Sung Backil, Lim Grewo, Mao Jianren
Massachusetts General Hospital Pain Center, Department of Anesthesia and Critical Care, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
J Neurosci. 2003 Apr 1;23(7):2899-910. doi: 10.1523/JNEUROSCI.23-07-02899.2003.
The central glutamatergic system has been implicated in the pathogenesis of neuropathic pain, and a highly active central glutamate transporter (GT) system regulates the uptake of endogenous glutamate. Here we demonstrate that both the expression and uptake activity of spinal GTs changed after chronic constriction nerve injury (CCI) and contributed to neuropathic pain behaviors in rats. CCI induced an initial GT upregulation up to at least postoperative day 5 primarily within the ipsilateral spinal cord dorsal horn, which was followed by a GT downregulation when examined on postoperative days 7 and 14 by Western blot and immunohistochemistry. Intrathecal administration of the tyrosine kinase receptor inhibitor K252a and the mitogen-activated protein kinase inhibitor PD98059 for postoperative days 1-4 reduced and nearly abolished the initial GT upregulation in CCI rats, respectively. Prevention of the CCI-induced GT upregulation by PD98059 resulted in exacerbated thermal hyperalgesia and mechanical allodynia reversible by the noncompetitive NMDA receptor antagonist MK-801, indicating that the initial GT upregulation hampered the development of neuropathic pain behaviors. Moreover, CCI significantly reduced glutamate uptake activity of spinal GTs when examined on postoperative day 5, which was prevented by riluzole (a positive GT activity regulator) given intrathecally twice a day for postoperative days 1-4. Consistently, riluzole attenuated and gradually reversed neuropathic pain behaviors when the 4 d riluzole treatment was given for postoperative days 1-4 and 5-8, respectively. These results indicate that changes in the expression and glutamate uptake activity of spinal GTs may play a critical role in both the induction and maintenance of neuropathic pain after nerve injury via the regulation of regional glutamate homeostasis, a new mechanism relevant to the pathogenesis of neuropathic pain.
中枢谷氨酸能系统与神经性疼痛的发病机制有关，高度活跃的中枢谷氨酸转运体（GT）系统调节内源性谷氨酸的摄取。在此，我们证明，慢性缩窄性神经损伤（CCI）后脊髓GTs的表达和摄取活性均发生改变，并导致大鼠出现神经性疼痛行为。CCI诱导最初的GT上调，至少持续至术后第5天，主要发生在同侧脊髓背角，术后第7天和第14天通过蛋白质免疫印迹法和免疫组织化学检查发现随后出现GT下调。术后第1 - 4天鞘内注射酪氨酸激酶受体抑制剂K252a和丝裂原活化蛋白激酶抑制剂PD98059，分别减少并几乎消除了CCI大鼠最初的GT上调。PD98059预防CCI诱导的GT上调导致热痛觉过敏和机械性异常性疼痛加剧，非竞争性NMDA受体拮抗剂MK - 801可使其逆转，这表明最初的GT上调阻碍了神经性疼痛行为的发展。此外，术后第5天检查发现CCI显著降低了脊髓GTs的谷氨酸摄取活性，术后第1 - 4天每天两次鞘内注射利鲁唑（一种GT活性正向调节剂）可预防这种降低。同样，当分别在术后第1 - 4天和第5 - 8天给予4天的利鲁唑治疗时，利鲁唑减轻并逐渐逆转了神经性疼痛行为。这些结果表明，脊髓GTs表达和谷氨酸摄取活性的变化可能通过调节局部谷氨酸稳态在神经损伤后神经性疼痛的诱导和维持中起关键作用，这是一种与神经性疼痛发病机制相关的新机制。
