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.

项目概要 研究中对牵涉性疼痛的研究不足，临床上对其了解也知之甚少，特别是对于患有以下疾病的患者： 膀胱疾病。膀胱疼痛会显着降低生活质量，而未经承认或未承认的情况会加剧这种情况。 皮肤疼痛治疗不当。膀胱牵涉痛或躯体痛的诊断由于缺乏 明显的病理学，加剧了寻找有效治疗方法的挑战。虽根 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传入的相互作用，称为 内脏串扰。脊髓牵涉痛的机制无法解释患者的原因 患有盆腔疼痛的患者下肢皮肤感觉神经支配丧失，这可诊断为神经性疼痛。 初步数据表明，膀胱炎症小鼠后爪的机械超敏反应与膀胱炎症密切相关。 类似于神经损伤表型，反映患者对膀胱下肢敏感的体验 炎症或神经损伤。在周围神经系统中，背根神经节 (DRG) 神经元是 功能和神经支配组织存在广泛差异，其中受伤和未受伤的神经元及其周围 卫星神经胶质细胞在受伤后会发生变化，导致疼痛。未受伤膀胱之间的内脏体串扰 或 DRG 中的体细胞神经元可能会引起牵涉痛，但缺乏有关膀胱的信息 DRG 中的神经元串扰。逆行神经元追踪研究证实 DRG 可以同时容纳两者 膀胱和后爪皮肤感觉神经元强烈支持这种可能性。拟议的研究将测试 损伤后 DRG 内脏体串扰导致生理过度兴奋的假设 未受伤回路的反应，由感觉神经元的功能变化介导， 改变卫星神经胶质细胞的信号传导。为此，神经生理学实验将利用完整的 DRG 来 维持神经元和卫星神经胶质细胞之间的局部通讯，包括一种新型的离体制剂 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 蛋白质表达测定，实验将确定驱动示踪剂标记的激活的机制 通过探测卫星神经胶质细胞和两个关键膜受体的激活、瞬态电位来观察未受伤的神经元 V 通道成员 1 (TRPV1)，也称为辣椒素受体，以及广泛应用的嘌呤受体 3 (P2X3) 研究了三磷酸腺苷受体，这两种受体在由 膀胱炎症或神经损伤。目标 1 旨在研究未受伤的后爪神经元的情况 丙烯醛诱发的膀胱炎后生理发生改变，这些改变可能是由 TRPV1 或 P2X3 的变化。目标 2 将探索 Spared 如何影响未受伤的膀胱感觉神经元 神经损伤，下肢神经性疼痛的稳健模型。总的来说，这些数据将有助于阐明感官 DRG 中的神经元串扰是膀胱患者牵涉痛的新生物学机制 疾病并为改进诊断和新颖有效的治疗方法提供起点。