Solving the Opioid Crisis: Respiratory Depression by Opioids as Critical End Point

Abstract

Opioid overdose is caused by misuse of prescription pain killers, such as oxycodone, and misuse of street drugs, such as heroin or fentanyl. Opioid overdoses are responsible for the deaths of > 50,000 persons annually in North America. Opioid drugs are highly addictive and can lead to respiratory depression and death. Although opioid addiction is a critical health issue, the morbidity and mortality associated with opioid overdoses are caused by their respiratory depressant side effects, and not addiction per se. Even though respiratory depression and complete respiratory arrest are the major causes of mortality with opioid overdose, there is currently a serious knowledge gap in our understanding of the underlying mechanisms of opioid pain relief and respiratory depression by opioids, and how these mechanisms differ from each other. We propose that there should be a greater research focus on these mechanisms to help develop safer opioid pain therapies with reduced respiratory side effects. Here we provide a brief overview of the current research investigating the neural and molecular mechanisms underlying opioid-induced respiratory depression and analgesia. We focus our attention on the neural circuits of analgesia and respiratory depression, and the molecular pathways regulating opioid inhibition. We highlight the challenges in identifying distinct mechanisms that could be targeted to reduce respiratory depression without altering opioid analgesia. In conclusion, a better understanding of the underlying mechanisms linking pain relief with control of breathing is essential to identify pain therapies with minimal or no respiratory side effects. The current North American opioid epidemic is staggering, accounting for millions of emergency visits every year and > 50,000 overdose deaths annually.1Wilkerson R.G. Kim H.K. Windsor T.A. Mareiniss D.P. The opioid epidemic in the United States.Emerg Medicine Clin North Am. 2016; 34: e1-e23Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar Opioid drugs, whether they are synthetic opioids, such as fentanyl or oxycodone, or natural opioids, such as heroin and morphine, are highly addictive and can lead to respiratory depression2Nagappa M, Weingarten T.N. Montandon G. Sprung J. Chung F. Opioids, respiratory depression, and sleep-disordered breathing.Best Pract Res Clin Anaesthesiol. 2017; 31: 469-485Crossref PubMed Scopus (26) Google Scholar, 3Montandon G. Cushing S.L. Campbell F. Propst E.J. Horner R.L. Narang I. Distinct cortical signatures associated with sedation and respiratory rate depression by morphine in a pediatric population.Anesthesiology. 2016; 125: 889-903Crossref PubMed Scopus (19) Google Scholar and death. Opioid overdose is caused by misuse of prescription pain killers and misuse of street drugs such as heroin or fentanyl.4Gutstein H.B. Opioid analgesics.in: Goodman and Gilman’s the Pharmacological Basis for Therapeutics. Vol 10. McGraw-Hill, New York, NY2001: 569-618Google Scholar Opioids are still widely prescribed because of their potent analgesic properties. According to the International Association for the Study of Pain “opioids are indispensable for the treatment of severe short-lived pain, and there are currently no other oral medications that offer immediate and effective relief of severe pain.”5IASP Statement on Opioids. https://www.iasp-pain.org/Advocacy/. Accessed July 10, 2019.Google Scholar The National Institutes of Health (NIH) has initiated the Helping to End Addiction Over the Long-term program.6Collins F.S. Koroshetz W.J. Volkow N.D. Helping to End Addiction Over the Long-term: the research plan for the NIH HEAL initiative.JAMA. 2018; 320: 129-130Crossref PubMed Scopus (84) Google Scholar The main focus of this program is to support science that addresses addiction. This program is important, but since 2000, the number of deaths from opioids has increased three times faster than the increase in the number of individuals who have become addicted (data from the Centers for Disease Control and Prevention WONDER database). A major reason for this increase in mortality has been the appearance of highly potent synthetic opioids, such as oxycodone and fentanyl, which increased opioid-induced death because of respiratory arrest, but did not markedly increase the number of opioid-addicted individuals. Although there have been many approaches to tackle