Receptor-mediated dysfunction of satellite glia and uninjured sensory neurons as a novel link between referred neuropathic pain and bladder disease

卫星胶质细胞和未损伤感觉神经元受体介导的功能障碍是牵涉性神经性疼痛和膀胱疾病之间的新联系

• 批准号: 10602919
• 负责人: Emily L Tran
• 金额: $ 3.62万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-26 至 2026-04-25
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10602919
• 关键词: Acrolein; Address; Adenosine Triphosphate; Affect; Afferent Neurons; Automobile Driving; Behavioral; Biological; Biological Assay; Biopsy; Bladder; Bladder Diseases; Bladder Dysfunction; Bladder Injury; Blood - brain barrier anatomy; Body part; Central Nervous System; Chemicals; Clinic; Communication; Creativeness; Curiosities; Cystitis; Data; Development; Diagnosis; Diagnostic; Distant; Experimental Designs; Exposure to; Female; Functional disorder; Ganglia; Human; Hypersensitivity; Inflammation; Injury; Interneurons; Interstitial Cystitis; Label; Link; Literature; Lower Extremity; Measures; Mechanics; Mediating; Membrane; Modeling; Molecular; Molecular Target; Mus; Nerve; Neurogenic Bladder; Neuroglia; Neurons; Neurosciences; Organ; Pain; Pain Attribute; Pain management; Pathology; Patients; Pattern; Pelvic Pain; Peripheral; Peripheral Nervous System; Phenotype; Physiological; Play; Preparation; Purinoceptor; Quality of life; Research; Rodent Model; Role; Sensory; Sensory Ganglia; Signal Transduction; Site; Skin; Spinal; Spinal Cord; Spinal Ganglia; Syndrome; TRP channel; TRPV1 gene; Testing; Therapeutic; Tissues; Tracer; Training; Urology; Vertebral column; Visceral; behavior measurement; bladder pain; capsaicin receptor; dermatome; design; experience; experimental study; improved; injured; intercellular communication; member; mouse model; nerve damage; nerve injury; nerve supply; neuronal excitability; neurophysiology; novel; painful neuropathy; protein expression; receptor; receptor expression; response; spared nerve; sural; therapeutically effective

PROJECT SUMMARY Referred pain is both understudied in research and poorly understood in the clinic, particularly for patients with bladder disease. Bladder pain can significantly lessen quality of life, which is amplified by unacknowledged or improperly treated pain from the skin. Diagnosis of referred bladder or somatic pain is obfuscated by a lack of obvious pathology, exacerbating the challenges of finding effective therapeutic approaches. Though the root cause of such referred pain is unknown, it likely relies on visceral and skin afferent interactions, termed viscerosomatic crosstalk. Mechanisms of referred pain attributed to the spinal cord fail to explain why patients with pelvic pain have sensory innervation loss of the lower limb skin that is diagnostic for neuropathic pain. Preliminary data shows that mechanical hypersensitivity in hind paws of mice with bladder inflammation closely resembles nerve injury phenotypes and reflect patient experiences of lower limb sensitivity from bladder inflammation or nerve damage. In the peripheral nervous system, dorsal root ganglia (DRG) neurons are widely diverse in function and in innervating tissue, where injured and uninjured neurons, and their surrounding satellite glia, undergo changes after injury that drive pain. Viscerosomatic crosstalk between uninjured bladder or somatic neurons in DRG could be causing referred pain, but there is a dearth of information about bladder neuron crosstalk in the DRG. Retrograde neuronal tracing studies confirming DRG can co-housing both bladder and hind paw skin sensory neurons strongly support this possibility. The proposed research will test the hypothesis that viscerosomatic crosstalk in DRG after injury results in hyperexcitable physiological responses of the uninjured circuit, mediated by functional changes in their sensory neurons and altered signaling with satellite glia. To do this, neurophysiology experiments will utilize intact DRGs to maintain local communication between neurons and satellite glia, including a novel ex vivo preparation that leaves the mouse sensory circuit from the hind paw skin to the spinal cord intact. Together with molecular assays of protein expression, experiments will determine the mechanisms driving activation of tracer-labeled uninjured neurons by probing activation of satellite glia and two key membrane receptors, transient potential channel V member 1 (TRPV1), also known as the capsaicin receptor, and Purinocepter 3 (P2X3), a widely studied adenosine triphosphate receptor, both of which are poorly understood in referred pain that results from bladder inflammation or nerve injury. Aim 1 is designed to investigate how uninjured hind paw neurons are physiologically altered after acrolein-induced cystitis, and the possibility that these alterations are mediated by changes in TRPV1 or P2X3. Aim 2 will explore how uninjured bladder sensory neurons are affected by Spared Nerve Injury, a robust model of lower limb neuropathic pain. Collectively, these data will help elucidate sensory neuron crosstalk in DRG as a new biological mechanism underlying referred pain in patients with bladder disease and provide a starting point for improved diagnosis and novel, effective therapeutic approaches.

