Department of Pharmacology, University of Texas Health Science Center at San Antonio.
Addiction Research, Treatment & Training Center of Excellence, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.
Behav Pharmacol. 2022 Sep 1;33(6):377-394. doi: 10.1097/FBP.0000000000000684. Epub 2022 Aug 3.
Drugs targeting mu opioid receptors are the mainstay of clinical practice for treating moderate-to-severe pain. While they can offer excellent analgesia, their use can be limited by adverse effects, including constipation, respiratory depression, tolerance, and abuse liability. Multifunctional ligands acting at mu opioid and nociceptin/orphanin FQ peptide receptors might provide antinociception with substantially improved adverse-effect profiles. This study explored one of these ligands, OREX-1038 (BU10038), in several assays in rodents and nonhuman primates. Binding and functional studies confirmed OREX-1038 to be a low-efficacy agonist at mu opioid and nociceptin/orphanin FQ peptide receptors and an antagonist at delta and kappa opioid receptors with selectivity for opioid receptors over other proteins. OREX-1038 had long-acting antinociceptive effects in postsurgical and complete Freund's adjuvant (CFA)-induced thermal hyperalgesia assays in rats and a warm water tail-withdrawal assay in monkeys. OREX-1038 was active for at least 24 h in each antinociception assay, and its effects in monkeys did not diminish over 22 days of daily administration. This activity was coupled with limited effects on physiological signs (arterial pressure, heart rate, and body temperature) and no evidence of withdrawal after administration of naltrexone or discontinuation of treatment in monkeys receiving OREX-1038 daily. Over a range of doses, OREX-1038 was only transiently self-administered, which diminished rapidly to nonsignificant levels; overall, both OREX-1038 and buprenorphine maintained less responding than remifentanil. These results support the concept of dual mu and nociceptin/orphanin FQ peptide receptor partial agonists having improved pharmacological profiles compared with opioids currently used to treat pain.
靶向μ阿片受体的药物是治疗中重度疼痛的临床实践的主要手段。虽然它们可以提供出色的镇痛效果，但由于不良反应，包括便秘、呼吸抑制、耐受性和滥用倾向，它们的使用可能会受到限制。作用于μ阿片和孤啡肽/孤啡肽 FQ 肽受体的多功能配体可能提供镇痛作用，同时显著改善不良反应谱。这项研究在啮齿动物和非人类灵长类动物中探索了这些配体之一 OREX-1038（BU10038）的几种测定方法。结合和功能研究证实，OREX-1038 是μ阿片和孤啡肽/孤啡肽 FQ 肽受体的低效能激动剂，也是δ和κ阿片受体的拮抗剂，对阿片受体具有选择性，对其他蛋白无作用。OREX-1038 在大鼠手术后和完全弗氏佐剂（CFA）诱导的热痛觉过敏测定中以及猴子的温水尾巴撤离测定中具有长效镇痛作用。在每个镇痛测定中，OREX-1038 的作用至少持续 24 小时，在猴子中，其作用在 22 天的每日给药中没有减弱。这种活性与对生理体征（动脉压、心率和体温）的有限影响相关，并且在接受 OREX-1038 每日治疗的猴子中给予纳曲酮或停止治疗后没有戒断迹象。在一系列剂量下，OREX-1038 仅短暂地自我给药，很快减少到无显著水平；总体而言，OREX-1038 和丁丙诺啡的反应均少于瑞芬太尼。这些结果支持双重μ和孤啡肽/孤啡肽 FQ 肽受体部分激动剂的概念，与目前用于治疗疼痛的阿片类药物相比，具有改善的药理学特征。
