title: [Serotonin receptor 1A-modulated dephosphorylation of glycine receptor α3: a new molecular mechanism of breathing control for compensation of opioid-induced respiratory depression without loss of analgesia].
abstract: To control the breathing rhythm the medullary respiratory network generates periodic salvo activities for inspiration, post-inspiration and expiration. These are under permanent modulatory control by serotonergic neurons of the raphe which governs the degree of phosphorylation of the inhibitory glycine receptor α3. The specific activation of serotonin receptor type 1A (5-HTR(1A)), which is strongly expressed in the respiratory neurons, functions via inhibition of adenylate cyclase and the resulting reduction of the intracellular cAMP level and a gradual dephosphorylation of the glycine receptor type α3 (GlyRα3). This 5-HTR(1A)-GlyRα3 signal pathway is independent of the µ-opioidergic transduction pathway and via a synaptic inhibition caused by an increase in GlyRα3 stimulates a disinhibition of some target neurons not only from excitatory but also from inhibitory neurons. Our physiological investigations show that this 5-HTR(1A)-GlyRα3 modulation allows treatment of respiratory depression due to opioids without affecting the desired analgesic effects of opioids. The molecular mechanism presented here opens new pharmacological possibilities to treat opioid-induced respiratory depression and respiratory disorders due to disturbed inhibitory synaptic transmission, such as hyperekplexia.
authors.affiliation: Abteilung Neuro- und Sinnesphysiologie, Universität Göttingen, Humboldtallee 23, 37073 Göttingen, Deutschland. tmanzke@gwdg.de
authors.forename: T
authors.initials: T
authors.lastname: Manzke
authors.forename: M
authors.initials: M
authors.lastname: Niebert
authors.forename: U R
authors.initials: UR
authors.lastname: Koch
authors.forename: A
authors.initials: A
authors.lastname: Caley
authors.forename: S
authors.initials: S
authors.lastname: Vogelgesang
authors.forename: A-M
authors.initials: AM
authors.lastname: Bischoff
authors.forename: S
authors.initials: S
authors.lastname: Hülsmann
authors.forename: E
authors.initials: E
authors.lastname: Ponimaskin
authors.forename: U
authors.initials: U
authors.lastname: Müller
authors.forename: T G
authors.initials: TG
authors.lastname: Smart
authors.forename: R J
authors.initials: RJ
authors.lastname: Harvey
authors.forename: D W
authors.initials: DW
authors.lastname: Richter
mesh_terms: D000067956:Adenylyl Cyclase Inhibitors; D000262:Adenylyl Cyclases / Q000502:physiology; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000633:toxicity*; D000818:Animals; D002065:Buspirone / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D045853:Exhalation / Q000502:physiology*; D005283:Fentanyl / Q000008:administration & dosage / Q000633:toxicity*; D066298:In Vitro Techniques; D001239:Inhalation / Q000502:physiology*; D007395:Interneurons / Q000187:drug effects / Q000502:physiology; D008297:Male; D008526:Medulla Oblongata / Q000187:drug effects / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009415:Nerve Net / Q000187:drug effects / Q000503:physiopathology; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D009619:Nociceptors / Q000187:drug effects / Q000502:physiology; D017288:Pain Threshold / Q000187:drug effects* / Q000502:physiology; D010424:Pentobarbital / Q000008:administration & dosage / Q000633:toxicity; D010766:Phosphorylation / Q000502:physiology; D011292:Premedication; D011903:Raphe Nuclei / Q000187:drug effects / Q000502:physiology*; D044282:Receptor, Serotonin, 5-HT1A / Q000187:drug effects / Q000502:physiology*; D018009:Receptors, Glycine / Q000502:physiology*; D012131:Respiratory Insufficiency / Q000139:chemically induced* / Q000503:physiopathology*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology
chemical_list: D000067956:Adenylyl Cyclase Inhibitors; D000701:Analgesics, Opioid; D018009:Receptors, Glycine; D017366:Serotonin Receptor Agonists; C113965:glycine receptor alpha3 subunit; D044282:Receptor, Serotonin, 5-HT1A; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; D010424:Pentobarbital; D002065:Buspirone; D005283:Fentanyl