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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.

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* These authors contributed equally to this work.

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

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