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

神经卫星胶质细胞信号传导在盆腔疼痛和内脏交叉敏化中的作用

• 批准号: 10837287
• 负责人: SYLVIA OTTILIE SUADICANI
• 金额: $ 70.33万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-20 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10837287
• 关键词: Afferent Neurons; Animals; Attenuated; Behavioral; Biochemical; Bladder; Cells; Chemicals; Chronic Disease; Colitis; Colon; Colonic inflammation; Communication; Complex; Connexin 43; Coupling; Cyclophosphamide; Development; Dinitrobenzenes; Disease; Dyes; Electrophysiology (science); Functional disorder; Future; Gap Junctions; Hindlimb; Homeostasis; Hyperactivity; Hyperalgesia; Hypersensitivity; Image; Inflammasome; Inflammation; Interstitial Cystitis; Irritable Bowel Syndrome; Label; Maintenance; Mediating; Mediator; Methods; Modeling; Molecular; Molecular Target; Mus; Neuroglia; Neurons; Organ; Pain; Paper; Paracrine Communication; Pathologic; Pelvic Pain; Pelvis; Persons; Play; Process; Reporting; Role; Sensory; Sensory Ganglia; Signal Transduction; Spinal Ganglia; Stains; Sulfonic Acids; Supporting Cell; Symptoms; Tactile; Testing; Tissues; Transgenic Mice; Visceral; allodynia; autocrine; behavior test; cellular targeting; chronic pain; chronic pelvic pain; clinical translation; colon distension; comorbidity; cytokine; glial activation; intercellular communication; mouse model; neural; neuronal excitability; neurotransmission; new therapeutic target; novel; orofacial; pain chronification; pain model; pharmacologic; receptor; response; therapeutically effective

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.

抽象的 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）与多种因素有关。 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。 这一提议的灵感来自于我们之前对感觉神经节中神经元-胶质细胞相互作用的研究 并证明它们在涉及口面部和后肢炎症的慢性疼痛模型中的重要性。 根据这些发现，我们重点关注感觉神经节（背根）内发生的神经整合过程 神经节：DRG）支配盆腔器官，并研究细胞间质是否发生改变以及改变程度如何 DRG 感觉神经元和卫星胶质细胞 (SGC) 之间的信号传导提供了一种共同机制 此外，我们认为这种神经元-神经胶质细胞的相互作用可能会导致盆腔器官疼痛。 串扰是 IC/BPS 和 IBS 已知合并症的基础。 我们已经证明感觉神经节中的神经元与 SGC 具有密切的空间和功能联系。 支持神经元稳态，但也通过释放“胶质递质”对神经元刺激做出反应 其他化学介质，如 ATP 和细胞因子，可调节神经兴奋性。 有证据表明，中枢神经系统和三七总神经系统中神经胶质细胞的激活在疼痛的发生和维持中发挥着关键作用，并且 SGC 和神经元之间的串扰在病理性疼痛中的重要性日益凸显 然而，对于 SGC 和神经元之间是否存在串扰以及串扰程度如何，目前仍知之甚少。 有助于盆腔器官敏化和交叉敏化，SGC-神经元通过这种机制 我们已经证明，在实验性结肠炎中，信号传导可能会增强，从而导致盆腔疼痛。 间隙连接 (GJ) 介导的神经元-SGC 信号在支配结肠的 DRG 中得到增强。 我们通过删除 P2X7 受体和 pannexin 1 (Panx1) 通道（主要分子）的研究发现 SGC-神经元信号传导的介质表明，通过激活 P2X7R-Panx1 复合物在 DRG 过度兴奋和触觉超敏反应的发展中发挥着关键作用。 基于这些发现，我们探究了细胞间 GJ 和 P2X7R-Panx1 介导的信号传导 DRG 通过增强 SGC 的机制在盆腔传入神经的敏化中发挥关键作用 激活和神经兴奋性，并可能有助于结肠-膀胱交叉敏化。 假设，我们将采用成熟的直接膀胱和结肠损伤模型，以及结合的行为， 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 这些研究的结果有望证明 Cx43、Panx1 和 P2X7R 的关键作用。 增强 SGC 神经元信号在盆腔疼痛和内脏交叉敏化发展中的作用，并揭示 间隙连接和 P2X7R-Panx1 功能复合物驱动增强的 SGC 神经元细胞间 这一过程中的信号传导，为未来的临床转化提供了新的治疗靶点。