Department of Anesthesiology, Rutgers New Jersey Medical School, The State University of New Jersey, 185 S. Orange Ave., MSB, F-661, Newark, NJ, 07103, USA.
Department of Physiology, Rutgers New Jersey Medical School, The State University of New Jersey, Pharmacology & Neuroscience, Newark, NJ, 07103, USA.
Neurotherapeutics. 2021 Oct;18(4):2436-2448. doi: 10.1007/s13311-021-01158-8. Epub 2021 Nov 18.
Metastatic bone pain and chemotherapy-induced peripheral neuropathic pain are the most common clinical symptoms in cancer patients. The current clinical management of these two disorders is ineffective and/or produces severe side effects. The present study employed a dual-target compound named as ZL006-05 and examined the effect of systemic administration of ZL006-05 on RM-1-induced bone cancer pain and paclitaxel-induced neuropathic pain. Intravenous injection of ZL006-05 dose-dependently alleviated RM-1-induced mechanical allodynia, heat hyperalgesia, cold hyperalgesia, and spontaneously ongoing nociceptive responses during both induction and maintenance periods, without analgesic tolerance, affecting basal/acute pain and locomotor function. Similar behavioral results were observed in paclitaxel-induced neuropathic pain. This injection also decreased neuronal and astrocyte hyperactivities in the lumbar dorsal horn after RM-1 tibial inoculation or paclitaxel intraperitoneal injection. Mechanistically, intravenous injection of ZL006-05 potentiated the GABA receptor agonist-evoked currents in the neurons of the dorsal horn and anterior cingulate cortex and also blocked the paclitaxel-induced increase in postsynaptic density-95-neuronal nitric oxide synthase interaction in dorsal horn. Our findings strongly suggest that ZL006-05 may be a new candidate for the management of cancer pain and chemotherapy-induced peripheral neuropathic pain.
转移性骨痛和化疗诱导的周围神经性疼痛是癌症患者最常见的临床症状。目前这两种疾病的临床治疗效果不佳和/或产生严重的副作用。本研究采用一种名为 ZL006-05 的双靶化合物，考察了 ZL006-05 全身给药对 RM-1 诱导的骨癌痛和紫杉醇诱导的神经性疼痛的作用。ZL006-05 静脉注射剂量依赖性地缓解 RM-1 诱导的机械性痛觉过敏、热痛觉过敏、冷痛觉过敏和自发性持续性伤害感受反应，在诱导和维持期均无镇痛耐受，不影响基础/急性疼痛和运动功能。在紫杉醇诱导的神经性疼痛中也观察到类似的行为结果。这种注射还降低了 RM-1 胫骨接种或紫杉醇腹腔注射后腰椎背角神经元和星形胶质细胞的过度活跃。在机制上，ZL006-05 静脉注射增强了背角和前扣带皮层神经元中 GABA 受体激动剂诱发的电流，也阻断了紫杉醇诱导的背角中突触后密度-95-神经元型一氧化氮合酶相互作用的增加。我们的研究结果强烈表明，ZL006-05 可能是治疗癌症疼痛和化疗诱导的周围神经性疼痛的一种新的候选药物。
