Department of Diagnostic and Biological Sciences, School of Dentistry, University of Minnesota, Minneapolis, MN, USA.
Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, MN, USA.
Pain. 2018 Jul;159(7):1382-1391. doi: 10.1097/j.pain.0000000000001225.
Sickle cell disease (SCD) is a chronic inflammatory disorder accompanied by chronic pain. In addition to ongoing pain and hyperalgesia, vaso-occlusive crises-induced pain can be chronic or episodic. Because analgesics typically used to treat pain are not very effective in SCD, opioids, including morphine, are a primary treatment for managing pain in SCD but are associated with many serious side effects, including constipation, tolerance, addiction, and respiratory depression. Thus, there is a need for the development of novel treatments for pain in SCD. In this study, we used the Townes transgenic mouse model of SCD to investigate the antinociceptive efficacy of the bivalent ligand, MCC22, and compared its effectiveness with morphine. MCC22 consists of a mu-opioid receptor agonist and a chemokine receptor-5 (CCR5) antagonist that are linked through a 22-atom spacer. Our results show that intraperitoneal administration of MCC22 produced exceptionally potent dose-dependent antihyperalgesia as compared to morphine, dramatically decreased evoked responses of nociceptive dorsal horn neurons, and decreased expression of proinflammatory cytokines in the spinal cord. Moreover, tolerance did not develop to its analgesic effects after repeated administration. In view of the extraordinary potency of MCC22 without tolerance, MCC22 and similar compounds may vastly improve the management of pain associated with SCD.
镰状细胞病（SCD）是一种伴有慢性疼痛的慢性炎症性疾病。除了持续疼痛和痛觉过敏外，血管阻塞性危象引起的疼痛可能是慢性的也可能是间歇性的。由于通常用于治疗疼痛的镇痛药在 SCD 中效果不佳，因此包括吗啡在内的阿片类药物是治疗 SCD 疼痛的主要治疗方法，但它们会引起许多严重的副作用，包括便秘、耐受、成瘾和呼吸抑制。因此，需要开发治疗 SCD 疼痛的新方法。在这项研究中，我们使用 Townes 转基因 SCD 小鼠模型来研究二价配体 MCC22 的镇痛效果，并将其与吗啡进行比较。MCC22 由μ-阿片受体激动剂和趋化因子受体 5（CCR5）拮抗剂组成，通过 22 个原子的间隔物连接在一起。我们的结果表明，与吗啡相比，腹腔内给予 MCC22 可产生异常强效的剂量依赖性抗痛觉过敏作用，显著降低伤害性背角神经元的诱发反应，并降低脊髓中促炎细胞因子的表达。此外，重复给药后不会产生对其镇痛作用的耐受。鉴于 MCC22 的非凡效力而没有耐受，MCC22 和类似化合物可能会极大地改善与 SCD 相关的疼痛管理。
