Behavioral Biology Program, McLean Hospital, Belmont, Massachusetts and Department of Psychiatry, Harvard Medical School, Boston, Massachusetts.
Behavioral Biology Program, McLean Hospital, Belmont, Massachusetts and Department of Psychiatry, Harvard Medical School, Boston, Massachusetts
J Pharmacol Exp Ther. 2021 Apr;377(1):100-107. doi: 10.1124/jpet.120.000423. Epub 2021 Jan 13.
Nicotine has previously been shown to augment the antinociceptive effects of -opioid agonists in squirrel monkeys without producing a concomitant increase in behavioral disruption. The present studies were conducted to extend these findings by determining the ability of the nicotinic acetylcholine receptor (nAChR) agonist epibatidine and partial 42 nAChR agonist varenicline to selectively augment the antinociceptive effects of the -opioid receptor (MOR) full agonist fentanyl, the MOR partial agonist nalbuphine, and the -opioid receptor (KOR) agonist U69,593 in male squirrel monkeys. Results indicate that both nAChR ligands selectively increased the antinociceptive effects of nalbuphine and that epibatidine increased the antinociceptive effects of U69,593 without altering effects on operant behavior. However, neither epibatidine nor varenicline enhanced the antinociceptive effects of fentanyl, perhaps due to its high efficacy. The enhancement of nalbuphine's antinociceptive effects by epibatidine, but not varenicline, could be antagonized by either mecamylamine or dihydro--erythroidine, consistent with 42 mediation of epibatidine's effects but suggesting the involvement of non-nAChR mechanisms in the effects of varenicline. The present results support previous findings showing that an nAChR agonist can serve as an adjuvant for MOR antinociception and, based on results with U69,593, further indicate that the adjuvant effects of nAChR drugs may also apply to antinociception produced by KOR. Our findings support the further evaluation of nAChR agonists as adjuvants of opioid pharmacotherapy for pain management and point out the need for further investigation into the mechanisms by which they produce opioid-adjuvant effects. SIGNIFICANCE STATEMENT: Nicotine has been shown to augment the antinociceptive effects of -opioid receptor analgesics without exacerbating their effects on operant performance. The present study demonstrates that the nicotinic acetylcholine receptor (nAChR) agonist epibatidine and partial α4β2 nAChR agonist varenicline can also augment the antinociceptive effects of nalbuphine, as well as those of a -opioid receptor agonist, without concomitantly exacerbating their behaviorally disruptive effects. These findings support the view that nAChR agonists and partial agonists may have potential as adjuvant therapies for opioid-based analgesics.
尼古丁先前已被证明可增强 - 阿片受体激动剂在松鼠猴中的抗伤害效应，而不会同时增加行为障碍。本研究通过确定烟碱型乙酰胆碱受体 (nAChR) 激动剂埃派他丁和部分 42 nAChR 激动剂伐仑克林选择性增强 - 阿片受体 (MOR) 完全激动剂芬太尼、MOR 部分激动剂纳布啡和 - 阿片受体 (KOR) 激动剂 U69,593 的抗伤害效应，扩展了这些发现。结果表明，两种 nAChR 配体均选择性地增强了纳布啡的抗伤害效应，埃派他丁增加了 U69,593 的抗伤害效应，而不改变操作行为的效应。然而，埃派他丁或伐仑克林均未增强芬太尼的抗伤害效应，这可能是由于其高效力。埃派他丁增强纳布啡的抗伤害效应，但伐仑克林却没有，这可以被美加明或二氢 - 育亨宾拮抗，这与埃派他丁作用的 42 介导一致，但表明伐仑克林的作用涉及非 nAChR 机制。本研究结果支持先前的研究结果，表明 nAChR 激动剂可用作 MOR 镇痛的佐剂，并且基于 U69,593 的结果，进一步表明 nAChR 药物的佐剂作用也可能适用于 KOR 产生的镇痛作用。我们的研究结果支持进一步评估 nAChR 激动剂作为阿片类药物治疗疼痛管理的佐剂，并指出需要进一步研究它们产生阿片类药物佐剂作用的机制。重要性声明：尼古丁已被证明可增强 - 阿片受体镇痛剂的抗伤害效应，而不会加重其对操作性表现的影响。本研究表明，烟碱型乙酰胆碱受体 (nAChR) 激动剂埃派他丁和部分 α4β2 nAChR 激动剂伐仑克林也可以增强纳布啡以及 - 阿片受体激动剂的抗伤害效应，而不会同时加重其行为障碍作用。这些发现支持这样一种观点，即 nAChR 激动剂和部分激动剂可能具有作为基于阿片类药物的镇痛药的佐剂治疗的潜力。
