Transgene for morphine tolerance and withdrawal

吗啡耐受和戒断转基因

• 批准号: 6962677
• 负责人: SHUANGLIN HAO
• 金额: $ 7.65万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-01 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6962677
• 关键词: analgesia; behavior test; drug tolerance; drug withdrawal; enzyme linked immunosorbent assay; gene expression; immunocytochemistry; interleukin 4; laboratory rat; mitogen activated protein kinase; morphine; phosphorylation; prostaglandin E; spinal ganglion; transfection /expression vector

DESCRIPTION (provided by applicant): Neuropathic pain is a chronic disabling condition. Opiate drugs can be effective in treatment of neuropathic pain, but continuous administration of these drugs is complicated by the development of tolerance to analgesia and by dependence which results in an unpleasant withdrawal syndrome. Preventing the transition from drug use to drug tolerance/withdrawal has important clinical implications. Accumulating evidence suggests that neuropathic pain, chronic morphine tolerance and withdrawal-evoked hyperalgesia may be mediated through changes of proinflammatory cytokines, the phosphorylation of mitogen-activated protein kinases (MARK) and prostaglandin E2 (PGE2) in the spinal cord. We have demonstrated that highly defective herpes simplex virus (HSV)-based vectors can be used to efficiently transduce neurons of the dorsal root ganglion (DRG) in vivo to release bioactive peptides from nerve terminals in spinal cord. We will test the hypothesis that reduction of the inflammatory response by HSV vector-mediated release of the anti-inflammatory cytokine, interleukin-4 (IL-4) will decrease morphine tolerance and physical withdrawal in animals with neuropathic pain. Two specific aims are porposed: (1) To determine whether transgenemediated IL-4 release decreases morphine tolerance and physical withdrawal and (2) To investigate the effect of transgene-mediated IL-4 on neurochemical changes in spinal level during morphine tolerance and withdrawal. These studies will provide insight into role of proinflammatory cytokines in chronic morphine tolerance and withdrawal and important preliminary data that could serve as the basis for a subsequent grant application for junior principal investigator in this field.

描述（由申请人提供）： 神经性疼痛是一种慢性致残性疾病。阿片类药物可有效治疗神经性疼痛，但这些药物的连续给药由于对镇痛的耐受性的发展和导致不愉快的戒断综合征的依赖性而变得复杂。防止从药物使用过渡到药物耐受/戒断具有重要的临床意义。越来越多的证据表明，神经病理性疼痛、慢性吗啡耐受和戒断诱发的痛觉过敏可能是通过脊髓中促炎细胞因子、有丝分裂原活化蛋白激酶（MARK）和前列腺素E2（PGE 2）的磷酸化的变化来介导的。我们已经证明，高度缺陷的单纯疱疹病毒（HSV）为基础的载体，可用于有效地包裹背根神经节（DRG）在体内的神经元，在脊髓中的神经末梢释放生物活性肽。我们将测试的假设，即通过HSV载体介导的抗炎细胞因子，白细胞介素-4（IL-4）的释放的炎症反应的减少将减少吗啡耐受性和身体戒断与神经性疼痛的动物。本研究有两个目的：（1）确定转基因介导的IL-4释放是否降低吗啡耐受和身体戒断;（2）研究转基因介导的IL-4对吗啡耐受和戒断过程中脊髓水平神经化学变化的影响。这些研究将深入了解促炎细胞因子在慢性吗啡耐受和戒断中的作用，并提供重要的初步数据，这些数据可以作为该领域初级首席研究员随后申请资助的基础。