PAIN FACILITATION BY GP120 AND HIV ENVELOPE PROTEIN

GP120 和 HIV 包膜蛋白促进疼痛

• 批准号: 6188002
• 负责人: LINDA WATKINS
• 金额: $ 41.44万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-01 至 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6188002
• 关键词: HIV envelope protein gp120; astrocytes; cytokine; excitatory aminoacid; glia; human immunodeficiency virus 1; immunocytochemistry; in situ hybridization; interleukin 1; interleukin 6; laboratory rat; microglia; neural facilitation; neurotrophic factors; nitric oxide; pain; spinal cord; tumor necrosis factor alpha

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.

描述：（改编自申请人摘要）本提案的前提是 免疫系统激活脊髓小胶质细胞和星形胶质细胞 产品可以产生疼痛促进作用。这些脊髓神经胶质细胞识别并 被细菌和病毒等外来物质激活， 特定的受体介导的过程。胶质细胞，而不是神经元， 被HIV-1激活。胶质细胞对HIV-1的识别是通过受体 介导的HIV-1包膜糖蛋白gp 120的结合。这种神经胶质 激活导致多种神经活性物质的释放， 包括促炎性细胞因子（白细胞介素-1 [IL 1]、IL 6和肿瘤坏死因子 因子）、神经生长因子一氧化氮和兴奋性氨基酸。这些 预期这些物质会导致痛觉过敏和异常性疼痛。这是 可能与艾滋病疼痛有关，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 艾滋病患者脊髓胶质细胞激活和（B）不明原因疼痛 可能是由脊髓神经胶质细胞激活引起的。 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 鞘内给予GP 120产生的易化作用。一 多学科方法将用于检查单个鞘内gp 120 模型利用该模型，研究了gp 120对疼痛行为指标的影响。 神经胶质细胞产生的疼痛增强终产物的水平 对这些终产物的免疫组织化学和mRNA表达的影响 得到考验 这种方法将被用来检查潜在的介质在疼痛 已知由鞘内GP 120：神经生长因子产生的促进作用， 促炎细胞因子、一氧化氮和兴奋性氨基酸。在 此外，将确定gp 120是否增加了 脊髓神经胶质细胞中的激活标记物，以及神经胶质细胞功能的破坏 将阻断gp 120诱导的疼痛反应、终产物和mRNA的变化。