Department of Neuropharmacology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi, Japan.
PLoS One. 2011;6(8):e23510. doi: 10.1371/journal.pone.0023510. Epub 2011 Aug 18.
There is accumulating evidence that the activation of spinal glial cells, especially microglia, is a key event in the pathogenesis of neuropathic pain. However, the inhibition of microglial activation is often ineffective, especially for long-lasting persistent neuropathic pain. So far, neuropathic pain remains largely intractable and a new therapeutic strategy for the pain is still required.
METHODS/PRINCIPAL FINDINGS: Using Seltzer model mice, we investigated the temporal aspect of two types of neuropathic pain behaviors, i.e., thermal hyperalgesia and mechanical allodynia, as well as that of morphological changes in spinal microglia and astrocytes by immunohistochemical studies. Firstly, we analyzed the pattern of progression in the pain behaviors, and found that the pain consisted of an "early induction phase" and subsequent "late maintenance phase". We next analyzed the temporal changes in spinal glial cells, and found that the induction and the maintenance phase of pain were associated with the activation of microglia and astrocytes, respectively. When Bushi, a Japanese herbal medicine often used for several types of persistent pain, was administered chronically, it inhibited the maintenance phase of pain without affecting the induction phase, which was in accordance with the inhibition of astrocytic activation in the spinal cord. These analgesic effects and the inhibition of astrocytic activation by Bushi were mimicked by the intrathecal injection of fluorocitrate, an inhibitor of astrocytic activation. Finally, we tested the direct effect of Bushi on astrocytic activation, and found that Bushi suppressed the IL-1β- or IL-18-evoked ERK1/2-phosphorylation in cultured astrocytes but not the ATP-evoked p38- and ERK1/2-phosphorylation in microglia in vitro.
Our results indicated that the activation of spinal astrocytes was responsible for the late maintenance phase of neuropathic pain in the Seltzer model mice and, therefore, the inhibition of astrocytic activation by Bushi could be a useful therapeutic strategy for treating neuropathic pain.
有越来越多的证据表明，脊髓神经胶质细胞（尤其是小胶质细胞）的激活是神经性疼痛发病机制中的一个关键事件。然而，小胶质细胞激活的抑制往往无效，特别是对于长期持续的神经性疼痛。到目前为止，神经性疼痛仍然在很大程度上难以治疗，仍然需要一种新的治疗疼痛的策略。
方法/主要发现：我们使用 Seltzer 模型小鼠，通过免疫组织化学研究，研究了两种神经性疼痛行为（即热痛觉过敏和机械性痛觉过敏）的时间方面，以及脊髓小胶质细胞和星形胶质细胞形态变化的时间方面。首先，我们分析了疼痛行为的进展模式，发现疼痛包括“早期诱导期”和随后的“晚期维持期”。然后，我们分析了脊髓神经胶质细胞的时间变化，发现疼痛的诱导和维持期分别与小胶质细胞和星形胶质细胞的激活有关。当 Bushi（一种常用于几种类型的持续性疼痛的日本草药）被长期给予时，它抑制了疼痛的维持期，而不影响诱导期，这与脊髓中星形胶质细胞的激活抑制一致。Bushi 的这种镇痛作用和对星形胶质细胞激活的抑制作用可以通过鞘内注射氟柠檬酸来模拟，氟柠檬酸是一种星形胶质细胞激活抑制剂。最后，我们测试了 Bushi 对星形胶质细胞激活的直接作用，发现 Bushi 抑制了培养的星形胶质细胞中 IL-1β 或 IL-18 诱导的 ERK1/2 磷酸化，但不抑制小胶质细胞中 ATP 诱导的 p38 和 ERK1/2 磷酸化。
我们的结果表明，脊髓星形胶质细胞的激活是 Seltzer 模型小鼠神经性疼痛晚期维持期的原因，因此，Bushi 对星形胶质细胞激活的抑制可能是治疗神经性疼痛的一种有用的治疗策略。
