5-HT4(a) receptors avert opioid-induced breathing depression without loss of analgesia.
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.
Manzke
Till
T
Department of Neuro- and Sensory Physiology, University of Goettingen, Humboldtallee 23, 37073 Goettingen, Germany.
Guenther
Ulf
U
Ponimaskin
Evgeni G
EG
Haller
Miriam
M
Dutschmann
Mathias
M
Schwarzacher
Stephan
S
Richter
Diethelm W
DW
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
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