the opioid epidemic, including addressing opioid addiction, increasing the availability of overdose-reversing medications, strengthening public health reporting, and enhancing pain management, we propose that there should be a much greater research focus on developing safer opioid pain therapies with reduced respiratory side effects. We think a better understanding of the underlying mechanisms linking pain relief with control of breathing is essential to achieve this goal. According to the NIH Research Portfolio Online Reporting Tools, the NIH is currently funding $188 million in grants to study opioids, but only $2 million is directly dedicated to research programs focused on increasing our understanding of respiratory depression by opioids, highlighting the paucity of research in this discipline. Opioid medications act on mu, delta, and kappa opioid receptors,4Gutstein H.B. Opioid analgesics.in: Goodman and Gilman’s the Pharmacological Basis for Therapeutics. Vol 10. McGraw-Hill, New York, NY2001: 569-618Google Scholar which are expressed in discrete brain circuits. Although a wide range of opioids targeting these opioid receptors exist, the most potent opioid drugs, such as fentanyl and oxycodone, are largely selective for the mu opioid receptors. Because mu opioid receptors are expressed in neural circuits involved in several functions, including breathing, nociception, and arousal, opioids present effects beyond their intended therapeutic analgesic properties. Drugs with high potency for the mu opioid receptors induce side effects such as constipation, drowsiness, addiction, sedation,3Montandon G. Cushing S.L. Campbell F. Propst E.J. Horner R.L. Narang I. Distinct cortical signatures associated with sedation and respiratory rate depression by morphine in a pediatric population.Anesthesiology. 2016; 125: 889-903Crossref PubMed Scopus (19) Google Scholar and hypoventilation.2Nagappa M, Weingarten T.N. Montandon G. Sprung J. Chung F. Opioids, respiratory depression, and sleep-disordered breathing.Best Pract Res Clin Anaesthesiol. 2017; 31: 469-485Crossref PubMed Scopus (26) Google Scholar Hypoventilation induced by opioids is characterized by reduced respiratory rate, reduced airflow, increased sleep apnea,2Nagappa M, Weingarten T.N. Montandon G. Sprung J. Chung F. Opioids, respiratory depression, and sleep-disordered breathing.Best Pract Res Clin Anaesthesiol. 2017; 31: 469-485Crossref PubMed Scopus (26) Google Scholar and severe hypoxemia. Respiratory arrest and subsequent bradycardia is the main cause of death by opioid overdose.7van der Schier R. Roozekrans M. van Velzen M. Dahan A. Niesters M. Opioid-induced respiratory depression: reversal by non-opioid drugs.F1000Prime Rep. 2014; 6: 79Crossref PubMed Scopus (54) Google Scholar To develop safe opioid pain therapies, it is critical to identify the neural and molecular mechanisms regulating opioid-induced respiratory depression, and how they differ from the mechanisms that regulate analgesia. Activation of mu opioid receptors produces potent analgesia because of their effects on nociceptive pathways (Fig 1). Opioids inhibit ascending nociceptive circuits and enhance descending inhibition of nociceptive inputs.8Heinricher M.M. Tavares I. Leith J.L. Lumb B.M. Descending control of nociception: specificity, recruitment and plasticity.Brain Res Rev. 2009; 60: 214-225Crossref PubMed Scopus (590) Google Scholar The midbrain periaqueductal gray, and its descending projections to the rostral ventromedial medulla and spinal cord, forms an essential neural circuit for opioid-mediated analgesia. By binding to mu opioid receptors in the periaqueductal gray and/or the rostroventral medulla,8Heinricher M.M. Tavares I. Leith J.L. Lumb B.M. Descending control of nociception: specificity, recruitment and plasticity.Brain Res Rev. 2009; 60: 214-225Crossref PubMed Scopus (590) Google Scholar opioids disinhibit GABAergic circuits, which leads to reduced nociception in the spinal cord. In addition to these subcortical areas, opioids also inhibit the ventrolateral prefrontal cortex and the anterior cingular cortex, two cortical areas involved in volitional control of breathing.9Pattinson K.T. Governo R.J. MacIntosh B.J. et al.Opioids depress cortical centers responsible for the volitional control of respiration.J Neurosci. 