Interleukin-1Beta in Central Pain Modulating Circuits

中枢疼痛调节回路中的 Interleukin-1Beta

• 批准号: 6639671
• 负责人: Mary Magdalen Heinricher
• 金额: $ 27.84万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-05-01 至 2005-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6639671
• 关键词: NMDA receptors; analgesia; behavioral /social science research tag; brain mapping; brain stem; cell population study; chemical structure function; endogenous opioid; histology; interleukin 1; laboratory rat; microinjections; neural information processing; neural plasticity; neural transmission; neurons; neuropsychology; neurotransmitter antagonist; nociceptors; pain; prostaglandins; psychopharmacology; single cell analysis; stimulus /response; time resolved data

DESCRIPTION:(adapted from applicant's abstract) The attention of investigators interested in pain and analgesia has in recent years been increasingly directed toward understanding the mechanisms that underlie persistent pain states. The most intense effort has been focused upon elucidating the now well-documented plasticity of elements in nociceptive transmission pathways, including primary afferent nociceptors and ascending transmission circuits. By contrast, the possibility that changes in descending modulatory systems might contribute to persistent pain states has received comparatively little attention. Nevertheless, there is now mounting evidence pointing to an important role for a well-characterized brainstem pain modulating system in hyperalgesia and persistent pain. This system, with links in the midbrain periaqueductal gray (PAG) and rostral ventromedial medulla (RVM), was once viewed as an "analgesia system" activated by acute stress or pain or by opioid analgesic drugs to inhibit spinal nociceptive processing. It is now known to be more complex, with a potential for bi-directional control of nociception. The aim of the present proposal is to analyze recruitment of this brainstem pain modulating system by interleukin-1beta (IL-1beta), a pro-inflammatory cytokine that orchestrates immune and neural responses to injury and infection. The applicants propose to use a combination of behavioral pharmacology and single cell recording methods to characterize the effects of IL-1beta on nociceptive responding, and to identify the central circuitry mediating these effects. They have found that administration of IL-1beta evokes a biphasic alteration in nociceptive responding, with a period of hyperalgesia followed by a later phase of hypoalgesia. They will therefore determine the time course of changes in nociceptive responding following systemic and intracerebroventricular administration of IL-1beta in both awake and isoflurane-anesthetized rats, and identify potential roles of prostanoids, NMDA, endogenous opioids or corticotropin releasing factor. Using a microinjection mapping technique, the investigators will test the hypothesis that IL-1beta acts directly within the hypothalamus and within RVM. They will further test the role of specific cell populations within the RVM using lesion and electrophysiological approaches. The role of brainstem pain modulating systems in opioid analgesia is well documented, but when and how this system is recruited to enhance pain is almost completely unknown. By elucidating mechanisms through which pro-inflammatory cytokines bring descending control systems into play, the proposed work should advance our understanding of the processes involved in pain modulation. In providing additional tools to manipulate these systems, this work may ultimately lead to improved clinical treatment of pain.

描述：（改编自申请人的摘要） 近年来，对疼痛和镇痛感兴趣的研究者的注意力 多年来越来越多地致力于了解其机制 是持续疼痛状态的基础。最集中的努力已集中在 阐明了伤害感受中元素的可塑性，现已有充分记录 传播途径，包括初级传入伤害感受器和上行伤害感受器 传输电路。相比之下，变化的可能性呈下降趋势 调节系统可能会导致持续性疼痛状态 关注度相对较低。尽管如此，现在有越来越多的证据表明 指出明确的脑干疼痛的重要作用 痛觉过敏和持续性疼痛的调节系统。这个系统，有链接 中脑导水管周围灰质 (PAG) 和延髓头端腹内侧区 （RVM），曾被视为由急性应激或应激激活的“镇痛系统” 止痛或通过阿片类镇痛药物来抑制脊髓伤害性感受处理。它 现在已知更加复杂，具有双向控制的潜力 伤害感受。 本提案的目的是分析该脑干的招募 通过白细胞介素-1β (IL-1β) 调节疼痛系统，这是一种促炎剂 协调对损伤和感染的免疫和神经反应的细胞因子。 申请人建议结合使用行为药理学和 单细胞记录方法表征 IL-1β 对细胞的影响 伤害感受反应，并识别介导这些反应的中央电路 影响。他们发现，给予 IL-1beta 会引起双相 伤害性反应发生改变，随后出现一段时期的痛觉过敏 痛觉减退的后期阶段。因此，他们将确定 全身和后伤害性反应的变化 清醒和清醒状态下脑室内注射IL-1β 异氟烷麻醉大鼠，并确定前列腺素的潜在作用， NMDA，内源性阿片类药物或促肾上腺皮质激素释放因子。使用 显微注射绘图技术，研究人员将检验假设 IL-1β 直接作用于下丘脑和 RVM 内。他们会 使用病变进一步测试 RVM 内特定细胞群的作用 和电生理学方法。 脑干疼痛调节系统在阿片类镇痛中的作用已得到充分证实 记录在案，但是何时以及如何招募该系统来增强疼痛几乎是 完全未知。通过阐明促炎机制 细胞因子使下行控制系统发挥作用，拟议的工作应该 增进我们对疼痛调节过程的理解。在 提供额外的工具来操纵这些系统，这项工作可能 最终改善疼痛的临床治疗。