Wilson S P, Yeomans D C, Bender M A, Lu Y, Goins W F, Glorioso J C
Department of Pharmacology and Physiology, University of South Carolina School of Medicine, Columbia, SC 29208, USA.
Proc Natl Acad Sci U S A. 1999 Mar 16;96(6):3211-6. doi: 10.1073/pnas.96.6.3211.
To test the utility of gene therapeutic approaches for the treatment of pain, a recombinant herpes simplex virus, type 1, has been engineered to contain the cDNA for an opioid peptide precursor, human preproenkephalin, under control of the human cytomegalovirus promoter. This virus and a similar recombinant containing the Escherichia coli lacZ gene were applied to the abraded skin of the dorsal hindpaw of mice. After infection, the presence of beta-galactosidase in neuronal cell bodies of the relevant spinal ganglia (lacZ-containing virus) and of human proenkephalin (preproenkephalin-encoding virus) in the central terminals of these neurons indicated appropriate gene delivery and expression. Baseline foot withdrawal responses to noxious radiant heat mediated by Adelta and C fibers were similar in animals infected with proenkephalin-encoding and beta-galactosidase-encoding viruses. Sensitization of the foot withdrawal response after application of capsaicin (C fibers) or dimethyl sulfoxide (Adelta fibers) observed in control animals was reduced or eliminated in animals infected with the proenkephalin-encoding virus for at least 7 weeks postinfection. Hence, preproenkephalin cDNA delivery selectively blocked hyperalgesia without disrupting baseline sensory neurotransmission. This blockade of sensitization was reversed by administration of the opioid antagonist naloxone, apparently acting in the spinal cord. The results demonstrate that the function of sensory neurons can be selectively altered by viral delivery of a transgene. Because hyperalgesic mechanisms may be important in establishing and maintaining neuropathic and other chronic pain states, this approach may be useful for treatment of chronic pain and hyperalgesia in humans.
为了测试基因治疗方法在疼痛治疗中的效用，一种重组1型单纯疱疹病毒已被改造，使其在人巨细胞病毒启动子的控制下包含阿片肽前体——人前脑啡肽原的cDNA。将这种病毒和一种含有大肠杆菌β-半乳糖苷酶基因的类似重组体应用于小鼠后足背的擦伤皮肤。感染后，相关脊髓神经节神经元细胞体中β-半乳糖苷酶（含lacZ基因的病毒）的存在以及这些神经元中枢终末中人脑啡肽原（编码前脑啡肽原的病毒）的存在表明基因传递和表达正常。在感染编码前脑啡肽原病毒和编码β-半乳糖苷酶病毒的动物中，由Aδ和C纤维介导的对有害辐射热的基线足部退缩反应相似。在感染编码前脑啡肽原病毒的动物中，感染后至少7周，观察到对照动物在应用辣椒素（C纤维）或二甲基亚砜（Aδ纤维）后足部退缩反应的敏化作用减弱或消除。因此，前脑啡肽原cDNA传递选择性地阻断了痛觉过敏，而不破坏基线感觉神经传递。这种敏化作用的阻断可通过给予阿片拮抗剂纳洛酮逆转，纳洛酮显然作用于脊髓。结果表明，通过病毒传递转基因可以选择性地改变感觉神经元的功能。由于痛觉过敏机制在建立和维持神经性疼痛及其他慢性疼痛状态中可能很重要，这种方法可能对治疗人类慢性疼痛和痛觉过敏有用。
