Role of neuron-satellite glia cell signaling in pelvic pain and visceral cross-sensitization

摘要 数以百万计的人患有慢性盆腔疼痛，这种疼痛往往与间质性膀胱炎/膀胱疼痛有关 综合征(IC/BPS)和肠易激综合征(IBS)。有几个因素被牵连到了 这些疾病的病理生理学，但潜在的疼痛时代化机制仍然知之甚少。 这一建议是由我们之前对感觉神经节中神经元-神经胶质相互作用的研究推动的。 并展示了它们在涉及口腔面部和后肢炎症的慢性疼痛模型中的重要性。基座 基于这些发现，我们重点研究了发生在感觉神经节(背根)内的神经整合过程 神经节：DRG)支配盆腔器官，并调查细胞间是否以及在多大程度上改变 DRG感觉神经元和卫星胶质细胞(SGCs)之间的信号传递提供了一种共同的机制 膀胱和结肠疼痛。此外，我们认为这种神经元-神经胶质细胞的相互作用可能对盆腔器官有贡献。 串扰是IC/BPS和IBS已知的共病的基础。 我们已经证明感觉神经节中的神经元与SGCs在空间和功能上有密切的联系。SGCS 支持神经元的动态平衡，但也通过释放“胶质递质”和 其他化学介质，如三磷酸腺苷和细胞因子，调节神经元的兴奋性。有很强的 有证据表明，中枢神经系统和三叉神经节中神经胶质细胞的激活在疼痛的发生和维持中发挥关键作用，以及 SGCs和神经元之间的串扰在病理性疼痛中的重要性正变得越来越重要 很明显。然而，对于SGCs和神经元之间的串扰是否以及在多大程度上，人们仍然知之甚少 有助于盆腔器官敏化和交叉敏化，以及SGC-神经元通过什么机制 信号可能会增强，从而导致骨盆疼痛。我们已经证明，在实验性结肠炎中， 缝隙连接(GJ)介导的神经元-SGC信号在支配结肠的DRG中增强。此外， 我们的研究发现，主要分子P2X7受体和pAnnexin 1(Panx1)通道缺失 SGC-神经元信号的介体，提示通过激活SGC-神经元信号通路增强SGC-神经元的通讯 P2X7R-Panx1复合体在DRG超兴奋性和触觉超敏的发生发展中起关键作用。 基于这些发现，我们假设细胞间GJ和P2X7R-Panx1介导的信号转导在 背根神经节通过促进SGC的机制在盆腔传入敏化中发挥关键作用 激活和神经元兴奋性，可促进结肠-膀胱的交叉敏感化。为了测试这一点 假设，我们将采用公认的直接膀胱和结肠侮辱的模型，并结合行为， 使用野生型和转基因小鼠的功能和分子方法，这些小鼠具有全局或细胞特异性的缺失 Cx43、Panx1和P2X7R。这些研究的结果有望证明病理上的关键作用 增强的SGC神经元信号在盆腔疼痛和内脏交叉敏感化发展中的作用，并揭示 缝隙连接和P2X7R-Panx1功能复合体驱动增强的SGC神经元细胞间 在这一过程中传递信号，为未来的临床翻译提供新的治疗靶点。

Abstract Millions of people suffer from chronic pelvic pain that is often associated with interstitial cystitis/bladder pain syndrome (IC/BPS) and irritable bowel syndrome (IBS). Several factors have been implicated in the pathophysiology of these disorders but mechanisms underlying pain chronification are still poorly understood. This proposal is motivated by our previous studies characterizing neuron-glial interactions in sensory ganglia and demonstrating their importance in chronic pain models involving orofacial and hindlimb inflammation. Based on these findings, we focus on neural integration processes that occur within the sensory ganglia (dorsal root ganglia: DRG) that innervate pelvic organs, and investigate whether and to what extent altered intercellular signaling between DRG sensory neurons and satellite glial cells (SGCs) provides a common mechanism in bladder and colon pain. Moreover, we propose that such neuron-glia interactions may contribute to pelvic organ crosstalk that underlies the known comorbidity of IC/BPS and IBS. We have shown that neurons in sensory ganglia are in close spatial and functional contact with SGCs. SGCs support neuronal homeostasis but also respond to neuronal stimulation through release of “gliotransmitters” and other chemical mediators, such as ATP and cytokines, which modulate neuronal excitability. There is strong evidence that activation of glia in the CNS and PNS play key roles in development and maintenance of pain, and the importance of the crosstalk between SGCs and neurons in pathological pain is becoming increasingly evident. Little is still known, however, of whether and to what extent the crosstalk between SGCs and neurons contributes to pelvic organ sensitization and cross-sensitization, and through which mechanisms SGC-neuron signaling may be enhanced and thereby contribute to pelvic pain. We have shown that in experimental colitis, gap junction (GJ) mediated neuron-SGC signaling is enhanced in the DRG innervating the colon. Moreover, findings from our studies with deletion of P2X7 receptors and pannexin 1 (Panx1) channels, main molecular mediators of SGC-neuron signaling, suggest that enhanced SGC-neuron communication through activation of the P2X7R-Panx1 complex plays a key role in development of DRG hyperexcitability and tactile hypersensitivity. Based on these findings, we hypothesize that intercellular GJ and P2X7R-Panx1 mediated signaling in the DRG play a key role in sensitization of pelvic afferents by contributing mechanisms that enhance SGC activation and neuronal excitability and can contribute to colon-bladder cross-sensitization. To test this hypothesis, we will employ well established models of direct bladder and colon insult, and combined behavioral, functional and molecular approaches using wildtype and transgenic mice with global or cell-specific deletion of Cx43, Panx1 and P2X7R. Findings from these studies are expected to demonstrate the key role of pathologically enhanced SGC-neuron signaling in the development of pelvic pain and visceral cross-sensitization, and reveal that gap junctions and the P2X7R-Panx1 functional complex drive the enhanced SGC-neuron intercellular signaling in this process, providing novel therapeutic targets for future clinical translation.