title: 5-HT4(a) receptors avert opioid-induced breathing depression without loss of analgesia.
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 PBC neurons 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.
authors.affiliation: Department of Neuro- and Sensory Physiology, University of Goettingen, Humboldtallee 23, 37073 Goettingen, Germany.
authors.forename: Till
authors.initials: T
authors.lastname: Manzke
authors.forename: Ulf
authors.initials: U
authors.lastname: Guenther
authors.forename: Evgeni G
authors.initials: EG
authors.lastname: Ponimaskin
authors.forename: Miriam
authors.initials: M
authors.lastname: Haller
authors.forename: Mathias
authors.initials: M
authors.lastname: Dutschmann
authors.forename: Stephan
authors.initials: S
authors.lastname: Schwarzacher
authors.forename: Diethelm W
authors.initials: DW
authors.lastname: Richter
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D001933:Brain Stem / Q000166:cytology / Q000378:metabolism*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D005283:Fentanyl / Q000494:pharmacology* / Q000633:toxicity; D066298:In Vitro Techniques; D007395:Interneurons / Q000378:metabolism; D008526:Medulla Oblongata / Q000166:cytology / Q000378:metabolism; D009270:Naloxone / Q000494:pharmacology; D009474:Neurons / Q000378:metabolism*; D010147:Pain Measurement; D018408:Patch-Clamp Techniques; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018040:Receptors, Neurokinin-1 / Q000235:genetics / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000235:genetics / Q000378:metabolism; D011985:Receptors, Serotonin / Q000378:metabolism*; D044422:Receptors, Serotonin, 5-HT4; D012119:Respiration / Q000187:drug effects*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D015398:Signal Transduction; D013116:Spinal Cord
chemical_list: D000701:Analgesics, Opioid; D001562:Benzimidazoles; D019086:Bridged Bicyclo Compounds, Heterocyclic; D012333:RNA, Messenger; D018040:Receptors, Neurokinin-1; D017450:Receptors, Opioid, mu; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; C070189:(endo-N-8-methyl-8-azabicyclo-(3.2.1)oct-3-yl)-2,3-dihydro-3-isopropyl-2-oxo-1H-benzimidazol-1-carboxamide; D044422:Receptors, Serotonin, 5-HT4; D009270:Naloxone; D000242:Cyclic AMP; D005283:Fentanyl