Lim Grewo, Sung Backil, Ji Ru-Rong, Mao Jianren
Department of Anesthesia and Critical Care, MGH Pain Center, WACC 324, Massachusetts General Hospital, Harvard Medical School, 15 Parkman Street, Boston, MA 02114, USA.
Pain. 2003 Sep;105(1-2):275-83. doi: 10.1016/s0304-3959(03)00242-2.
Exogenous cannabinoids are effective in attenuating neuropathic pain behaviors induced by peripheral nerve injury, but the mechanisms of their effectiveness remain unclear. Here we examined the expression of spinal cannabinoid-1-receptors (CB1Rs) following chronic constriction sciatic nerve injury (CCI) and its relation to the effects of a CBR agonist (Win 55,212-2) on neuropathic pain in rats. CCI induced a time-dependent upregulation of spinal CB1Rs primarily within the ipsilateral superficial spinal cord dorsal horn as revealed by both Western blot and immunohistochemistry. This CCI-induced CB1R upregulation was at least in part mediated through tyrosine kinase receptors (Trk), because intrathecal treatment with the Trk inhibitor K252a (1 microg) for postoperative days 1-6 significantly reduced the CB1R upregulation in CCI rats. At the intracellular level, the mitogen-activated protein kinase (ERK-MAPK) inhibitor PD98059 (1 microg) prevented, while the protein kinase C inhibitor chelerythrine (10 microg) partially reduced, the CCI-induced CB1R upregulation when each agent was administered intrathecally for postoperative days 1-6. Importantly, the CCI-induced upregulation of spinal CB1Rs enhanced the effects of Win 55,212-2 on both thermal hyperalgesia and mechanical allodynia, since inhibition of the CB1R upregulation by PD98059 resulted in a significant reduction of the effects of Win 55,212-2 in CCI rats. These results indicate that upregulation of spinal CB1Rs following peripheral nerve injury may contribute to the therapeutic effects of exogenous cannabinoids on neuropathic pain.
外源性大麻素可有效减轻周围神经损伤诱导的神经性疼痛行为，但其作用机制尚不清楚。在此，我们研究了慢性坐骨神经压迫损伤（CCI）后脊髓大麻素1型受体（CB1Rs）的表达及其与CB1R激动剂（Win 55,212-2）对大鼠神经性疼痛影响的关系。蛋白质印迹法和免疫组织化学法显示，CCI主要在同侧脊髓背角浅层诱导脊髓CB1Rs的时间依赖性上调。CCI诱导的CB1R上调至少部分是通过酪氨酸激酶受体（Trk）介导的，因为在术后第1至6天鞘内注射Trk抑制剂K252a（1微克）可显著降低CCI大鼠的CB1R上调。在细胞内水平，有丝分裂原活化蛋白激酶（ERK-MAPK）抑制剂PD98059（1微克）可阻止，而蛋白激酶C抑制剂白屈菜红碱（10微克）可部分降低CCI诱导的CB1R上调，前提是在术后第1至6天鞘内注射每种药物。重要的是，CCI诱导的脊髓CB1Rs上调增强了Win 55,212-2对热痛觉过敏和机械性异常性疼痛的作用，因为PD98059抑制CB1R上调导致Win 55,212-2对CCI大鼠的作用显著降低。这些结果表明，周围神经损伤后脊髓CB1Rs上调可能有助于外源性大麻素对神经性疼痛的治疗作用。
