Department of Diagnostic & Biological Sciences, School of Dentistry, University of Minnesota, Minneapolis, MN, USA.
Department of Medicinal Chemistry, College of Pharmacy University of Minnesota, Minneapolis, MN, USA.
Neuropharmacology. 2019 Nov 1;158:107598. doi: 10.1016/j.neuropharm.2019.04.004. Epub 2019 Apr 7.
Cisplatin and other widely employed platinum-based anticancer agents produce chemotherapy-induced peripheral neuropathy (CIPN) that often results in pain and hyperalgesia that are difficult to manage. We investigated the efficacy of a novel bivalent ligand, MCC22, for the treatment of pain arising from CIPN. MCC22 consists of mu opioid receptor (MOR) agonist and chemokine receptor 5 (CCR5) antagonist pharmacophores connected through a 22-atom spacer and was designed to target a putative MOR-CCR5 heteromer localized in pain processing areas. Mice received once daily intraperitoneal (i.p.) injections of cisplatin (1 mg/kg) for seven days and behavior testing began 7 days later. Cisplatin produced mechanical hyperalgesia that was decreased dose-dependently by MCC22 given by intrathecal (ED = 0.004 pmol) or i.p. (3.07 mg/kg) routes. The decrease in hyperalgesia was associated with decreased inflammatory response by microglia in the spinal cord. Unlike morphine, MCC22 given daily for nine days did not exhibit tolerance to its analgesic effect and its characteristic antihyperalgesic activity was fully retained in morphine-tolerant mice. Furthermore, MCC22 did not alter motor function and did not exhibit rewarding properties. Given the exceptional potency of MCC22 without tolerance or reward, MCC22 has the potential to vastly improve management of chronic pain due to CIPN. This article is part of the Special Issue entitled 'New Vistas in Opioid Pharmacology'.
顺铂和其他广泛使用的基于铂的抗癌药物会导致化疗引起的周围神经病（CIPN），通常会导致疼痛和痛觉过敏，难以治疗。我们研究了一种新型双价配体 MCC22 治疗 CIPN 引起的疼痛的疗效。MCC22 由 μ 阿片受体（MOR）激动剂和趋化因子受体 5（CCR5）拮抗剂通过一个 22 个原子的间隔物连接而成，旨在针对定位于疼痛处理区域的假定 MOR-CCR5 异源二聚体。小鼠接受每日一次腹腔（i.p.）注射顺铂（1mg/kg），共 7 天，行为测试于 7 天后开始。顺铂产生机械性痛觉过敏，MCC22 通过鞘内（ED=0.004pmol）或腹腔内（3.07mg/kg）途径给药可剂量依赖性地减轻。痛觉过敏的减轻与脊髓中小胶质细胞炎症反应的减少有关。与吗啡不同，MCC22 连续 9 天每日给药不会产生其镇痛作用的耐受，并且其特征性的抗痛觉过敏活性在吗啡耐受的小鼠中完全保留。此外，MCC22 不改变运动功能，也不表现出奖赏特性。鉴于 MCC22 具有无耐受或无奖赏的卓越效力，MCC22 有可能极大地改善 CIPN 引起的慢性疼痛的管理。本文是专题“阿片类药物药理学的新视角”的一部分。
