HSV-mediated gene transfer of the glial cell-derived neurotrophic factor provides an antiallodynic effect on neuropathic pain
HSV-mediated gene transfer of the glial cell-derived neurotrophic factor provides an antiallodynic effect on neuropathic pain
复制标题
DOI：
10.1016/s1525-0016(03)00185-0
复制
发表时间：
2003-09-01
影响因子：
12.4
通讯作者：
Fink, DJ
中科院分区：
文献类型：
--
作者：
Hao, SL;Mata, M;Fink, DJ
神经性疼痛是一个棘手的临床问题，通常难以通过药物治疗来治疗。在神经性疼痛动物模型中，鞘内注射胶质源性神经营养因子（GDNF）已被证明可以预防或减轻疼痛，但无法以治疗人类疼痛所需的剂量进行递送。我们之前已经证明，基于无复制能力的单纯疱疹病毒（HSV）载体的外周皮下接种可用于转导背根神经节的神经元。为了检查 HSV 介导的 GDNF 表达是否可用于改善神经性疼痛，我们构建了表达 GDNF 的复制无能的 HSV 载体。脊神经结扎后一周皮下接种载体可产生持续的镇痛效果，并维持 3-4 周。载体的重新接种重新建立了抗异常疼痛效果，其强度至少与初始效果相当。载体介导的 GDNF 表达阻断了无害性触摸引起的背角 c-fos 表达的增加，这是疼痛状态的特征。产生营养因子的基因转移提供了一种治疗神经性疼痛的新方法，可能适合人类治疗。
Neuropathic pain is a difficult clinical problem that is often refractory to medical management. Glial-derived neurotrophic factor (GDNF) administered intrathecally has been shown to prevent or reduce pain in an animal model of neuropathic pain, but cannot be delivered in the required doses to treat human pain. We have previously demonstrated that peripheral subcutaneous inoculation of a replication-incompetent herpes simplex virus (HSV)-based vector can be used to transduce neurons of the dorsal root ganglion. To examine whether HSV-mediated expression of GDNF could be used to ameliorate neuropathic pain, we constructed a replication-incompetent HSV vector expressing GDNF. Subcutaneous inoculation of the vector I week after spinal nerve ligation resulted in a continuous antiallodynic effect that was maintained for 3-4 weeks. Reinoculation of the vector reestablished the antiallodynic effect with a magnitude that was at least equivalent to the initial effect. Vector-mediated GDNF expression blocked the nonnoxious touch-induced increase in c-fos expression in dorsal horn characteristic of the painful state. Gene transfer to produce a trophic factor offers a novel approach to the treatment of neuropathic pain that may be appropriate for human therapy.