Distinct roles of matrix metalloproteases in the early- and late-phase development of neuropathic pain
Distinct roles of matrix metalloproteases in the early- and late-phase development of neuropathic pain
复制标题
DOI：
10.1038/nm1723
复制
发表时间：
2008-03-01
期刊：
影响因子：
82.9
通讯作者：
Ji, Ru-Rong
中科院分区：
文献类型：
--
作者：
Kawasaki, Yasuhiko;Xu, Zhen-Zhong;Ji, Ru-Rong
治疗由神经系统的多重损伤引发的神经性疼痛是一项临床挑战，因为神经性疼痛发展的潜在机制仍然知之甚少（1-4）。大多数治疗方法不区分神经性疼痛病理生理学的不同阶段，而只是专注于阻断神经传递，产生短暂的疼痛缓解。在这里，我们报告，早期和晚期神经病理性疼痛的发展在大鼠和小鼠神经损伤后需要不同的基质金属蛋白酶（MMPs）。脊神经结扎后，MMP-9在损伤的背根神经节（DRG）初级感觉神经元中显示出与神经性疼痛的早期相一致的快速和瞬时上调，而MMP-2在DRG卫星细胞和脊髓星形胶质细胞中显示出与神经性疼痛的晚期相一致的延迟反应。通过鞘内途径局部抑制MMP-9抑制神经性疼痛的早期阶段，而抑制MMP-2抑制神经性疼痛的晚期阶段。此外，鞘内施用MMP-9或MMP-2足以产生神经性疼痛症状。神经损伤后，MMP-9通过早期白细胞介素-1 β裂解和小胶质细胞活化诱导神经性疼痛，而MMP-2通过后期白细胞介素-1b裂解和星形胶质细胞活化维持神经性疼痛。抑制MMP可能为治疗不同阶段的神经病理性疼痛提供一种新的治疗方法。
Treatment of neuropathic pain, triggered by multiple insults to the nervous system, is a clinical challenge because the underlying mechanisms of neuropathic pain development remain poorly understood(1-4). Most treatments do not differentiate between different phases of neuropathic pain pathophysiology and simply focus on blocking neurotransmission, producing transient pain relief. Here, we report that early- and late-phase neuropathic pain development in rats and mice after nerve injury require different matrix metalloproteinases (MMPs). After spinal nerve ligation, MMP-9 shows a rapid and transient upregulation in injured dorsal root ganglion (DRG) primary sensory neurons consistent with an early phase of neuropathic pain, whereas MMP-2 shows a delayed response in DRG satellite cells and spinal astrocytes consistent with a late phase of neuropathic pain. Local inhibition of MMP-9 by an intrathecal route inhibits the early phase of neuropathic pain, whereas inhibition of MMP-2 suppresses the late phase of neuropathic pain. Further, intrathecal administration of MMP-9 or MMP-2 is sufficient to produce neuropathic pain symptoms. After nerve injury, MMP-9 induces neuropathic pain through interleukin-1 beta cleavage and microglial activation at early times, whereas MMP-2 maintains neuropathic pain through interleukin-1b cleavage and astrocyte activation at later times. Inhibition of MMP may provide a novel therapeutic approach for the treatment of neuropathic pain at different phases.