Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Logo for

Science 301 (5630): 226-229

Copyright © 2003 by the American Association for the Advancement of Science

5-HT4(a) Receptors Avert Opioid-Induced Breathing Depression Without Loss of Analgesia

Till Manzke,1* Ulf Guenther,2* Evgeni G. Ponimaskin,1 Miriam Haller,1 Mathias Dutschmann,1 Stephan Schwarzacher,3 Diethelm W. Richter1{dagger}

Abstract: Opiates are widely used analgesics in anesthesiology, but they have serious adverse effects such as depression of breathing. This is caused by direct inhibition of rhythm-generating respiratory neurons in the Pre-Boetzinger complex (PBC) of the brainstem. We report that serotonin 4(a) [5-HT4(a)] receptors are strongly expressed in respiratory PBCneurons and that their selective activation protects spontaneous respiratory activity. Treatment of rats with a 5-HT4 receptor–specific agonist overcame fentanyl-induced respiratory depression and reestablished stable respiratory rhythm without loss of fentanyl's analgesic effect. These findings imply the prospect of a fine-tuned recovery from opioid-induced respiratory depression, through adjustment of intracellular adenosine 3',5'-monophosphate levels through the convergent signaling pathways in neurons.

1 Department of Neuro- and Sensory Physiology, University of Goettingen, Humboldtallee 23, 37073 Goettingen, Germany. 2 Center of Anesthesiology, University of Goettingen, Robert-KochStreet 40, 37075 Goettingen, Germany. 3 Department of Anatomy, Kreuzbergring 36, 37075 Goettingen, Germany.

