Disruption of Homeostatic Neuroimmune Interactions in Descending Circuitry in the Development of Pain Chronicity

数以百万计的人患有慢性或持续性疼痛，这是一个重大的医疗问题。海流 对慢性疼痛状况的治疗并不令人满意。近年来，大量证据证明了 神经胶质细胞及其与神经元的相互作用在持续性疼痛发展中的作用。尽管压倒性地 来自临床前研究的证据表明，使用神经胶质调节剂治疗慢性疼痛的临床试验尚未 取得了成功，这与我们对机制的了解不完全有关。虽然大多数人 研究表明，与损伤相关的胶质细胞活动的疼痛促进方面，潜在的抑制/保护作用 神经元-神经胶质细胞相互作用在持续性疼痛的发展过程中在很大程度上被忽视了。中环 神经系统(CNS)的动态平衡受到多条抑制性信号通路的支持，其中 CD200-CD200R信号转导系统已经引起了人们的关注。来自神经元的免疫球蛋白CD200通过其信号通路 小胶质细胞上的CD200R受体维持小胶质细胞处于监视状态。损失或减少200加元- 损伤后的CD200R信号促进小胶质细胞的激活。 下行通路提供平衡的调制，以维持正常的疼痛敏感性。促进或 从延髓头端腹内侧(RVM)--下行通路的枢轴结构--去抑制 脊髓/三叉神经背角有助于慢性疼痛的发展。我们的初步结果表明 从前扣带回(ACC)直接投射到RVM的新下行通路 参与5-HT3受体(5-HT3R)依赖的痛觉易化。其背后的细胞机制 这种直接的ACC-RVM连接的功能尚不清楚。 我们建议分析新型ACC-RVM下行疼痛中抑制/有益神经胶质细胞的相互作用 调制回路并验证中断抑制的神经胶质活性导致出现的假说 慢性疼痛的症状。我们的工作假设是，CNS CD200-CD200R信号轴是 动态平衡和信号不充分/中断会扰乱平衡并导致慢性疼痛 条件。 目标1将检验这样一种假设，即来自新的ACC-RVM通路的疼痛易化涉及不足 动态平衡CD200-CD200R信号与5-羟色胺能神经元的超兴奋性。目标2将测试 干扰RVM中抑制CD200-CD200R信号的假说有助于 慢性疼痛。目的3将验证CD200/CD200R信号对抗-HBs的重要性这一假设。 RVM中小胶质细胞的炎症表型及其与下游叉头盒P3(Foxp3)和信号转导的关系 转录转导和激活因子6(STAT6)活性。 探索神经胶质活动的有益影响将填补我们理解上的空白，并导致一种变革性的 寻求改善慢性疼痛管理的转变。

Millions of people suffer from chronic or persistent pain, which is a major medical problem. The current treatment for chronic pain conditions is unsatisfactory. In recent years, ample evidence has documented the role of glia and their interactions with neurons in the development of persistent pain. Despite overwhelming evidence from preclinical studies, clinical trials for the treatment of chronic pain with glial modulators have not been successful, which is related to our incomplete understanding of the mechanisms. While a majority of studies show the pain-facilitating aspect of the injury-related glial activity, a potential inhibitory/protective role of neuron-glial interactions in the development of persistent pain has been largely overlooked. The central nervous system (CNS) homeostasis is supported by multiple inhibitory signaling pathways, among which the CD200-CD200R signaling tandem has attracted attention. Immunoglobulin CD200 from neurons signals via its receptor CD200R on microglia to maintain microglia at the surveillance state. Loss of or reduced CD200- CD200R signaling after injury facilitates microglial activation. Descending pathways provide balanced modulation to maintain normal pain sensitivity. Facilitation or disinhibition from the rostral ventromedial medulla (RVM), a pivot structure in descending pathways, to the spinal/ trigeminal dorsal horn contributes to the development of chronic pain. Our preliminary results point to a new descending pathway from the anterior cingulate cortex (ACC) that directly projects to the RVM and is involved in the 5-HT3 receptor (5-HT3R)-dependent pain facilitation. The cellular mechanisms underlying the function of this direct ACC-RVM connection is unclear. We propose to analyze inhibitory/beneficial neuroglial interactions in the novel ACC-RVM descending pain modulatory circuitry and test the hypothesis that disrupted inhibitory glial activity contributes to the emergence of chronic pain. Our working hypothesis is that the CNS CD200-CD200R signaling axis is necessary for homeostasis and insufficient/disrupted signaling of which disturbs the balance and contributes to chronic pain conditions. Aim 1 will test the hypothesis that pain facilitation from the novel ACC-RVM pathway involves insufficient homeostatic CD200-CD200R signaling and hyperexcitability of 5-HT-containing neurons. Aim 2 will test the hypothesis that disrupted inhibitory CD200-CD200R signaling in the RVM contributes to the emergence of chronic pain. Aim 3 will test the hypothesis that the CD200/CD200R signaling is important for the anti- inflammatory phenotype of microglia in the RVM and involves downstream forkhead box P3 (Foxp3) and signal transducer and activator of transcription 6 (STAT6) activity. Exploring the beneficial effect of glial activity will fill the gap in our understanding and lead to a transformative shift in the search for improved management for chronic pain.