Nociceptin opioid peptide (NOP) receptor modulates pain transmission and is considered a prospective target for pain management. Under acute pain conditions in rodents, however, no definitive conclusions about effects of systemically intervening NOP receptors on nociception, classical opioid-induced antinociception, tolerance and physical dependence have been drawn. Given that opioid analgesia has sex differences, and females experience greater pain and consume more opioids, clarifying these issues in females will help develop novel analgesics. To clarify the role of NOP receptors on the pharmacological profiles of µ-opioid receptor agonists, in this study, a selective agonist (SCH221510) and antagonist (SB612111) of the NOP receptor were subcutaneously administered in female mice in multiple animal models. In hot-plate test, neither SCH221510 (3 and 10 mg/kg, sc) nor SB612111 (10 mg/kg, sc) produced significant antinociception. SCH221510 (3 mg/kg, sc) attenuated but SB612111 (10 mg/kg, sc) enhanced morphine-induced antinociception, with rightward and leftward shift of morphine dose-response curves, respectively. SCH221510 (3 mg/kg, sc) combined with morphine (10 mg/kg, sc) accelerated the development of morphine antinociceptive tolerance. Conversely, SB612111 (10 mg/kg, sc) delayed morphine tolerance development. Neither SCH221510 (3 mg/kg, sc) nor SB612111 (10 mg/kg, sc) statistically significantly altered the development of morphine-induced physical dependence. Therefore, systemic activation of NOP receptors attenuated morphine antinociception to acute thermal stimuli, facilitated morphine-induced antinociceptive tolerance but did not robustly alter physical dependence in female mice. Systemic blockade of NOP receptors produced opposite actions. These findings demonstrate that N/OFQ-NOP receptor system plays diverse roles in modulating pharmacological profiles of µ-opioid receptor agonists.

中文翻译：

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伤害感受肽阿片肽受体参与吗啡诱导的雌性小鼠的镇痛、耐受和身体依赖性。


痛敏肽阿片肽 (NOP) 受体可调节疼痛传递，被认为是疼痛管理的潜在靶点。然而，在啮齿动物的急性疼痛条件下，关于系统性干预 NOP 受体对伤害感受、经典阿片类药物诱导的抗伤害感受、耐受性和身体依赖性的影响，尚未得出明确的结论。鉴于阿片类镇痛存在性别差异，女性会经历更大的疼痛并消耗更多的阿片类药物，澄清女性的这些问题将有助于开发新型镇痛药。为了阐明 NOP 受体对 µ-阿片受体激动剂药理学特征的作用，在本研究中，在多种动物模型的雌性小鼠中皮下注射 NOP 受体的选择性激动剂 (SCH221510) 和拮抗剂 (SB612111)。在热板试验中，SCH221510（3 和 10 mg/kg，皮下）和 SB612111（10 mg/kg，皮下）均未产生显着的镇痛作用。 SCH221510 (3 mg/kg, sc) 减弱但 SB612111 (10 mg/kg, sc) 增强吗啡诱导的镇痛作用，吗啡剂量反应曲线分别向右和向左移动。 SCH221510（3 mg/kg，皮下注射）与吗啡（10 mg/kg，皮下注射）联合加速吗啡镇痛耐受的发展。相反，SB612111（10 mg/kg，皮下注射）延迟吗啡耐受性的发展。 SCH221510（3 mg/kg，皮下注射）和SB612111（10 mg/kg，皮下注射）均未统计显着改变吗啡诱导的身体依赖性的发展。因此，NOP受体的全身激活减弱了吗啡对急性热刺激的镇痛作用，促进吗啡诱导的镇痛耐受，但并没有显着改变雌性小鼠的身体依赖性。系统性阻断 NOP 受体会产生相反的作用。 这些发现表明，N/OFQ-NOP 受体系统在调节 µ-阿片受体激动剂的药理学特性中发挥着多种作用。