Hiranita Takato, Ho Nicholas P, France Charles P
Departments of Pharmacology (T.H., N.P.H., C.P.F.) and Psychiatry (C.P.F.) and Addiction Research, Treatment and Training Center of Excellence (T.H., N.P.H., C.P.F.), University of Texas Health Science Center at San Antonio, San Antonio, Texas.
Departments of Pharmacology (T.H., N.P.H., C.P.F.) and Psychiatry (C.P.F.) and Addiction Research, Treatment and Training Center of Excellence (T.H., N.P.H., C.P.F.), University of Texas Health Science Center at San Antonio, San Antonio, Texas
J Pharmacol Exp Ther. 2024 Sep 18;391(1):4-17. doi: 10.1124/jpet.123.002032.
The number of opioid overdose deaths has increased significantly over the past decade. The life-threatening effect of opioids is hypoventilation, which can be reversed by the -opioid receptor (MOR) antagonist naloxone; however, because of the very short duration of action of naloxone, reemergence of MOR agonist-induced hypoventilation can occur, requiring additional doses of naloxone. The MOR antagonist methocinnamox (MCAM) antagonizes hypoventilation by the nonmorphinan fentanyl and the morphinan heroin in laboratory animals with an unusually long duration of action. Whole-body plethysmography was used to compare the potency and effectiveness of MCAM and naloxone for preventing and reversing hypoventilation by fentanyl, heroin, and the ultrapotent and longer-acting fentanyl analogs carfentanil and 3-methylfentanyl in male rats breathing normal air. Sessions comprised a 45-minute habituation period followed by intravenous administration of saline or an acute dose of MOR agonist. The rank order of potency to decrease ventilation was 3-methylfentanyl > carfentanil > fentanyl > heroin. MCAM (0.0001-0.1 mg/kg) and naloxone (0.0001-0.01 mg/kg) dose dependently reversed hypoventilation by 3-methylfentanyl (0.01 mg/kg), carfentanil (0.01 mg/kg), fentanyl (0.1 mg/kg), or heroin (3.2 mg/kg). For prevention studies, MCAM, naloxone, or vehicle was administered intravenously 22, 46, or 70 hours prior to a MOR agonist. When administered 22 hours earlier, MCAM (0.1-1.0 mg/kg) but not naloxone (1.0 mg/kg) prevented hypoventilation by each MOR agonist. This study demonstrates the effectiveness of MCAM at reversing and preventing hypoventilation by MOR agonists including ultrapotent fentanyl analogs that have a long duration of action. SIGNIFICANCE STATEMENT: The number of opioid overdose deaths increased over the past decade despite the availability of antagonists that can prevent and reverse the effects of opioids. This study demonstrates the effectiveness and long duration of action of the -opioid receptor (MOR) antagonist methocinnamox (MCAM) for reversing and preventing hypoventilation by MOR agonists including ultrapotent fentanyl analogs. These results provide support for the notion that MCAM has the potential to positively impact the ongoing opioid crisis by reversing and preventing opioid overdose.
在过去十年中，阿片类药物过量致死的人数显著增加。阿片类药物危及生命的效应是通气不足，这可通过μ-阿片受体（MOR）拮抗剂纳洛酮逆转；然而，由于纳洛酮的作用持续时间非常短，MOR激动剂诱导的通气不足可能再次出现，需要额外剂量的纳洛酮。MOR拮抗剂甲氧基肉桂肟（MCAM）在实验动物中可拮抗非吗啡类芬太尼和吗啡类海洛因引起的通气不足，且作用持续时间异常长。采用全身体积描记法比较MCAM和纳洛酮预防和逆转芬太尼、海洛因以及超效和长效芬太尼类似物卡芬太尼和3-甲基芬太尼在呼吸正常空气的雄性大鼠中引起的通气不足的效价和有效性。实验环节包括45分钟的适应期，随后静脉注射生理盐水或急性剂量的MOR激动剂。降低通气的效价顺序为3-甲基芬太尼＞卡芬太尼＞芬太尼＞海洛因。MCAM（0.0001 - 0.1mg/kg）和纳洛酮（0.0001 - 0.01mg/kg）剂量依赖性地逆转3-甲基芬太尼（0.01mg/kg）、卡芬太尼（0.01mg/kg）、芬太尼（0.1mg/kg）或海洛因（3.2mg/kg）引起的通气不足。在预防研究中，在给予MOR激动剂前22、46或70小时静脉注射MCAM、纳洛酮或赋形剂。提前22小时给药时，MCAM（0.1 - 1.0mg/kg）而非纳洛酮（1.0mg/kg）可预防每种MOR激动剂引起的通气不足。本研究证明了MCAM在逆转和预防包括具有长效作用的超效芬太尼类似物在内的MOR激动剂引起的通气不足方面的有效性。重要声明：尽管有可预防和逆转阿片类药物作用的拮抗剂，但在过去十年中阿片类药物过量致死的人数仍在增加。本研究证明了μ-阿片受体（MOR）拮抗剂甲氧基肉桂肟（MCAM）在逆转和预防包括超效芬太尼类似物在内的MOR激动剂引起的通气不足方面的有效性和长效性。这些结果为MCAM通过逆转和预防阿片类药物过量对当前阿片类药物危机产生积极影响这一观点提供了支持。
