Interleukin-1Beta in Central Pain Modulating Circuits

描述：(改编自申请者摘要) 近年来，对疼痛和止痛感兴趣的研究人员的关注 多年来，人们越来越多地致力于了解 持续的疼痛状态是其基础。最激烈的努力已经集中在 阐明伤害性感受器中元素的可塑性 传递途径，包括初级传入伤害性感受器和上行通路 传输电路。相比之下，在下降中改变的可能性 调节系统可能有助于持续的疼痛状态 相对较少的关注。然而，现在有越来越多的证据表明 指出具有良好特征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)和头端延髓腹内侧区 (RVM)，曾被视为急性应激或刺激激活的“止痛系统” 疼痛或由阿片类止痛药抑制脊髓伤害性信息的处理。它 现在已知更复杂，有可能双向控制 伤害性感受。 本提案的目的是分析这一脑干的招募 促炎因子白细胞介素1β(IL-1β)的痛觉调节系统 协调免疫和神经对损伤和感染反应的细胞因子。 申请者建议使用行为药理学和 用单细胞记录法研究IL-1β对血管内皮细胞的影响 伤害性反应，并识别调节这些反应的中央电路 效果。他们发现，服用IL-1β会引起一种双相 伤害性反应的改变，伴随着一段时期的痛觉过敏 痛觉减退的后期阶段。因此，它们将决定 全身和全身创伤后伤害性反应的变化 脑室注射IL-1β在清醒和非睡眠状态下的作用 异氟醚麻醉的大鼠，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 显微注射测绘技术，调查人员将验证这一假说 IL-1β直接作用于下丘脑和右室。他们会 使用病变进一步测试特定细胞群在RVM中的作用 和电生理学方法。 脑干痛觉调制系统在阿片类药物镇痛中的作用 记录在案，但这个系统何时以及如何被用来增强疼痛几乎是 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 促进我们对痛觉调制过程的理解。在……里面 提供其他工具来操纵这些系统，这项工作可能 最终导致改善疼痛的临床治疗。

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.