Antinociceptive effect of a genomic herpes simplex virus-based vector expressing human proenkephalin in rat dorsal roof ganglion
Antinociceptive effect of a genomic herpes simplex virus-based vector expressing human proenkephalin in rat dorsal roof ganglion
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DOI：
10.1038/sj.gt.3301430
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发表时间：
2001-04-01
期刊：
影响因子：
5.1
通讯作者：
Fink, DJ
中科院分区：
文献类型：
--
作者：
Goss, JR;Mata, M;Fink, DJ
内源性阿片肽作用于脊髓背角突触前和突触后，抑制伤害性刺激的传递。我们通过足垫接种30穆尔（3 × 10（7）p.f.u.）复制缺陷型（ICP 4缺失型）单纯疱疹病毒（HSV）载体，该载体具有包含编码5-甲硫氨酸和1-亮脑啡肽分子的人脑啡肽原基因的一部分的盒，该基因在插入HSV胸苷激酶（tk）基因座中的人巨细胞病毒立即早期启动子（HCMV IEp）的控制下。通过福尔马林足垫试验测量，脑啡肽的载体定向表达产生了显著的抗伤害效应，这在福尔马林给药后20-70分钟的延迟（“强直”）相中最为突出。在转导后4周内，抗伤害效应的幅度减小，但是载体的再接种重新建立了镇痛效应，没有耐受性发展的证据。鞘内注射纳洛酮可完全阻断其镇痛作用。这些结果表明，用产生脑啡肽的疱疹病毒载体进行基因治疗可能对疼痛的治疗有用。
Endogenous opiate peptides acting pre- and post-synaptically in the dorsal horn of spinal cord inhibit transmission of nociceptive stimuli. We transfected neurons of the dorsal root ganglion in vivo by footpad inoculation with 30 mul (3 x 10(7) p.f.u.) of a replication-incompetent (ICP4-deleted) herpes simplex virus (HSV) vector with a cassette containing a portion of the human proenkephalin gene coding for 5 metand 1 leu-enkephalin molecules under the control of the human cytomegalovirus immediate-early promoter (HCMV IEp) inserted in the HSV thymidine kinase (tk) locus. Vector-directed expression of enkephalin produced a significant antinociceptive effect measured by the formalin footpad test, that was most prominent in the delayed ('tonic') phase 20-70 min after the administration of formalin. The magnitude of the antinociceptive effect diminished over 4 weeks after transduction, but reinoculation of the vector reestablished the analgesic effect, without evidence for the development of tolerance. The antinociceptive effect was blocked completely by intrathecal naltrexone, These results suggest that gene therapy with an enkephalin-producing herpes-based vector may prove useful in the treatment of pain.