项目总结 牵涉性疼痛在研究中研究不足，在临床上也知之甚少，尤其是对患有 膀胱病。膀胱疼痛会显著降低生活质量，而不被承认的或 不恰当地治疗皮肤的疼痛。有关膀胱痛或躯体疼痛的诊断因缺乏 明显的病理，加剧了寻找有效治疗方法的挑战。虽然根部 这种牵涉性疼痛的原因尚不清楚，它可能依赖于内脏和皮肤的传入相互作用，称为 内脏-躯体的相声。被归因于脊髓的牵涉性疼痛机制无法解释为什么患者 伴有盆腔疼痛的患者有感觉神经支配缺失，这是神经病理性疼痛的诊断。 初步数据显示，膀胱炎小鼠的后爪机械超敏反应密切相关。 与神经损伤表型相似，反映患者对膀胱下肢敏感的经历 炎症或神经损伤。在周围神经系统中，背根神经节(DRG)神经元 在功能和神经组织上差异很大，损伤和未损伤的神经元及其周围 星形胶质细胞在受伤后会发生变化，从而导致疼痛。未受伤的膀胱之间的内脏-体串扰 或者，背根神经节中的体细胞神经元可能引起牵涉性疼痛，但关于膀胱的信息很少。 背根神经节的神经元串扰。逆行神经元追踪研究证实背根神经节可以共同容纳两者 膀胱和后爪皮肤感觉神经元强烈支持这种可能性。拟议中的研究将检验 损伤后背根神经节内脏-体串扰导致过度兴奋的生理学假说 未受损伤的回路的反应，由其感觉神经元和 改变了卫星神经胶质细胞的信号。为了做到这一点，神经生理学实验将利用完整的DRG 维持神经元和卫星胶质细胞之间的局部通讯，包括一种新的体外制剂 使小鼠从后爪皮肤到脊髓的感觉回路完好无损。与分子一起 蛋白质表达的分析，实验将确定驱动示踪剂标记激活的机制 通过探测激活卫星胶质细胞和两个关键的膜受体瞬时电位而未损伤的神经元 通道V成员1(TRPV1)，也被称为辣椒素受体，以及普利诺受体3(P2X3)，广泛的 研究了三磷酸腺苷受体，这两种受体在由 膀胱炎或神经损伤。Aim 1旨在研究未受损伤的后爪神经元 丙烯醛诱导的膀胱炎后的生理性改变，以及这些改变是由 TRPV1或P2X3的变化。目标2将探索未损伤的膀胱感觉神经元如何受到Saved的影响 神经损伤，一种健壮的下肢神经性疼痛模型。总的来说，这些数据将有助于阐明感官 背根节神经元串扰是引起膀胱牵涉性疼痛的一种新的生物学机制 并为改进诊断和新的有效治疗方法提供了一个起点。