Back to Top

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: d.richter{at}gwdg.de


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
CrossTalk proposal: The preBotzinger complex is essential for the respiratory depression following systemic administration of opioid analgesics.
G. Montandon and R. Horner (2014)
J. Physiol. 592, 1159-1162
   Full Text »    PDF »
Changes in neurochemicals within the ventrolateral medullary respiratory column in awake goats after carotid body denervation.
J. R. Miller, S. Neumueller, C. Muere, S. Olesiak, L. Pan, M. R. Hodges, and H. V. Forster (2013)
J Appl Physiol 115, 1088-1098
   Abstract »    Full Text »    PDF »
Hypoxic ventilatory response in Tac1-/- neonatal mice following exposure to opioids.
J. Berner, Y. Shvarev, A. Zimmer, and R. Wickstrom (2012)
J Appl Physiol 113, 1718-1726
   Abstract »    Full Text »    PDF »
Pontine {mu}-opioid receptors mediate bradypnea caused by intravenous remifentanil infusions at clinically relevant concentrations in dogs.
I. Prkic, S. Mustapic, T. Radocaj, A. G. Stucke, E. A. E. Stuth, F. A. Hopp, C. Dean, and E. J. Zuperku (2012)
J Neurophysiol 108, 2430-2441
   Abstract »    Full Text »    PDF »
Control of Breathing by Raphe Obscurus Serotonergic Neurons in Mice.
S. D. DePuy, R. Kanbar, M. B. Coates, R. L. Stornetta, and P. G. Guyenet (2011)
J. Neurosci. 31, 1981-1990
   Abstract »    Full Text »    PDF »
PreBotzinger Complex Neurokinin-1 Receptor-Expressing Neurons Mediate Opioid-Induced Respiratory Depression.
G. Montandon, W. Qin, H. Liu, J. Ren, J. J. Greer, and R. L. Horner (2011)
J. Neurosci. 31, 1292-1301
   Abstract »    Full Text »    PDF »
Acute and chronic treatment with serotonin reuptake inhibitors exert opposite effects on respiration in rats: possible implications for panic disorder.
K. Annerbrink, M. Olsson, J. Hedner, and E. Eriksson (2010)
J Psychopharmacol 24, 1793-1801
   Abstract »    PDF »
Correction of respiratory disorders in a mouse model of Rett syndrome.
A. P. L. Abdala, M. Dutschmann, J. M. Bissonnette, and J. F. R. Paton (2010)
PNAS 107, 18208-18213
   Abstract »    Full Text »    PDF »
State-Dependent Interactions between Excitatory Neuromodulators in the Neuronal Control of Breathing.
A. Doi and J.-M. Ramirez (2010)
J. Neurosci. 30, 8251-8262
   Abstract »    Full Text »    PDF »
EFFECTS OF SEROTONIN AGONISTS AND DOXAPRAM ON RESPIRATORY DEPRESSION AND HYPOXEMIA IN ETORPHINE-IMMOBILIZED IMPALA (AEPYCEROS MELAMPUS).
L. C. R. Meyer, R. S. Hetem, L. G. Fick, D. Mitchell, and A. Fuller (2010)
J. Wildl. Dis. 46, 514-524
   Abstract »    Full Text »    PDF »
Clinically Relevant Infusion Rates of {micro}-Opioid Agonist Remifentanil Cause Bradypnea in Decerebrate Dogs but not Via Direct Effects in the pre-Botzinger Complex Region.
S. Mustapic, T. Radocaj, A. Sanchez, Z. Dogas, A. G. Stucke, F. A. Hopp, E. A. E. Stuth, and E. J. Zuperku (2010)
J Neurophysiol 103, 409-418
   Abstract »    Full Text »    PDF »
Activation of the retrotrapezoid nucleus by posterior hypothalamic stimulation.
M. G. Fortuna, R. L. Stornetta, G. H. West, and P. G. Guyenet (2009)
J. Physiol. 587, 5121-5138
   Abstract »    Full Text »    PDF »
Serotonin targets inhibitory synapses to induce modulation of network functions.
T. Manzke, M. Dutschmann, G. Schlaf, M. Morschel, U. R. Koch, E. Ponimaskin, O. Bidon, P. M. Lalley, and D. W. Richter (2009)
Phil Trans R Soc B 364, 2589-2602
   Abstract »    Full Text »    PDF »
The potency of different serotonergic agonists in counteracting opioid evoked cardiorespiratory disturbances.
M. Dutschmann, H. Waki, T. Manzke, A. E. Simms, A. E. Pickering, D. W. Richter, and J. F. R. Paton (2009)
Phil Trans R Soc B 364, 2611-2623
   Abstract »    Full Text »    PDF »
Opioid receptor mechanisms at the hypoglossal motor pool and effects on tongue muscle activity in vivo.
M. Hajiha, M.-A. DuBord, H. Liu, and R. L. Horner (2009)
J. Physiol. 587, 2677-2692
   Abstract »    Full Text »    PDF »
Raphe Neurons Stimulate Respiratory Circuit Activity by Multiple Mechanisms via Endogenously Released Serotonin and Substance P.
K. Ptak, T. Yamanishi, J. Aungst, L. S. Milescu, R. Zhang, G. B. Richerson, and J. C. Smith (2009)
J. Neurosci. 29, 3720-3737
   Abstract »    Full Text »    PDF »
Inhibitory and excitatory effects of {micro}-, {delta}-, and {kappa}-opioid receptor activation on breathing in awake turtles, Trachemys scripta.
S. M. Johnson, M. E. Kinney, and L. M. Wiegel (2008)
Am J Physiol Regulatory Integrative Comp Physiol 295, R1599-R1612
   Abstract »    Full Text »    PDF »
The 2008 Carl Ludwig Lecture: retrotrapezoid nucleus, CO2 homeostasis, and breathing automaticity.
P. G. Guyenet (2008)
J Appl Physiol 105, 404-416
   Abstract »    Full Text »    PDF »
Opioids and the control of respiration.
K. T. S. Pattinson (2008)
Br. J. Anaesth. 100, 747-758
   Abstract »    Full Text »    PDF »
Metabotropic glutamate receptors activate dendritic calcium waves and TRPM channels which drive rhythmic respiratory patterns in mice.
S. L. Mironov (2008)
J. Physiol. 586, 2277-2291
   Abstract »    Full Text »    PDF »
Anatomical and functional development of the pre-Botzinger complex in prenatal rodents.
M. Thoby-Brisson and J. J. Greer (2008)
J Appl Physiol 104, 1213-1219
   Abstract »    Full Text »    PDF »
Generation of Eupnea and Sighs by a Spatiochemically Organized Inspiratory Network.
