Kölliker–Fuse nucleus, a key network involved with regulating the eupnoeic pattern (St-John & Paton, 2004). The synaptic interconnectivity throughout the respiratory network creates a significant problem for delineating the individual role of these two areas in opioid-related respiratory depression. In this issue of The Journal of Physiology, Varga et al. (2020) reveal a significant dose-dependent distinction in the role for the Kolliker–Fuse nucleus and the preBötzinger complex leading to respiratory depression. Employing a viral strategy to target genetic ablation of MORs in the preBötzinger complex and the Kölliker–Fuse nucleus of mice, Levitt and colleagues assess how loss of MORs from each network influences opioid-induced respiratory disturbances. At clinically relevant analgesic doses of morphine, genetic deletion of MORs in either the preBötzinger complex or the Kölliker–Fuse nucleus lessens respiratory depression. However, at a larger dose of morphine, which is associated with overdose, a fundamentally different picture emerges. While deletion of MORs from the Kölliker–Fuse nucleus attenuates respiratory rate depression by morphine, respiratory depression and ataxic breathing emerges with targeted ablation of MORs from the preBötzinger complex. These findings elegantly demonstrate that at high doses of morphine, activation of the Kölliker–Fuse nucleus is critically important during opioid-mediated respiratory depression, as it can provide a drive to maintain breathing when no longer vulnerable to morphine. The unexpected respiratory instability caused by a high dose of morphine when MORs are eliminated from the preBötzinger complex highlights the need for a greater understanding in the orchestration of the control of breathing by neuromodulation. Despite the extensive knowledge of the impact of neuromodulation on the inspiratory network (Doi & Ramirez, 2008), the potential for neuromodulation to interact with inhibitory drive involved in the regulation of breathing is much less appreciated. Opioid neuromodulation outside of the preBötzinger complex appears to cause an imbalance between excitation and inhibition of the inspiratory network causing ataxic breathing to emerge. Indeed, the balance between inhibition and excitation in the inspiratory network appears critical to the stability and flexibility of breathing (Harris et al. 2017). Furthermore, future studies are also needed to further resolve how opioid neuromodulation influences the respiratory pattern versus the basis of rhythmogenesis. Thus, while the work by Varga and coworkers bring greater clarity to understanding the physiological basis for opioid-induced respiratory depression, their work also serves as a source of inspiration for future studies aimed at unravelling the mechanisms and consequences of site-specific neuromodulation in the control of breathing. None declared. Both authors have read and approved the final version of this manuscript and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All persons designated as authors qualify for authorship, and all those who qualify for authorship are listed. This work was supported by NIH PO 1 HL 144454, and NIH R01 NS10742101 awarded to AJG. CS was also supported by NIH T32DA043469.