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

• Published in: Science (American Association for the Advancement of Science) 2003-07, Vol.301 (5630), p.226-229
• Main Authors: Manzke, Till, Guenther, Ulf, Ponimaskin, Evgeni G., Haller, Miriam, Dutschmann, Mathias, Schwarzacher, Stephan, Richter, Diethelm W.
• Format: Article
• Language: English
• Subjects: Analgesics, Opioid - pharmacology; Analgesics, Opioid - toxicity; Animals; Antibodies; Benzimidazoles - pharmacology; Biological and medical sciences; Brain stem; Brain Stem - cytology; Brain Stem - metabolism; Breathing; Bridged Bicyclo Compounds, Heterocyclic - pharmacology; Cyclic AMP - metabolism; Drug toxicity and drugs side effects treatment; Fentanyl - pharmacology; Fentanyl - toxicity; In Vitro Techniques; Interneurons - metabolism; Medical sciences; Medulla Oblongata - cytology; Medulla Oblongata - metabolism; Messenger RNA; Naloxone - pharmacology; Neurons; Neurons - metabolism; Pain Measurement; Patch-Clamp Techniques; Pharmacology. Drug treatments; Protein isoforms; Rats; Rats, Sprague-Dawley; Receptors; Receptors, Neurokinin-1 - genetics; Receptors, Neurokinin-1 - metabolism; Receptors, Opioid, mu - genetics; Receptors, Opioid, mu - metabolism; Receptors, Serotonin - metabolism; Receptors, Serotonin, 5-HT4; Respiration - drug effects; Respiratory insufficiency; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; RNA, Messenger - metabolism; Serotonin Receptor Agonists - pharmacology; Serotonin receptors; Signal Transduction; Spinal Cord; Toxicity: respiratory system, ent, stomatology
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.1084674

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)$[5-HT_{4(a)}]$receptors are strongly expressed in respiratory PBC neurons and that their selective activation protects spontaneous respiratory activity. Treatment of rats with a$5-HT_4$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.