A. Ruangkittisakul, S. W. Schwarzacher, L. Secchia, Y. Ma, N. Bobocea, B. Y. Poon, G. D. Funk, and K. Ballanyi (2008)
J. Neurosci. 28, 2447-2458
   Abstract »    Full Text »    PDF »
Defects in Breathing and Thermoregulation in Mice with Near-Complete Absence of Central Serotonin Neurons.
M. R. Hodges, G. J. Tattersall, M. B. Harris, S. D. McEvoy, D. N. Richerson, E. S. Deneris, R. L. Johnson, Z.-F. Chen, and G. B. Richerson (2008)
J. Neurosci. 28, 2495-2505
   Abstract »    Full Text »    PDF »
Necdin Plays a Role in the Serotonergic Modulation of the Mouse Respiratory Network: Implication for Prader-Willi Syndrome.
S. Zanella, F. Watrin, S. Mebarek, F. Marly, M. Roussel, C. Gire, G. Diene, M. Tauber, F. Muscatelli, and G. Hilaire (2008)
J. Neurosci. 28, 1745-1755
   Abstract »    Full Text »    PDF »
Serotonergic Neurons Activate Chemosensitive Retrotrapezoid Nucleus Neurons by a pH-Independent Mechanism.
D. K. Mulkey, D. L. Rosin, G. West, A. C. Takakura, T. S. Moreira, D. A. Bayliss, and P. G. Guyenet (2007)
J. Neurosci. 27, 14128-14138
   Abstract »    Full Text »    PDF »
5-Hydroxytryptamine 1A/7 and 4{alpha} Receptors Differentially Prevent Opioid-Induced Inhibition of Brain Stem Cardiorespiratory Function.
X. Wang, O. Dergacheva, H. Kamendi, C. Gorini, and D. Mendelowitz (2007)
Hypertension 50, 368-376
   Abstract »    Full Text »    PDF »
Effects of medullary Raphe stimulation on fictive lung ventilation during development in Rana catesbeiana.
O. Belzile, R. Gulemetova, and R. Kinkead (2007)
J. Exp. Biol. 210, 2046-2056
   Abstract »    Full Text »    PDF »
Neurokinin Receptor-Expressing Pre-Botzinger Complex Neurons in Neonatal Mice Studied In Vitro.
J. A. Hayes and C. A. Del Negro (2007)
J Neurophysiol 97, 4215-4224
   Abstract »    Full Text »    PDF »
High Sensitivity to Neuromodulator-Activated Signaling Pathways at Physiological [K+] of Confocally Imaged Respiratory Center Neurons in On-Line-Calibrated Newborn Rat Brainstem Slices..
A. Ruangkittisakul, S. W. Schwarzacher, L. Secchia, B. Y. Poon, Y. Ma, G. D. Funk, and K. Ballanyi (2006)
J. Neurosci. 26, 11870-11880
   Abstract »    Full Text »    PDF »
Point:Counterpoint: The parafacial respiratory group (pFRG)/pre-Botzinger complex (preBotC) is the primary site of respiratory rhythm generation in the mammal.
H. Onimaru, I. Homma, J. L. Feldman, and W. A. Janczewski (2006)
J Appl Physiol 100, 2094-2098
   Full Text »    PDF »
Opiate slowing of feline respiratory rhythm and effects on putative medullary phase-regulating neurons.
P. M. Lalley (2006)
Am J Physiol Regulatory Integrative Comp Physiol 290, R1387-R1396
   Abstract »    Full Text »    PDF »
Zacopride and 8-OH-DPAT reverse opioid-induced respiratory depression and hypoxia but not catatonic immobilization in goats.
L. C. R. Meyer, A. Fuller, and D. Mitchell (2006)
Am J Physiol Regulatory Integrative Comp Physiol 290, R405-R413
   Abstract »    Full Text »    PDF »
Distinct rhythm generators for inspiration and expiration in the juvenile rat.
W. A. Janczewski and J. L. Feldman (2006)
J. Physiol. 570, 407-420
   Abstract »    Full Text »    PDF »
Agonist-Directed Trafficking of Response by Endocannabinoids Acting at CB2 Receptors.
J. L. Shoemaker, M. B. Ruckle, P. R. Mayeux, and P. L. Prather (2005)
J. Pharmacol. Exp. Ther. 315, 828-838
   Abstract »    Full Text »    PDF »
Morphine Side Effects in {beta}-Arrestin 2 Knockout Mice.
K. M. Raehal, J. K. L. Walker, and L. M. Bohn (2005)
J. Pharmacol. Exp. Ther. 314, 1195-1201
   Abstract »    Full Text »    PDF »
Uncoupling and Endocytosis of 5-Hydroxytryptamine 4 Receptors: DISTINCT MOLECULAR EVENTS WITH DIFFERENT GRK2 REQUIREMENTS.
G. Barthet, F. Gaven, B. Framery, K. Shinjo, T. Nakamura, S. Claeysen, J. Bockaert, and A. Dumuis (2005)
J. Biol. Chem. 280, 27924-27934
   Abstract »    Full Text »    PDF »
D1-dopamine receptor agonists prevent and reverse opiate depression of breathing but not antinociception in the cat.
P. M. Lalley (2005)
Am J Physiol Regulatory Integrative Comp Physiol 289, R45-R51
   Abstract »    Full Text »    PDF »
Emergence of the Pre-Botzinger Respiratory Rhythm Generator in the Mouse Embryo.
M. Thoby-Brisson, J.-B. Trinh, J. Champagnat, and G. Fortin (2005)
J. Neurosci. 25, 4307-4318
   Abstract »    Full Text »    PDF »
Fluorescent Tagging of Rhythmically Active Respiratory Neurons within the Pre-Botzinger Complex of Rat Medullary Slice Preparations.
S. Pagliardini, T. Adachi, J. Ren, G. D. Funk, and J. J. Greer (2005)
J. Neurosci. 25, 2591-2596
   Abstract »    Full Text »    PDF »
Transient attenuation of CO2 sensitivity after neurotoxic lesions in the medullary raphe area of awake goats.
M. R. Hodges, C. Opansky, B. Qian, S. Davis, J. Bonis, J. Bastasic, T. Leekley, L. G. Pan, and H. V. Forster (2004)
J Appl Physiol 97, 2236-2247
   Abstract »    Full Text »    PDF »
Attenuated Response to Stress and Novelty and Hypersensitivity to Seizures in 5-HT4 Receptor Knock-Out Mice.
V. Compan, M. Zhou, R. Grailhe, R. A. Gazzara, R. Martin, J. Gingrich, A. Dumuis, D. Brunner, J. Bockaert, and R. Hen (2004)
J. Neurosci. 24, 412-419
   Abstract »    Full Text »    PDF »
On the opiate trail of respiratory depression.
D. R. McCrimmon and G. F. Alheid (2003)
Am J Physiol Regulatory Integrative Comp Physiol 285, R1274-R1275
   Full Text »    PDF »
Separating Opioid Analgesia from Opioid Asphyxia.
(2003)
Journal Watch (General) 2003, 3
   Full Text »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882