2009; 29: 8177-8186Crossref PubMed Scopus (116) Google Scholar Respiratory depression by opioids is regulated by parallel, often overlapping, neural circuits, composed of discrete populations of midbrain and brainstem neurons regulating breathing. Several key brainstem centers (Fig 1) are sensitive to opioid ligands and can potentially depress breathing, depending on the dosage, type of opioid drugs, and species studied. Opioid inhibition of the pre-Bötzinger complex,10Montandon G. Qin W. Liu H. Ren J. Greer J.J. Horner R.L. PreBotzinger complex neurokinin-1 receptor-expressing neurons mediate opioid-induced respiratory depression.J Neurosci. 2011; 31: 1292-1301Crossref PubMed Scopus (113) Google Scholar the medullary raphe,11Zhang Z. Xu F. Zhang C. Liang X. Activation of opioid mu receptors in caudal medullary raphe region inhibits the ventilatory response to hypercapnia in anesthetized rats.Anesthesiology. 2007; 107: 288-297Crossref PubMed Scopus (55) Google Scholar the Kolliker-Fuse,12Levitt E.S. Abdala A.P. Paton J.F. Bissonnette J.M. Williams J.T. μ opioid receptor activation hyperpolarizes respiratory-controlling Kolliker-Fuse neurons and suppresses post-inspiratory drive.J Physiol. 2015; 593: 4453-4469Crossref PubMed Scopus (58) Google Scholar and the parabrachial nucleus13Miller J.R. Zuperku E.J. Stuth E.A.E. Banerjee A. Hopp F.A. Stucke A.G. A subregion of the parabrachial nucleus partially mediates respiratory rate depression from intravenous remifentanil in young and adult rabbits.Anesthesiology. 2017; 127: 502-514Crossref PubMed Scopus (22) Google Scholar can contribute to respiratory depression by opioid ligands, but their precise contributions need to be clarified.14Montandon G. Horner R. CrossTalk proposal: the preBotzinger complex is essential for the respiratory depression following systemic administration of opioid analgesics.J Physiol. 2014; 592: 1159-1162Crossref PubMed Scopus (38) Google Scholar The roles of the neural circuits regulating breathing in respiratory depression is even more complex, considering that opioids may inhibit circuits that can indirectly modulate breathing. For instance, opioids acting in the anterior cingular cortex and the periaqueductal gray affect volitional activation or inhibition of respiratory circuits,9Pattinson K.T. Governo R.J. MacIntosh B.J. et al.Opioids depress cortical centers responsible for the volitional control of respiration.J Neurosci. 2009; 29: 8177-8186Crossref PubMed Scopus (116) Google Scholar and can therefore modulate respiratory muscle activity—and can even stop it. Overall, these subcortical and brainstem circuits play significant roles in respiratory depression,14Montandon G. Horner R. CrossTalk proposal: the preBotzinger complex is essential for the respiratory depression following systemic administration of opioid analgesics.J Physiol. 2014; 592: 1159-1162Crossref PubMed Scopus (38) Google Scholar but some of those circuits are also involved in analgesia. Indeed, the anterior cingular cortex, the periaqueductal gray, and the rostral ventromedial medulla express mu opioid receptors and are involved in breathing and nociception; therefore, their separation may prove to be challenging. However, some key cell populations in the brain, such as the pre-Bötzinger complex10Montandon G. Qin W. Liu H. Ren J. Greer J.J. Horner R.L. PreBotzinger complex neurokinin-1 receptor-expressing neurons mediate opioid-induced respiratory depression.J Neurosci. 2011; 31: 1292-1301Crossref PubMed Scopus (113) Google Scholar, 15Manzke T. Guenther U. Ponimaskin E.G. et al.5-HT4(a) receptors avert opioid-induced breathing depression without loss of analgesia.Science. 2003; 301: 226-229Crossref PubMed Scopus (218) Google Scholar and the medullary raphe,11Zhang Z. Xu F. Zhang C. Liang X. Activation of opioid mu receptors in caudal medullary raphe region inhibits the ventilatory response to hypercapnia in anesthetized rats.Anesthesiology. 2007; 107: 288-297Crossref PubMed Scopus (55) Google Scholar are not involved in nociceptive descending pathways and could be potential targets to prevent respiratory depression without affecting analgesia.15Manzke T. Guenther U. Ponimaskin E.G. et al.5-HT4(a) receptors avert opioid-induced breathing depression without loss of analgesia.Science. 2003; 301: 226-229Crossref PubMed Scopus (218) Google Scholar, 16Ren J. Poon B.Y. Tang Y. Funk G.D. Greer J.J. Ampakines alleviate respiratory depression in rats.Am J Respir Crit Care Med. 2006; 174: 1384-1391Crossref PubMed Scopus (75) Google Scholar Most opioid drugs inhibit neuronal activity via mu opioid receptors through three canonical pathways. Activation of mu opioid receptors activates G-protein-gated inwardly rectifying potassium (GIRK) channels,17Marker C.L. Stoffel M. Wickman K. Spinal G-protein-gated K+ channels formed by GIRK1 and GIRK2 subunits modulate thermal nociception and contribute to morphine analgesia.J Neurosci. 