Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia (Z.A.C., J.L.W., D.B., S.L.K., N.P., G.D., M.A.M., J.L.P., D.A.G., M.I.D., A.H.L.); The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California (M.J.N., B.F.C.); and Department of Chemistry, University of Virginia, Charlottesville, Virginia (K.-L.H.).
Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia (Z.A.C., J.L.W., D.B., S.L.K., N.P., G.D., M.A.M., J.L.P., D.A.G., M.I.D., A.H.L.); The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California (M.J.N., B.F.C.); and Department of Chemistry, University of Virginia, Charlottesville, Virginia (K.-L.H.)
J Pharmacol Exp Ther. 2018 Jul;366(1):169-183. doi: 10.1124/jpet.117.245704. Epub 2018 Mar 14.
Although paclitaxel effectively treats various cancers, its debilitating peripheral neuropathic pain side effects often persist long after treatment has ended. Therefore, a compelling need exists for the identification of novel pharmacologic strategies to mitigate this condition. As inhibitors of monoacylglycerol lipase (MAGL), the primary hydrolytic enzyme of the endogenous cannabinoid, 2-arachidonyolglycerol, produces antinociceptive effects in numerous rodent models of pain, we investigated whether inhibitors of this enzyme (i.e., JZL184 and MJN110) would reverse paclitaxel-induced mechanical allodynia in mice. These drugs dose dependently reversed allodynia with respective ED values (95% confidence limit) of 8.4 (5.2-13.6) and 1.8 (1.0-3.3) mg/kg. Complementary genetic and pharmacologic approaches revealed that the antiallodynic effects of each drug require both cannabinoid receptors, CB and CB MJN110 reduced paclitaxel-mediated increased expression of monocyte chemoattractant protein-1 (MCP-1, CCL2) and phospho-p38 MAPK in dorsal root ganglia as well as MCP-1 in spinal dorsal horn. Whereas the antinociceptive effects of high dose JZL184 (40 mg/kg) underwent tolerance following 6 days of repeated dosing, repeated administration of a threshold dose (i.e., 4 mg/kg) completely reversed paclitaxel-induced allodynia. In addition, we found that the administration of MJN110 to control mice lacked intrinsic rewarding effects in the conditioned place preference (CPP) paradigm. However, it produced a CPP in paclitaxel-treated animals, suggesting a reduced paclitaxel-induced aversive state. Importantly, JZL184 did not alter the antiproliferative and apoptotic effects of paclitaxel in A549 and H460 non-small cell lung cancer cells. Taken together, these data indicate that MAGL inhibitors reverse paclitaxel-induced neuropathic pain without interfering with chemotherapeutic efficacy.
虽然紫杉醇能有效治疗多种癌症，但它会导致衰弱性周围神经性疼痛副作用，这些副作用在治疗结束后很长时间内仍会持续存在。因此，迫切需要寻找新的药物治疗策略来缓解这种情况。作为单酰基甘油脂肪酶（MAGL）的抑制剂，内源性大麻素 2-花生四烯酸甘油的主要水解酶，在许多啮齿动物疼痛模型中产生镇痛作用，我们研究了这种酶的抑制剂（即 JZL184 和 MJN110）是否会逆转紫杉醇诱导的小鼠机械性痛觉过敏。这些药物呈剂量依赖性地逆转了痛觉过敏，各自的 ED 值（95%置信限）分别为 8.4（5.2-13.6）和 1.8（1.0-3.3）mg/kg。补充遗传和药理学方法表明，每种药物的抗痛觉过敏作用都需要大麻素受体 CB1 和 CB2，MJN110 降低了紫杉醇介导的背根神经节中单核细胞趋化蛋白-1（MCP-1，CCL2）和磷酸化 p38 MAPK 的表达，以及脊髓背角中的 MCP-1。虽然高剂量 JZL184（40mg/kg）在重复给药 6 天后出现了耐受现象，但重复给予阈值剂量（即 4mg/kg）完全逆转了紫杉醇诱导的痛觉过敏。此外，我们发现 MJN110 给予对照小鼠在条件性位置偏爱（CPP）范式中没有内在的奖赏作用。然而，它在紫杉醇处理的动物中产生了 CPP，表明减轻了紫杉醇引起的厌恶状态。重要的是，JZL184 没有改变紫杉醇在 A549 和 H460 非小细胞肺癌细胞中的增殖和凋亡作用。总之，这些数据表明 MAGL 抑制剂可逆转紫杉醇引起的神经性疼痛，而不干扰化疗疗效。
