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; 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 数以百万计 综合征（IC/BP）和肠易激综合症（IBS）。在 这些疾病的病理生理学，但疼痛回19的机制仍然鲜为人知。 该提议是由我们先前的研究表征神经神经节中神经胶质相互作用的动机的动机 并证明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 在这些发现中，我们专注于感官神经节内发生的神经整合过程（背根 神经节：drg）支配骨盆器官，并研究了细胞间的改变以及在何种程度上改变 DRG感觉神经元和卫星神经胶质细胞（SGC）之间的信号传导提供了一种常见的机制 膀胱和结肠疼痛。此外，我们建议这种神经胶质相互作用可能有助于骨盆器官 IC/BPS和IBS已知合并症的串扰是基础。 我们已经表明，感觉神经节中的神经元与SGC紧密接触。 支持神经元稳态，但也通过释放“ Gliotransmitters”和 其他化学介质（例如ATP和细胞因子）调节神经元兴奋性。有强大 CNS和PNS中神经胶质激活在疼痛的发展和维持中起关键作用的证据，以及 SGC和神经元之间串扰在病理疼痛中的重要性越来越多 证据。然而，鲜为人知的是SGC和神经元之间的串扰是否以及在何种程度上 有助于骨盆器官的敏感性和交叉敏化，并通过这些机制SGC-Neuron 信号传导可能会增强，从而导致骨盆疼痛。我们已经表明，在实验性结肠炎中， 在神经结肠的DRG中增强了间隙连接（GJ）介导的神经元-SGC信号传导。而且， 从我们研究中删除P2X7受体和Pannexin 1（Panx1）通道的研究结果，主要分子 SGC-Neuron信号传导的介体表明，通过激活的激活增强了SGC-Neuron的通信 P2X7R-PANX1复合物在DRG过度兴奋性和触觉超敏反应的发展中起关键作用。 基于这些发现，我们假设细胞间GJ和P2X7R-PANX1介导的信号传导 DRG通过贡献增强SGC的机制在骨盆传入的敏感性中起关键作用 激活和神经元的刺激性，可以导致结肠叶片的交叉敏化。测试这个 假设，我们将采用良好的直接膀胱和结肠损伤的模型，并结合行为， 使用野生型和转基因小鼠具有全球或细胞特异性缺失的功能和分子方法 CX43，PANX1和P2X7R。这些研究的发现预计将证明病理上的关键作用 增强的SGC-Neuron信号传导在骨盆疼痛和内脏交叉敏化的发展中，并揭示 该差距连接和P2X7R-PANX1功能复合物驱动增强的SGC-Neuron间细胞间 在此过程中的信号传导，为将来的临床翻译提供了新颖的治疗靶标。