2004; 24: 2806-2812Crossref PubMed Scopus (110) Google Scholar inhibits N-type calcium channels, and/or inhibits adenylyl cyclase/cAMP (Fig 2A). Inhibition of respiratory circuits by opioids opens GIRK channels18Montandon G. Ren J. Victoria N.C. et al.G-protein-gated inwardly rectifying potassium channels modulate respiratory depression by opioids.Anesthesiology. 2016; 124: 641-650Crossref PubMed Scopus (62) Google Scholar and inhibits the adenylyl cyclase/cAMP pathway (Fig 2C). Such inhibition is regulated by beta-arrestins,19Raehal K.M. Walker J.K. Bohn L.M. Morphine side effects in beta-arrestin 2 knockout mice.J Pharmacol Exp Ther. 2005; 314: 1195-1201Crossref PubMed Scopus (397) Google Scholar which hinder G-protein interaction (Fig 2B). In beta-arrestin-2 knockout mice, opioid analgesia is enhanced, which is consistent with reduced desensitization of mu opioid receptors in the absence of beta-arrestin-2.20Bohn L.M. Lefkowitz R.J. Gainetdinov R.R. Peppel K. Caron M.G. Lin F.T. Enhanced morphine analgesia in mice lacking beta-arrestin 2.Science. 1999; 286: 2495-2498Crossref PubMed Scopus (741) Google Scholar Surprisingly, respiratory depression by opioids was reduced in these mice,19Raehal K.M. Walker J.K. Bohn L.M. Morphine side effects in beta-arrestin 2 knockout mice.J Pharmacol Exp Ther. 2005; 314: 1195-1201Crossref PubMed Scopus (397) Google Scholar which suggests that either mu opioid receptor inhibition of respiratory circuits involved molecular pathways independent of G-proteins (Fig 2C) or that compensatory mechanisms take place in these animals. However, a recent study demonstrated that knock-in mice with a series of mutations that render the mu opioid receptors unable to recruit beta-arrestin did not impact respiratory depression by opioids, strongly suggesting that beta-arrestin does not contribute to the severity of opioid respiratory side effects.21Kliewer A. Schmiedel F. Sianati S. et al.Phosphorylation-deficient G-protein-biased mu-opioid receptors improve analgesia and diminish tolerance but worsen opioid side effects.Nat Commun. 2019; 10: 367Crossref PubMed Scopus (115) Google Scholar Interestingly, activation of mu opioid receptors in nociceptive circuits also triggers GIRK channels17Marker C.L. Stoffel M. Wickman K. Spinal G-protein-gated K+ channels formed by GIRK1 and GIRK2 subunits modulate thermal nociception and contribute to morphine analgesia.J Neurosci. 2004; 24: 2806-2812Crossref PubMed Scopus (110) Google Scholar and inhibits calcium channels4Gutstein H.B. Opioid analgesics.in: Goodman and Gilman’s the Pharmacological Basis for Therapeutics. Vol 10. McGraw-Hill, New York, NY2001: 569-618Google Scholar to produce analgesia (Fig 2D). Considering that pain and respiratory circuits often overlap, and that analgesia and respiratory depression share similar molecular mechanisms, the identification of distinct and separate molecular targets inducing analgesia without affecting breathing is difficult. Therefore, what are the potential strategies to develop opioid pain medications without respiratory side effects? Although directly antagonizing the binding of opioid drugs to mu opioid receptors with the selective antagonist naloxone is highly effective at reversing the hazardous effects of opioids, it is not a viable preventive strategy because it eliminates opioid analgesia and has a short half-life compared with potent analgesics such as fentanyl. However, there are several strategies currently in development that could prevent and reduce opioid side effects. The concept of biased agonism suggests that some opioid ligands act preferentially through the G-protein pathway, with low beta-arrestin recruitment. As such, new opioid ligands called biased mu opioid receptor ligands have been developed. Theoretically, opioid biased ligands would produce potent analgesia without respiratory depression by taking advantage of the differential effects of beta-arrestin on analgesia and respiratory depression. In some studies, these biased opioid ligands showed enhanced analgesia, but reduced respiratory side effects (Fig 2D).22Manglik A. Lin H. Aryal D.K. et al.Structure-based discovery of opioid analgesics with reduced side effects.Nature. 