PAIN FACILITATION BY GP120 AND HIV ENVELOPE PROTEIN

描述：(改编自申请人的摘要)本提案的前提是 免疫系统对脊髓小胶质细胞和星形胶质细胞的激活 产品可以起到促进疼痛的作用。这些脊髓胶质细胞识别和 通过细菌和病毒等外来物质激活 特定的受体介导的过程。神经胶质细胞，而不是神经元，识别和 被HIV-1激活。胶质细胞对HIV-1的识别是通过受体实现的 介导的HIV-1包膜糖蛋白gp120的结合。如此狡猾 激活会导致各种神经活性物质的释放， 包括促炎细胞因子(白介素1、白介素6和肿瘤坏死 因子)、神经生长因子、一氧化氮和兴奋性氨基酸。这些 物质可能会导致痛觉过敏和痛觉异常。这是 可能与艾滋病的疼痛有关，因为它表明：(A)已知的疼痛 艾滋病患者的外周起源可能被正在进行的HIV-1夸大 诱导脊髓神经胶质细胞激活&(B)艾滋病患者不明原因的疼痛 可能是由脊髓神经胶质细胞激活产生的。 这个项目将研究脊髓小胶质细胞和星形胶质细胞在疼痛中的作用。 鞘内注射gp120所产生的促进作用。一个 将使用多学科方法来检查单个鞘内gp120。 模特。利用这个模型，gp120对疼痛行为指数的影响 反应，对推测的胶质产生的疼痛增强终末产物的水平 以及这些终产物的免疫组织化学和mRNA表达 接受测试。 这种方法将被用来检查疼痛的潜在介体。 已知鞘内gp120产生的促进作用：神经生长因子， 促炎细胞因子、一氧化氮和兴奋性氨基酸。在……里面 此外，还将确定gp120是否增加了 脊髓神经胶质细胞中的激活标志物，以及神经胶质功能是否被破坏 将阻断gp120诱导的疼痛反应、最终产物和mRNA的变化。

DESCRIPTION:(adapted from applicant's abstract) The premise of this proposal is that activation of spinal cord microglia and astrocytes by immune system products can produce pain facilitation. These spinal cord glia recognize and become activated by foreign substances such as bacteria and viruses via specific receptor-mediated processes. Glia, but not neurons, recognize and become activated by HIV-1. Recognition by glia of HIV-1 is through receptor mediated binding of the HIV-1 envelope glycoprotein gp120. Such glial activation leads to the release of a variety of neuroactive substances, including proinflammatory cytokines (interleukin-1[IL1], IL6 & tumor necrosis factor), nerve growth factor nitric oxide and excitatory amino acids. These substances would be expected to lead to hyperalgesia and allodynia. This is potentially relevant to pain in AIDS as it suggests that: (a) pain of known peripheral origin in AIDS patients may be exaggerated by the ongoing HIV-1 induced spinal glial activation & (b) pain of unknown origin in AIDS patients may be created by spinal glial activation. This project will examine the role of spinal microglia and astrocytes in pain facilitation produced by intrathecal administration of gp120. A multidisciplinary approach will be used to examine a single intrathecal gp120 model. Using this model, the effects of gp120 on behavioral indices of pain response, on levels of presumptive glially produced pain enhancing endproducts and on immunohistochemical and mRNA expression for these same endproducts will be tested. This approach will be used to examine the potential mediators in pain facilitation known to be produced by intrathecal gp120: nerve growth factor, proinflammatory cytokines, nitric oxide and excitatory amino acids. In addition, it will be determined whether gp120 increases expression of activation markers in spinal glia, and whether disruption of glial function will block gp120-induced changes in pain response, end products and mRNA.