Countering Opioid-induced Respiratory Depression in Male Rats with Nicotinic Acetylcholine Receptor Partial Agonists Varenicline and ABT 594

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 alpha 4 beta 2 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 mu g/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 alpha 4 beta 2 nicotinic acetylcholine receptors by varenicline and ABT 594 counters opioid-induced respiratory depression without interfering with analgesia.