2016; 537: 185-190Crossref PubMed Scopus (513) Google Scholar, 23DeWire S.M. Yamashita D.S. Rominger D.H. et al.A G protein-biased ligand at the mu-opioid receptor is potently analgesic with reduced gastrointestinal and respiratory dysfunction compared with morphine.J Pharmacol Exp Ther. 2013; 344: 708-717Crossref PubMed Scopus (395) Google Scholar PZM21, a relatively new biased opioid agonist, was thought to have enhanced analgesic effects along with reduced respiratory side effects.22Manglik A. Lin H. Aryal D.K. et al.Structure-based discovery of opioid analgesics with reduced side effects.Nature. 2016; 537: 185-190Crossref PubMed Scopus (513) Google Scholar However, PZM21 was tested by another group and was found to cause significant respiratory depression,24Hill R. Disney A. Conibear A. et al.The novel mu-opioid receptor agonist PZM21 depresses respiration and induces tolerance to antinociception.Br J Pharmacol. 2018; 175: 2653-2661Crossref PubMed Scopus (101) Google Scholar which is consistent with recent studies showing that beta-arrestin may not be involved in opioid-induced respiratory depression.21Kliewer A. Schmiedel F. Sianati S. et al.Phosphorylation-deficient G-protein-biased mu-opioid receptors improve analgesia and diminish tolerance but worsen opioid side effects.Nat Commun. 2019; 10: 367Crossref PubMed Scopus (115) Google Scholar Although the concept of biased opioid ligands is promising, the rationale for developing these ligands may be flawed because the underlying rationale as to how low beta-arrestin-2 recruitment would lead to reduced respiratory depression while maintaining potent analgesia may be incorrect. Indeed, the direct effects of biased opioid ligands onto respiratory circuits regulating respiratory depression have not been tested, and it is plausible that beta-arrestin does not act on respiratory circuits but rather on other brain circuits indirectly regulating breathing. For instance, opioid inhibition of brain regions involved in arousal10Montandon G. Qin W. Liu H. Ren J. Greer J.J. Horner R.L. PreBotzinger complex neurokinin-1 receptor-expressing neurons mediate opioid-induced respiratory depression.J Neurosci. 2011; 31: 1292-1301Crossref PubMed Scopus (113) Google Scholar and their subsequent sedative effects may aggravate respiratory depression,3Montandon G. Cushing S.L. Campbell F. Propst E.J. Horner R.L. Narang I. Distinct cortical signatures associated with sedation and respiratory rate depression by morphine in a pediatric population.Anesthesiology. 2016; 125: 889-903Crossref PubMed Scopus (19) Google Scholar and may be responsible of the differential effects of biased ligands vs traditional opioids. In other words, are opioid biased ligands different from partial opioid ligands? For instance, mixed opioid and nonclassical nociception/orphanin FQ receptor agonists such as cebranopadol also have analgesic properties—with minimal side effects—for certain types of pain,25Calo G. Lambert D.G. Nociceptin/orphanin FQ receptor ligands and translational challenges: focus on cebranopadol as an innovative analgesic.Br J Anaesth. 2018; 121: 1105-1114Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar and may provide effective and safe analgesia. A second approach by which it may be possible to develop opioid analgesics with minimal respiratory impact would be to identify whether inhibition of respiratory circuits by mu opioid receptors involves distinct molecular pathways from those regulating analgesia. By targeting and potentially antagonizing these mechanisms, respiratory depression could be prevented without compromising analgesia. In principle, GIRK channels may be potential targets because they are involved in respiratory depression (Fig 2C).18Montandon G. Ren J. Victoria N.C. et al.G-protein-gated inwardly rectifying potassium channels modulate respiratory depression by opioids.Anesthesiology. 2016; 124: 641-650Crossref PubMed Scopus (62) Google Scholar Blocking GIRK channels can prevent respiratory depression, but the lack of drug compounds to specifically inhibit GIRK channel subunits, and the fact that some GIRK subunits are involved in analgesia,17Marker C.L. Stoffel M. Wickman K. Spinal G-protein-gated K+ channels formed by GIRK1 and GIRK2 subunits modulate thermal nociception and contribute to morphine analgesia.J Neurosci. 