Department of Cellular and Integrative Physiology and Center for Biomedical Neuroscience, University of Texas Health San Antonio, San Antonio, TX
J Pharmacol Exp Ther. 2021 Aug;378(2):96-107. doi: 10.1124/jpet.121.000535. Epub 2021 May 14.
Opioid overdose intervention by naloxone, a high affinity receptor antagonist, reverses opioid-induced respiratory depression (OIRD) and analgesia by displacing opioids. Systemic naloxone stimulates release of the hypothalamic neuropeptide oxytocin, which has analgesic properties and participates in cardiorespiratory homeostasis. To test the hypothesis that oxytocin can reverse OIRD, we assessed the rescue potential of graded doses (0, 0.1, 2, 5, 10, 50 nmol/kg, i.v.) of oxytocin to counter fentanyl (60 nmol/kg, i.v.)-induced depression of neural inspiration indexed by recording phrenic nerve activity (PNA) in anesthetized (urethane/-chloralose), vagotomized, and artificially ventilated rats. Oxytocin dose-dependently rescued fentanyl OIRD by almost immediately reversing PNA burst arrest ( = 0.0057) and restoring baseline burst frequency ( = 0.0016) and amplitude ( = 0.0025) at low but not high doses, resulting in inverted bell-shaped dose-response curves. Oxytocin receptor antagonism (40 nmol/kg, i.v.) prevented oxytocin reversal of OIRD (arrest: = 0.0066, frequency: = 0.0207, amplitude: = 0.0022). Vasopressin 1A receptor (V1aR) antagonism restored high-dose oxytocin efficacy to rescue OIRD ( = 0.0170 to < 0.0001), resulting in classic sigmoidal dose-response curves, and prevented ( = 0.0135) transient hypertension from V1aR cross-activation ( = 0.0275). Alone, vasopressin (5 nmol/kg, i.v.) failed to reverse fentanyl respiratory arrest ( = 0.6184). The nonpeptide oxytocin receptor agonist WAY-267464 (75 nmol/kg, i.v.), which has V1aR antagonist properties, quickly reversed fentanyl OIRD ( < 0.0001), with rapid recovery of PNA frequency ( = 0.0011) and amplitude ( = 0.0044) without adverse hemodynamic consequences ( = 0.9991). Findings indicate that peptide and nonpeptide agonist activation of oxytocin receptors without V1aR cross-activation rescues fentanyl OIRD. Oxytocin receptor agonists could be lifesaving resuscitation agents that enhance rather than interrupt opioid analgesia. SIGNIFICANCE STATEMENT: Oxytocin receptor activation produces analgesia. Here, we demonstrate that activation by the US Food and Drug Administration-approved agonist oxytocin and the nonpeptide partial agonist WAY-267464 can each reverse fentanyl cardiorespiratory depression. Selective targeting of oxytocin receptors for resuscitation from opioid overdose, alone or in combination with an opioid antagonist, could eliminate or attenuate negative side effects associated with traditional opioid receptor antagonism.
阿片类药物过量干预通过纳洛酮，一种高亲和力受体拮抗剂，通过置换阿片类药物来逆转阿片类药物引起的呼吸抑制（OIRD）和镇痛。全身纳洛酮刺激下丘脑神经肽催产素的释放，催产素有镇痛作用，并参与心肺生理稳态。为了测试催产素可以逆转 OIRD 的假设，我们评估了递增剂量（0、0.1、2、5、10、50nmol/kg，静脉内）的催产素对芬太尼（60nmol/kg，静脉内）诱导的神经吸气抑制的挽救潜力，通过记录膈神经活动（PNA）在麻醉（尿烷/-氯醛）、迷走神经切断和人工通气的大鼠中进行评估。催产素剂量依赖性地挽救芬太尼 OIRD，几乎立即逆转 PNA 爆发停止（=0.0057），并恢复基线爆发频率（=0.0016）和幅度（=0.0025）在低剂量但不在高剂量下，导致倒置钟形剂量反应曲线。催产素受体拮抗剂（40nmol/kg，静脉内）防止催产素逆转 OIRD（停止：=0.0066，频率：=0.0207，幅度：=0.0022）。血管加压素 1A 受体（V1aR）拮抗剂恢复了高剂量催产素的疗效，以挽救 OIRD（=0.0170 至 <0.0001），产生典型的 S 形剂量反应曲线，并防止（=0.0135）V1aR 交叉激活引起的短暂高血压（=0.0275）。单独使用血管加压素（5nmol/kg，静脉内）不能逆转芬太尼呼吸停止（=0.6184）。非肽催产素受体激动剂 WAY-267464（75nmol/kg，静脉内），具有 V1aR 拮抗剂特性，迅速逆转芬太尼 OIRD（<0.0001），PNA 频率（=0.0011）和幅度（=0.0044）迅速恢复，无不良血液动力学后果（=0.9991）。研究结果表明，肽和非肽激动剂激活催产素受体而不发生 V1aR 交叉激活可挽救芬太尼 OIRD。催产素受体激动剂可能是救命的复苏剂，增强而不是中断阿片类药物的镇痛作用。意义声明：催产素受体激活产生镇痛作用。在这里，我们证明，美国食品和药物管理局批准的激动剂催产素和非肽部分激动剂 WAY-267464 的激活都可以逆转芬太尼的心肺抑制。单独或与阿片类药物拮抗剂联合使用，针对阿片类药物过量的催产素受体的选择性靶向治疗，可以消除或减轻与传统阿片类药物受体拮抗剂相关的负面副作用。
