Xiao W, Boroujerdi A, Bennett G J, Luo Z D
Department of Anesthesia, Anesthesia Research Unit, McGill University, Montreal, Quebec, Canada.
Neuroscience. 2007 Jan 19;144(2):714-20. doi: 10.1016/j.neuroscience.2006.09.044. Epub 2006 Nov 2.
Chemotherapeutics in the taxane and vinca-alkaloid classes sometimes produce a painful peripheral neuropathy for which there is no validated treatment. Experiments with rat models of paclitaxel- and vincristine-evoked pain suggest that these conditions may not respond to all of the analgesics that have efficacy in other models of painful peripheral neuropathy. We tested gabapentin as a potential analgesic for paclitaxel- and vincristine-evoked pain. We used a repeated dosing paradigm because there are precedents showing that repeated drug exposure may be necessary to demonstrate analgesia in neuropathic pain models. Gabapentin is believed to work via binding to voltage-gated calcium channels that contain the alpha-2-delta type-1 (alpha(2)delta-1) subunit, and the expression of this subunit is known to be increased in some painful peripheral neuropathy models. Thus we also examined whether the paclitaxel-evoked pain syndrome was accompanied by an alpha(2)delta-1 increase, and whether gabapentin had any effect on subunit expression. We found that the paclitaxel- and vincristine-evoked mechano-allodynia and mechano-hyperalgesia were significantly reduced by gabapentin, but only with repeated dosing. Paclitaxel-evoked painful peripheral neuropathy was associated with an increased expression of the alpha(2)delta-1 subunit in the spinal dorsal horn, but not in the dorsal root ganglia. The spinal cord increase was normalized by repeated gabapentin injections. Together, these findings suggest that repeated dosing with gabapentin may be beneficial in patients with chemotherapy-evoked painful peripheral neuropathy and that gabapentin's mechanisms of action may include normalization of the nerve injury-evoked increase in calcium channel alpha(2)delta-1 subunit expression.
紫杉烷类和长春花生物碱类化疗药物有时会引发疼痛性外周神经病变，对此尚无有效的治疗方法。对紫杉醇和长春新碱诱发疼痛的大鼠模型进行的实验表明，这些病症可能对在其他疼痛性外周神经病变模型中有效的所有镇痛药均无反应。我们测试了加巴喷丁作为治疗紫杉醇和长春新碱诱发疼痛的潜在镇痛药。我们采用了重复给药模式，因为有先例表明，在神经性疼痛模型中，可能需要重复给药才能显示出镇痛效果。加巴喷丁被认为是通过与含有α-2-δ 1型（α(2)δ-1）亚基的电压门控钙通道结合而起作用的，并且已知在一些疼痛性外周神经病变模型中该亚基的表达会增加。因此，我们还研究了紫杉醇诱发的疼痛综合征是否伴有α(2)δ-1增加，以及加巴喷丁对亚基表达是否有任何影响。我们发现，加巴喷丁可显著减轻紫杉醇和长春新碱诱发的机械性异常性疼痛和机械性痛觉过敏，但仅在重复给药时有效。紫杉醇诱发的疼痛性外周神经病变与脊髓背角中α(2)δ-1亚基的表达增加有关，但在背根神经节中则不然。重复注射加巴喷丁可使脊髓中的增加恢复正常。总之，这些发现表明，对化疗诱发的疼痛性外周神经病变患者重复给予加巴喷丁可能有益，并且加巴喷丁的作用机制可能包括使神经损伤诱发的钙通道α(2)δ-1亚基表达增加恢复正常。
