Interleukin-1Beta in Central Pain Modulating Circuits

描述：（改编自申请人摘要） 最近，对疼痛和镇痛感兴趣的研究人员的注意力 多年来，人们越来越多地致力于了解 是持续疼痛状态的基础最大的努力集中在 阐明了伤害性感受神经元的可塑性， 传递途径，包括初级传入伤害感受器和上行 传输电路相比之下，在下降过程中变化的可能性 调节系统可能有助于持续性疼痛状态已收到 相对较少的关注。然而，越来越多的证据表明 指出了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，与链接 中脑导水管周围灰质（PAG）和延髓头端腹内侧 (RVM)，曾被视为急性应激激活的"镇痛系统"， 疼痛或通过阿片类镇痛药来抑制脊髓伤害性处理。它 现在知道是更复杂的，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募集 白细胞介素-1 β（IL-1 β），一种促炎因子， 协调对损伤和感染的免疫和神经反应的细胞因子。 申请人建议使用行为药理学和 单细胞记录方法来表征IL-1 β对 伤害性反应，并确定中央电路介导这些 方面的影响.他们发现，IL-1 β的给药引起了一种双相的 伤害性反应的改变，伴随一段时间的痛觉过敏， 后期的痛觉减退因此，他们将决定时间进程， 在全身性和全身性疼痛后， 在清醒和清醒状态下脑室注射IL-1 β 异氟烷麻醉大鼠，并确定前列腺素类的潜在作用， NMDA，内源性阿片类或促肾上腺皮质激素释放因子。使用 微注射绘图技术，研究人员将测试假设 IL-1 β直接作用于下丘脑和RVM。他们将 使用损伤进一步测试RVM内特定细胞群的作用 和电生理学方法。 脑干痛调节系统在阿片类镇痛中的作用是很好的 记录在案，但何时以及如何招募这个系统来增强疼痛几乎是不可能的。 完全未知通过阐明促炎症反应的机制， 细胞因子使下行控制系统发挥作用，建议的工作应 推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，这项工作可以 最终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.