Wilson Steven P, Yeomans David C
Department of Pharmacology and Physiology, University of South Carolina School of Medicine, Columbia, South Carolina 29208, USA.
Ann N Y Acad Sci. 2002 Oct;971:515-21. doi: 10.1111/j.1749-6632.2002.tb04516.x.
We have constructed recombinant herpes simplex virus type 1 vectors for delivery of genes to sensory neurons in an attempt to modulate nociception. Delivery of recombinant viruses to the skin of mice results in expression of encoded complementary DNA (cDNA) genes in DRG neurons within three to four days. Expression of marker genes persists for at least 10 weeks. Testing of baseline thermal nociceptive latencies at the site of virus application revealed no differences between a control virus and a virus encoding human preproenkephalin (hPPE) when performed at either low stimulus intensities (C-fiber activation) or high stimulus intensities (Adelta neurons). By contrast, sensitization of nociceptors by capsaicin or dimethylsulfoxide was reduced or abolished by infection with the virus encoding hPPE, but not by a control virus. These antihyperalgesic responses are mediated by opioids released at the central terminals of the primary afferents because they are blocked by intrathecal administration of the opioid antagonist naloxone. Similar experiments performed in macaques demonstrated an antihyperalgesic effect of the herpes virus vector encoding hPPE. This hPPE-encoding virus was also tested in a model of neuropathic pain in mice, with similar effect. A virus containing an antisense cDNA for calcitonin gene-related peptide precursor (ACGRP) has also been constructed and found to reverse C-fiber hyperalgesia caused by application of capsaicin to the skin for up to 14 weeks postinfection. These results raise the possibility that herpes-mediated, gene-based approaches to treat chronic pain states may be useful in therapy of chronic pain in humans.
我们构建了重组单纯疱疹病毒1型载体，用于将基因传递给感觉神经元，以尝试调节伤害感受。将重组病毒递送至小鼠皮肤后，在三到四天内背根神经节（DRG）神经元中会出现编码互补DNA（cDNA）基因的表达。标记基因的表达持续至少10周。在病毒应用部位测试基线热痛觉潜伏期时，在低刺激强度（C纤维激活）或高刺激强度（Aδ神经元）下进行测试时，对照病毒与编码人前脑啡肽原（hPPE）的病毒之间没有差异。相比之下，辣椒素或二甲基亚砜引起的伤害感受器敏化通过感染编码hPPE的病毒而降低或消除，但对照病毒则无此作用。这些抗痛觉过敏反应是由初级传入神经中枢终末释放的阿片类物质介导的，因为鞘内注射阿片类拮抗剂纳洛酮可阻断这些反应。在猕猴身上进行的类似实验证明了编码hPPE的疱疹病毒载体具有抗痛觉过敏作用。这种编码hPPE的病毒也在小鼠神经性疼痛模型中进行了测试，效果类似。还构建了一种含有降钙素基因相关肽前体反义cDNA的病毒（ACGRP），并发现其可在感染后长达14周内逆转因辣椒素作用于皮肤引起的C纤维痛觉过敏。这些结果增加了疱疹介导的基于基因的慢性疼痛状态治疗方法可能对人类慢性疼痛治疗有用的可能性。
