Countering Opioid-induced Respiratory Depression in Male Rats with Nicotinic Acetylcholine Receptor Partial Agonists Varenicline and ABT 594
Autor: | Xiuqing Ding, Jun Ren, John J. Greer |
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Rok vydání: | 2020 |
Předmět: |
Male
Pyridines Remifentanil (+)-Naloxone Receptors Nicotinic Partial agonist Fentanyl Rats Sprague-Dawley 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine 030202 anesthesiology Animals Medicine Nicotinic Agonists Varenicline business.industry Rats Analgesics Opioid Drug Partial Agonism Anesthesiology and Pain Medicine Nicotinic agonist Opioid chemistry Anesthesia Morphine Azetidines Respiratory Insufficiency business 030217 neurology & neurosurgery medicine.drug |
Zdroj: | Anesthesiology. 132:1197-1211 |
ISSN: | 0003-3022 |
Popis: | Background Opioids can induce significant respiratory depression when administered as analgesics for the treatment of acute, postoperative, and chronic pain. There are currently no pharmacologic means of reversing opioid-induced respiratory depression without interfering with analgesia. Further, there is a growing epidemic of opioid overdose that could benefit from therapeutic advancements. The aim of this study was to test the ability of two partial agonists of α4β2 nicotinic acetylcholine receptors, varenicline (used clinically for smoking cessation) and ABT 594 (tebanicline, developed as an analgesic), to reduce respiratory depression induced by fentanyl, remifentanil, morphine, and a combination of fentanyl and diazepam. Methods Whole body plethysmographic recordings, nociception testing, and righting reflex testing were used to examine ventilation, analgesia, and sedation in adult male Sprague–Dawley rats. Results Pre-, co-, or postadministration of varenicline or ABT 594 did not alter baseline breathing but markedly reduced opioid-induced respiratory depression. Varenicline had no effect on fentanyl-induced analgesia and ABT 594 potentiated fentanyl-induced analgesia. Specifically, 10-min administration of fentanyl induced a decrease in respiratory rate to 43 ± 32% of control in vehicle group, which was alleviated by preadministration of varenicline (85 ± 14% of control, n = 8, P < 0.001) or ABT 594 (81 ± 36% of control, n = 8, P = 0.001). ABT 594 or varenicline with a low dose of naloxone (1 µg/kg), but not varenicline alone, partially reversed fentanyl-induced lethal apnea, but neither compound provided the very rapid and complete reversal of apnea achieved with high doses of naloxone (0.03 to 1 mg/kg). Administration of varenicline (n = 4, P = 0.034) or ABT 594 (n = 4, P = 0.034) prevented lethal apneas induced by the combination of fentanyl and diazepam. Conclusions Activation of α4β2 nicotinic acetylcholine receptors by varenicline and ABT 594 counters opioid-induced respiratory depression without interfering with analgesia. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New |
Databáze: | OpenAIRE |
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