2004; 24: 2806-2812Crossref PubMed Scopus (110) Google Scholar is a limiting factor. Potassium channel blockers, such as doxapram7van der Schier R. Roozekrans M. van Velzen M. Dahan A. Niesters M. Opioid-induced respiratory depression: reversal by non-opioid drugs.F1000Prime Rep. 2014; 6: 79Crossref PubMed Scopus (54) Google Scholar and Gal021 (which act on large conductance Ca2+/voltage activated K+ channels), have been shown to reverse opioid-induced respiratory depression,26Roozekrans M. Olofsen E. van der Schrier R. et al.Reversal of opioid-induced respiratory depression by BK-channel blocker GAL021: a pharmacokinetic-pharmacodynamic modeling study in healthy volunteers.Clin Pharmacol Ther. 2015; 97: 641-649Crossref PubMed Scopus (17) Google Scholar and may represent potential strategies to prevent respiratory depression without inducing additional side effects.7van der Schier R. Roozekrans M. van Velzen M. Dahan A. Niesters M. Opioid-induced respiratory depression: reversal by non-opioid drugs.F1000Prime Rep. 2014; 6: 79Crossref PubMed Scopus (54) Google Scholar Identification of drugs targeting specific potassium channel subunits could be a viable strategy. In summary, the lack of understanding of the neural sites of action of opioids14Montandon G. Horner R. CrossTalk proposal: the preBotzinger complex is essential for the respiratory depression following systemic administration of opioid analgesics.J Physiol. 2014; 592: 1159-1162Crossref PubMed Scopus (38) Google Scholar and the molecular pathways regulating inhibition of respiratory circuits is hindering the development of safe opioid pain therapies. Another promising strategy to prevent respiratory depression while administering opioids is to stimulate respiratory circuits. Stimulation of the neural circuits generating breathing can improve ventilation and can be achieved by activating excitatory circuits. Drugs acting on alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor or AMPA receptors such as ampakines16Ren J. Poon B.Y. Tang Y. Funk G.D. Greer J.J. Ampakines alleviate respiratory depression in rats.Am J Respir Crit Care Med. 2006; 174: 1384-1391Crossref PubMed Scopus (75) Google Scholar may stimulate breathing and could be used with existing opioids (Fig 2C). Although of great potential, ampakines also alter sedation and their efficacy at higher opioid dosages is unknown.7van der Schier R. Roozekrans M. van Velzen M. Dahan A. Niesters M. Opioid-induced respiratory depression: reversal by non-opioid drugs.F1000Prime Rep. 2014; 6: 79Crossref PubMed Scopus (54) Google Scholar Nevertheless, ampakines are currently being evaluated in clinical trials.27Oertel B.G. Felden L. Tran P.V. et al.Selective antagonism of opioid-induced ventilatory depression by an ampakine molecule in humans without loss of opioid analgesia.Clin Pharmacol Ther. 2010; 87: 204-211Crossref PubMed Scopus (89) Google Scholar Similarly, drugs such as 5-HT1A receptor agonists, which act on the serotonin system, may reverse respiratory depression,15Manzke T. Guenther U. Ponimaskin E.G. et al.5-HT4(a) receptors avert opioid-induced breathing depression without loss of analgesia.Science. 2003; 301: 226-229Crossref PubMed Scopus (218) Google Scholar, 28Ren J. Ding X. Greer J.J. 5-HT1A receptor agonist befiradol reduces fentanyl-induced respiratory depression, analgesia, and sedation in rats.Anesthesiology. 2015; 122: 424-434Crossref PubMed Scopus (25) Google Scholar but these drugs also impact opioid analgesia.28Ren J. Ding X. Greer J.J. 5-HT1A receptor agonist befiradol reduces fentanyl-induced respiratory depression, analgesia, and sedation in rats.Anesthesiology. 2015; 122: 424-434Crossref PubMed Scopus (25) Google Scholar Although opioid addiction is a critical health issue, the morbidity and mortality associated with opioid overdose are caused by their respiratory depressant side effects. There is currently a serious knowledge gap in our understanding of the mechanisms regulating mu opioid receptor inhibition of respiratory and nociceptive circuits. For instance, the roles of regulators of G-protein signaling proteins, voltage-gated calcium channels, or potassium channels and their potential as molecular targets to prevent or eliminate respiratory depression are unclear. It is also possible that novel excitatory pathways exist that could stimulate respiratory circuits without targeting nociceptive circuits. A better understanding of these mechanisms is critical to help identify new pharmacologic targets that could provide potent analgesia without the lethal risk of respiratory depression.