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

摘要 数百万人患有慢性盆腔疼痛，通常与间质性膀胱炎/膀胱疼痛有关 综合征（IC/BPS）和肠易激综合征（IBS）。有几个因素牵涉其中， 这些疾病的病理生理学，但疼痛慢性化的机制仍然知之甚少。 这一建议是由我们以前的研究特点神经胶质细胞的相互作用在感觉神经节 并证明了它们在涉及口面和后肢炎症的慢性疼痛模型中的重要性。基于 基于这些发现，我们集中研究感觉神经节（背根）内的神经整合过程 神经节：DRG），支配盆腔器官，并调查是否以及在多大程度上改变了细胞间 DRG感觉神经元和卫星神经胶质细胞（SGCs）之间的信号传导提供了一种共同的机制， 膀胱和结肠疼痛。此外，我们提出，这种神经元-胶质细胞的相互作用可能有助于盆腔器官， 串扰是IC/BPS和IBS的公知兼容性的基础。 我们已经表明，感觉神经节中的神经元与SGCs有着密切的空间和功能联系。SGCs 支持神经元稳态，而且还通过释放“胶质递质”对神经元刺激作出反应， 其他化学介质，如ATP和细胞因子，调节神经元兴奋性。有强有力 证据表明CNS和PNS中胶质细胞的激活在疼痛的发展和维持中起关键作用， SGCs与神经元之间的相互作用在病理性疼痛中的重要性日益突出 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， 有助于盆腔器官敏化和交叉敏化，并通过该机制SGC-神经元 信号传导可能增强，从而导致骨盆疼痛。我们已经证明在实验性结肠炎中， 间隙连接（GJ）介导的神经元-SGC信号传导在神经支配结肠的DRG中增强。此外，委员会认为， 我们的研究发现，P2 X7受体和泛连接蛋白1（Panx 1）通道，主要分子 神经元信号传导的介质，表明通过激活 P2 X7 R-Panx 1复合物在DRG过度兴奋性和触觉超敏性的发展中起关键作用。 基于这些发现，我们假设细胞间GJ和P2 X7 R-Panx 1介导的信号转导在细胞内的表达。 背根神经节通过促进SGC的机制在盆腔传入神经的敏化中发挥关键作用 激活和神经元兴奋性，并可有助于结肠-膀胱交叉致敏。为了验证这一 假设，我们将采用良好建立的直接膀胱和结肠损伤模型，并结合行为， 使用具有全局或细胞特异性缺失的野生型和转基因小鼠的功能和分子方法 Cx43、Panx 1和P2 X7 R。这些研究的结果预计将证明病理学上的关键作用， 增强的SGC-神经元信号在盆腔疼痛和内脏交叉敏化的发展，并揭示 缝隙连接和P2 X7 R-Panx 1功能复合体驱动增强的SGC-神经元细胞间 在这一过程中的信号传导，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.