Activating α4β2 Nicotinic Acetylcholine Receptors Alleviates Fentanyl-induced Respiratory Depression in Rats

• Published in: Anesthesiology (Philadelphia) 2019-06, Vol.130 (6), p.1017-1031
• Main Authors: Ren, Jun, Ding, Xiuqing, Greer, John J
• Format: Article
• Language: English
• Subjects: Analgesics, Opioid - adverse effects; Animals; Animals, Newborn; Azetidines - pharmacology; Female; Fentanyl - adverse effects; Male; Nicotinic Agonists - pharmacology; Nicotinic Agonists - therapeutic use; Pregnancy; Rats; Rats, Sprague-Dawley; Receptors, Nicotinic - metabolism; Respiratory Insufficiency - chemically induced; Respiratory Insufficiency - drug therapy; Respiratory Insufficiency - metabolism
• ISSN: 0003-3022; 1528-1175
• DOI: 10.1097/ALN.0000000000002676

WHAT WE ALREADY KNOW ABOUT THIS TOPICOpioid-induced respiratory depression results in part from direct activation of μ-opioid receptors expressed in the inspiratory rhythm generator located in the ventrolateral medulla, the preBötzinger ComplexRespiratory neurons within the medulla also express nicotinic acetylcholine receptors, which are made up of five subunits, arranged symmetrically around a central poreActivation of the nicotinic acetylcholine receptor α4, α7, and β2 subunits increases respiratory rhythm, whereas activation of the nicotinic acetylcholine receptor α4β2 or α7 subunits induces analgesia in multiple forms of pain WHAT THIS ARTICLE TELLS US THAT IS NEWThe nonselective nicotinic acetylcholine receptor agonist nicotine and the α4β2 nicotinic acetylcholine receptor agonist A85380, but not the α7 nicotinic acetylcholine receptor agonist PNU282987, reversed respiratory depression induced by activation of μ-opioid receptors in rats both in vitro and in vivoCoadministration of A85380 with fentanyl not only markedly reduced respiratory depression and apneas but also enhanced the fentanyl-induced analgesia BACKGROUND:Opioid analgesics are widely used for treatment of acute, postoperative, and chronic pain. However, activation of opioid receptors can result in severe respiratory depression. There is an unmet clinical need to develop a pharmacologic therapy to counter opioid-induced respiratory depression without interfering with analgesia. Further, additional advances to confront accidental lethal overdose with the use of fentanyl and other opioids are needed. Here, the authors test the hypothesis that activation of nicotinic receptors expressed within respiratory rhythm–generating networks would counter opioid-induced respiratory depression without compromising analgesia. METHODS:Respiratory neural discharge was measured using in vitro brainstem–spinal cord and medullary slice rat preparations. In vivo, plethysmographic recording, nociception testing, and righting reflexes were used to examine respiratory ventilation, analgesia, and sedation, respectively. RESULTS:The administration of nicotine, selective α4β2 nicotinic receptor agonist A85380, but not α7 nicotinic receptor agonist PNU282987, reversed opioid-induced respiratory depression in neonatal pups in vitro and in vivo. In adult rats in vivo, administration of A85380 (0.03 mg/kg), but not PNU282987, provides a rapid and robust reversal of fentanyl-induced decrease in respiratory rate (93.4 ±