Glial-cytokine-neuronal interactions in the mechanisms of persistent pain

人们越来越多地认识到神经免疫相互作用及其在疾病病因学中的作用 包括中风帕金森病和慢性疼痛尽管现在人们普遍认为胶质细胞和 炎性细胞因子通过多种细胞信号传导途径影响神经元功能和行为， 连接免疫和神经功能的潜在机制是未知的。我们打算雇一只老鼠 后爪炎性疼痛模型，以研究胶质细胞、细胞因子和神经元之间的相互作用， 它们在中枢神经系统对损伤的反应和持续性疼痛的发展中的意义。 最近的研究表明，脑干下行回路可以有力地促进疼痛处理， 这一过程有助于慢性疼痛状况的发展。受伤后的异常疼痛是 与延髓头端腹内侧（RVM）神经元活动增强有关，RVM是 下行疼痛调制新出现的文献强烈暗示了神经胶质细胞和炎性细胞的作用， 细胞因子在痛觉过敏发展中的作用通过仍然未知的机制，神经胶质细胞可以在 损伤并释放调节神经元活性化学介质。这种神经胶质细胞因子神经元 相互作用在慢性疼痛过程中可能是至关重要的。到目前为止，还没有研究涉及到 胶质细胞和相关化学物质在持续性疼痛下行易化中的作用。我们建议识别细胞和 组织损伤后疼痛易化的分子机制，重点是神经胶质细胞 RVM电路中的相互作用。我们假设：1）外周炎症诱导神经元可塑性， 涉及神经胶质活化的RVM回路;和2）RVM神经胶质活化和炎性细胞因子释放 通过与神经元N-甲基-D-天冬氨酸受体（NMDAR）的相互作用促进神经元可塑性， 有助于痛觉过敏的下行易化。 目的1将验证炎症后RVM中胶质细胞被激活并影响神经元的假设。 通过释放炎性细胞因子发挥作用。将完全弗氏佐剂注射到后腿中 爪产生炎症和行为痛觉过敏。目标2将确定神经元到神经胶质细胞是否 信号传导在炎症后的神经胶质活化中起作用。目的3将检验神经胶质细胞活化在 RVM和相关细胞因子释放通过与神经元相互作用促进神经元可塑性 NMDAR在痛觉过敏的发生发展中起关键作用。 因此，我们提出了一个模型的互惠神经胶质细胞的相互作用，在发展中的持久性 痛苦在以往研究的基础上，该模型强调损伤产生的神经元激活胶质细胞， 输入、伴随的细胞因子释放和通过细胞因子信号传导的NMDAR的翻译后调节。 这些研究的结果将增强我们对免疫和免疫系统之间的功能联系的理解。 神经系统，并帮助确定新的目标和代理管理慢性疼痛。我们建议采用大鼠炎性疼痛模型来研究胶质细胞，细胞因子和 神经元，并探讨其在中枢神经系统对损伤的反应和发展的意义， 持续性疼痛状况。尽管现在广泛认识到神经胶质细胞和炎性细胞因子影响 神经元的功能和行为通过各种细胞信号通路，其潜在机制 免疫和神经功能之间的联系在很大程度上是未知的。这些研究的结果将提高我们的 了解免疫和神经系统之间的功能联系，并帮助确定新的目标 以及用于控制慢性疼痛的药剂。

There has been increasing awareness of neuroimmune interactions and their role in the etiology of diseases including stroke, Parkinson's disease, and chronic pain. Although it is now widely appreciated that glia and inflammatory cytokines affect neuronal function and behavior through a variety of cellular signaling pathways, the underlying mechanisms linking immune and neuronal functions are unknown. We propose to employ a rat model of hind paw inflammatory pain to study interactions between glia, cytokines and neurons and explore their significance in the central nervous system response to injury and the development of persistent pain. Recent studies indicate that pain processing can be vigorously facilitated by brainstem descending circuitry, a process that contributes to the development of chronic pain conditions. Abnormal pains after injury are linked to an enhanced neuronal activity in the rostral ventromedial medulla (RVM), a pivotal structure in descending pain modulation. The emerging literature strongly implicates a role for glia and inflammatory cytokines in the development of hyperalgesia. Through still unknown mechanisms, glia can be activated after injury and release chemical mediators that modulate neuronal activity. Such glial-cytokine-neuronal interactions may be critical in the chronic pain process. To date, no studies have addressed the involvement of glia and related chemicals in descending facilitation of persistent pain. We propose to identify the cellular and molecular mechanisms of descending pain facilitation after tissue injury with an emphasis on neuronal-glial interactions in the RVM circuitry. We hypothesize that 1) peripheral inflammation induces neuronal plasticity in the RVM circuitry involving activation of glia; and 2) RVM glial activation and inflammatory cytokine release facilitate neuronal plasticity through interactions with neuronal N-methyl-D-aspartate receptors (NMDAR) and contribute to the descending facilitation of hyperalgesia. Aim 1 will test the hypothesis that glial cells are activated in the RVM after inflammation and affect neuronal function through release of inflammatory cytokines. Complete Freund's adjuvant will be injected into the hind paw to produce inflammation and behavioral hyperalgesia. Aim 2 will determine whether neuron-to-glia signaling plays a role in glial activation after inflammation. Aim 3 will test the hypothesis that glial activation in the RVM and associated cytokine release facilitate neuronal plasticity through interaction with neuronal NMDAR and play a critical role in the development of hyperalgesia. Thus, we have proposed a model of reciprocal neuronal-glial interactions in the development of persistent pain. Advancing from previous studies, the model emphasizes activation of glia by injury-generated neuronal input, concomitant cytokine release, and post-translational regulation of NMDAR through cytokine signaling. The outcome of these studies will enhance our understanding of functional linkage between the immune and nervous system and help to identify novel targets and agents for management of chronic pain. We propose to employ a rat model of inflammatory pain to study interactions between glia, cytokines and neurons and explore their significance in the central nervous system response to injury and the development of persistent pain conditions. Although it is now widely appreciated that glia and inflammatory cytokines affect neuronal function and behavior through a variety of cellular signaling pathways, the underlying mechanisms linking immune and neuronal functions are largely unknown. The outcome of these studies will enhance our understanding of functional linkage between the immune and nervous system and help to identify novel targets and agents for management of chronic pain.