On the opiate trail of respiratory depression.

Abstract

EDITORIAL FOCUSOn the opiate trail of respiratory depressionDonald R. McCrimmon, and George F. AlheidDonald R. McCrimmonDepartment of Physiology and Institute for Neuroscience, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611-3008, and George F. AlheidDepartment of Physiology and Institute for Neuroscience, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611-3008Published Online:01 Dec 2003https://doi.org/10.1152/ajpregu.00428.2003MoreSectionsPDF (37 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInEmailWeChat agonists at μ-opiate receptors are very important clinically in the alleviation of pain. A well known and unwanted side effect is the marked depression of breathing that complicates their clinical administration and is potentially life threatening when opiates are abused. Neuronal μ-opiate receptors are widespread in the ventrolateral medulla including on neurons in the region of the ventral respiratory column. Their activation reduces breathing frequency and tidal volume, as well as the respiratory response to chemoreceptor stimulation elicited by an elevation in arterial carbon dioxide. Many brain stem respiratory neurons are known to be sensitive to the application of μ-opiate agonists, but the specific neuronal targets causing respiratory depression are relatively poorly understood. In a technical tour de force in the cat, Lalley (8) in this issue of the American Journal of Physiology-Regulatory, Integrative and Comparative Physiology identifies specific classes of respiratory neurons whose activity is directly influenced by drugs with activity at central nervous system μ-opiate receptors and demonstrates that the respiratory effects of these opiates are not dependent on any concurrent anesthetic agents.Neurons important for the generation of respiratory rhythm and pattern are concentrated in the ventrolateral medulla. Extending the entire length of the ventrolateral medulla these neurons form the ventral respiratory column (VRC; 1) consisting of neurons that discharge bursts of action potentials with fixed temporal relationships to the breathing cycle. Within the VRC, neurons exhibit various degrees of segregation with respect to their hypothesized roles in generating respiratory rhythm (i.e., breathing frequency) or breathing pattern (i.e., the intensity and the temporal pattern of activation of different respiratory muscles such as the diaphragm and intercostal muscles).Opiate effects on respiratory rhythm generation.One VRC subregion, termed the pre-Bötzinger complex (pBC), contains propriobulbar neurons postulated to play an essential role in respiratory rhythm generation (14). Consistent with this view, in vitro pharmacological experiments have implicated pBC neurons that coexpress μ-opiate and neurokinin-1 receptors (i.e., receptors for substance P) as probable respiratory rhythmogenic neurons (4, 5). These neurons are likely candidates for explaining the effects of μ-opiate agonists on respiratory rhythm. Lalley (8) demonstrates that μ-opioid receptor agonists directly inhibit a subset of inspiratory neurons found within this region.This view of the role of the pBC in respiratory rhythm generation was recently expanded after identification of a second group of rhythm-generating neurons that are μ-opiate insensitive (12) and located rostroventral to the pBC (12). They synaptically interact with pBC neurons to form a circuit consisting of coupled oscillators, each capable of independently generating rhythmic firing in the absence of the other (11, 12). Agonists for μ-opiate receptors appear to selectively disrupt inspiratory rhythm generation by pBC neurons while sparing an expiratory rhythm generated in the more rostral area (11, 16). This rhythm does not appear to be transmitted to many of the expiratory muscles innervating the chest wall as Lalley (8) showed that the premotor input to these muscles began discharging tonically after suppression of inhibitory synaptic potentials. Interestingly, however, an opiate-insensitive expiratory rhythm persists at least on a subset of lumbar motoneurons innervating abdominal muscles (7, 11). The detailed functional consequences of this postulated dual oscillator system for the in vivo regulation of normal adult respiration (eupnea) has yet to be incorporated into computational models of respiratory rhythm generation.Opiate effects on respiratory pattern generation.In addition to depression of respiratory frequency, μ-opiate receptor activation also decreases chemoreceptor drive and tidal volume as well as altering pulmonary mechanics (13). Agonists at μ-opiate receptors also directly depress the activity of ventral medullary respiratory neurons likely to be involved in the control of respiratory motor pattern (3). Central to this role are the bulbospinal premotor neurons innervating spinal respiratory motoneurons including phrenic, intercostal, and abdominal motoneurons. Both inspiratory and expiratory bulbospinal neurons were clearly inhibited by μ-opiate agonists in the study of Lalley (8). Of particular note, he describes a potential mechanism for the decreased chest wall compliance that accompanies opiate administration. Suppression of expiratory phase synaptic inhibition causes expiratory bulbospinal neurons to discharge continuously, leading to a low-level tonic activation of spinal expiratory muscles.Interestingly, although phrenic premotor neurons are glutamatergic (6, 10, 15), the majority of these also appears to be enkephalinergic (15), so that direct actions of opiates