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

人们越来越多地意识到神经免疫相互作用及其在疾病病因中的作用。 包括中风、帕金森氏症和慢性疼痛。尽管现在人们普遍认为神经胶质细胞和 炎性细胞因子通过多种细胞信号通路影响神经元的功能和行为， 将免疫和神经功能联系起来的潜在机制尚不清楚。我们建议雇用一名老鼠 后爪炎性痛模型研究胶质细胞、细胞因子与神经元的相互作用 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具有重要意义。 最近的研究表明，脑干下行回路可以有力地促进疼痛的处理， 这一过程有助于慢性疼痛状况的发展。受伤后的异常疼痛有 与延髓吻侧腹内侧区(RVM)神经元活动增强有关，RVM是 下行痛觉调制。新出现的文献强烈暗示了神经胶质细胞和炎症的作用 细胞因子在痛觉过敏发展中的作用。通过尚不清楚的机制，胶质细胞可以在 损伤和释放调节神经元活动的化学介质。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 神经胶质细胞及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 组织损伤后促进下行疼痛的分子机制以神经元-神经胶质细胞为主 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。 涉及神经胶质细胞激活的RVM回路；以及2)RVM神经胶质细胞激活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)和 有助于痛觉过敏的下行易化。 Aim 1将验证炎症后RVM中的神经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。完全弗洛因德佐剂将被注射到后脑 爪子会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 信号在炎症后的神经胶质细胞激活中起着重要作用。目标3将测试假设，神经胶质细胞激活在 RVM及其相关细胞因子释放通过与神经元的相互作用促进神经元的可塑性 NMDAR在痛觉过敏的发生发展中起关键作用。 因此，我们提出了持续性发展过程中神经元-神经胶质细胞相互作用的模型。 疼痛。与以前的研究相比，该模型强调了损伤产生的神经元对神经胶质细胞的激活 NMDAR通过细胞因子信号的输入、伴随的细胞因子释放和翻译后调节。 这些研究的结果将加强我们对免疫和免疫之间的功能联系的理解。 治疗慢性疼痛可帮助确定新的靶点和药物。我们建议使用一个炎症性疼痛的大鼠模型来研究胶质细胞、细胞因子和 并探讨其在中枢神经系统损伤反应和脑损伤发生发展中的意义。 持续的疼痛状况。尽管现在人们普遍认识到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，潜在的机制 免疫和神经功能之间的联系在很大程度上是未知的。这些研究的结果将加强我们的 了解免疫和神经系统之间的功能联系，有助于识别新的靶点 以及治疗慢性疼痛的药物。

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.