Department of Psychology, University of Kentucky, Lexington, KY, USA.
College of Pharmacy, University of Kentucky, Lexington, KY, USA.
Environ Toxicol Pharmacol. 2024 Sep;110:104527. doi: 10.1016/j.etap.2024.104527. Epub 2024 Aug 4.
This study assessed the ability of α and α-adrenergic drugs to decrease fentanyl-induced locomotor and ventilatory depression. Rats were given saline or fentanyl, followed by: (1) naltrexone, (2) naloxone, (3) nalmefene, (4) α agonist phenylephrine, (5) α antagonist prazosin, (6) α antagonist BMY-7378, (7) α agonist clonidine, (8) α antagonist yohimbine or (9) vehicle. All µ-opioid antagonists dose-dependently reversed fentanyl-induced locomotor and ventilatory depression. While the α drugs did not alter the effects of fentanyl, clonidine dose-dependently decreased locomotion and respiration with and without fentanyl. Conversely, yohimbine given at a low dose (0.3-1 mg/kg) stimulated ventilation when given alone and higher doses (>1 mg/kg) partially reversed (∼50 %) fentanyl-induced ventilatory depression, but not locomotor depression. High doses of yohimbine in combination with a suboptimal dose of naltrexone reversed fentanyl-induced ventilatory depression, suggestive of additivity. Yohimbine may serve as an effective adjunctive countermeasure agent combined with naltrexone to rescue fentanyl-induced ventilatory depression.
本研究评估了α和α-肾上腺素能药物降低芬太尼引起的运动和通气抑制的能力。大鼠给予生理盐水或芬太尼，然后给予：（1）纳曲酮，（2）纳洛酮，（3）那美芬，（4）α激动剂苯肾上腺素，（5）α拮抗剂哌唑嗪，（6）α拮抗剂 BMY-7378，（7）α激动剂可乐定，（8）α拮抗剂育亨宾或（9）载体。所有μ-阿片受体拮抗剂均剂量依赖性地逆转了芬太尼引起的运动和通气抑制。虽然α药物不改变芬太尼的作用，但可乐定剂量依赖性地降低了芬太尼存在或不存在时的运动和呼吸。相反，育亨宾在低剂量（0.3-1mg/kg）时单独使用时刺激通气，而高剂量（>1mg/kg）部分逆转（约 50%）芬太尼引起的通气抑制，但不逆转运动抑制。育亨宾高剂量与纳曲酮亚最佳剂量联合使用可逆转芬太尼引起的通气抑制，提示具有相加作用。育亨宾可能作为一种有效的辅助对策药物与纳曲酮联合使用，以挽救芬太尼引起的通气抑制。