at the phrenic nucleus may also contribute to the regulation of respiratory motor pattern. Agonists at μ-opiate receptor agonists also inhibit cholinergic neurotransmission at airway smooth muscle and by this means can contribute to airway obstruction (2). However, a central mechanism of action is also implicated by Lalley's (8) observations that vagal motoneurons promoting dilation of the vocal folds are directly inhibited by μ-opiate agonists.Drugs acting at μ-opiate receptors are important clinical tools but are also widely abused. In either case, depression of breathing is a dangerous side effect. This complicates its beneficial application as an analgesic and has engendered pharmacological efforts to separate these two effects (9). Whatever the problems related to exogenous applications of μ-opiates, it is clear that endogenous opiate transmitters are intimately involved in the neuronal organization of normal respiration. Characterization of the multiple levels at which these neuromodulators contribute to the control of respiration has clearly become an important avenue for respiratory research and the present detailed observations of opiate actions at individual respiratory neurons described by Lalley (8) are an important contribution to this progress. References 1 Alheid GF, Gray PA, Jiang MC, Feldman JL, and McCrimmon DR. Parvalbumin in respiratory neurons of the ventrolateral medulla of the adult rat. J Neurocytol 31: 693-717, 2002.Crossref | PubMed | Google Scholar2 Barnes PJ. Neuromodulation in airways. In: Autonomic Control of the Respiratory System, edited by Barnes PJ. Amsterdam: Harwood Academic, 1997, pp. 139-184.Google Scholar3 Denavit-Saubié M, Champagnat J, and Zieglgänsberger W. Effects of opiates and methionine-enkephalin on pontine and bulbar respiratory neurones of the cat. Brain Res 155: 55-67, 1978.Crossref | PubMed | ISI | Google Scholar4 Gray PA, Rekling JC, Bocchiaro CM, and Feldman JL. Modulation of respiratory frequency by peptidergic input to rhythmogenic neurons in the preBötzinger complex. Science 286: 1566-1568, 1999.Crossref | PubMed | ISI | Google Scholar5 Gray PA, Janczewski WA, Mellen N, McCrimmon DR, and Feldman JL. Normal breathing requires preBötzinger complex neurokinin-1 receptor-expressing neurons. Nat Neurosci 4: 927-930, 2001.Crossref | PubMed | ISI | Google Scholar6 Greer JJ, Smith JC, and Feldman JL. Glutamate release and presynaptic action of AP4 during inspiratory drive to phrenic motoneurons. Brain Res 576: 355-357, 1992.Crossref | PubMed | ISI | Google Scholar7 Janczewski WA, Onimaru H, Homma I, and Feldman JL. Opioid-resistant respiratory pathway from the preinspiratory neurones to abdominal muscles: in vivo and in vitro study in the newborn rat. J Physiol 545: 1017-1026, 2002.Crossref | PubMed | ISI | Google Scholar8 Lalley PM. μ-Opioid receptor agonist effects on medullary respiratory neurons in the cat: evidence for involvement in certain types of ventilatory disturbances. Am J Physiol Regul Integr Comp Physiol 285: R1287-R1304, 2003.Link | ISI | Google Scholar9 Manzke T, Guenther U, Ponimaskin EG, Haller M, Dutschmann M, Schwarzacher S, and Richter DW. 5-HT4(a) receptors avert opioid-induced breathing depression without loss of analgesia. Science 301: 226-229, 2003.Crossref | PubMed | ISI | Google Scholar10 McCrimmon DR, Smith JC, and Feldman JL. Involvement of excitatory amino acids in neurotransmission of inspiratory drive to spinal respiratory motoneurons. J Neurosci 9: 1910-1921, 1989.Crossref | PubMed | ISI | Google Scholar11 Mellen NM, Janczewski WA, Bocchiaro CM, and Feldman JL. Opioid-induced quantal slowing reveals dual networks for respiratory rhythm generation. Neuron 37: 821-826, 2003.Crossref | PubMed | ISI | Google Scholar12 Onimaru H and Homma I. A novel functional neuronal group for respiratory rhythm generation in the ventrolateral medulla. J Neurosci 23: 1478-1486, 2003.Crossref | PubMed | ISI | Google Scholar13 Santiago TV and Edelman NH. Opioids and breathing. J Appl Physiol 59: 1675-1685, 1985.Link | ISI | Google Scholar14 Smith JC, Ellenberger HH, Ballanyi K, Richter DW, and Feldman JL. Pre-Bötzinger complex: a brainstem region that may generate respiratory rhythm in mammals. Science 254: 726-729, 1991.Crossref | PubMed | ISI | Google Scholar15 Stornetta RL, Rosin DL, Wang H, Sevigny CP, Weston MC, and Guyenet PG. A group of glutamatergic interneurons expressing high levels of both neurokinin-1 receptors and somatostatin identifies the region of the pre-Bötzinger complex. J Comp Neurol 455: 499-512, 2003.Crossref | PubMed | ISI | Google Scholar16 Takeda S, Eriksson LI, Yamamoto Y, Joensen H, Onimaru H, and Lindahl SG. Opioid action on respiratory neuron activity of the isolated respiratory network in newborn rats. Anesthesiology 95: 740-749, 2001.Crossref | PubMed | ISI | Google ScholarAUTHOR NOTES Address for reprint requests and correspondence: D. R. McCrimmon, Dept. Physiology—M211, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611-3008 (E-mail: [email protected]). 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R. Meyer, Andrea Fuller, and Duncan Mitchell1 February 2006 | American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, Vol. 290, No. 2Opioid mechanisms and opioid drugsAnaesthesia & Intensive Care Medicine, Vol. 6, No. 1 More from this issue > Volume 285Issue 6December 2003Pages R1274-R1275 Copyright & PermissionsCopyright © 2003 the American Physiological Societyhttps://doi.org/10.1152/ajpregu.00428.2003PubMed14615398History Published online 1 December 2003 Published in print 1 December 2003 Metrics