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.

项目摘要 引用的疼痛在研究中均已研究，在诊所中对 膀胱疾病。膀胱疼痛会大大减轻生活质量，这被未经批评或 皮肤不当治疗疼痛。缺乏诊断膀胱或躯体疼痛的诊断。 明显的病理，加剧了寻找有效治疗方法的挑战。虽然是根 这种转诊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。脊髓归因于疼痛的机制无法解释为什么患者 骨盆疼痛具有下肢皮肤的感觉神经损失，这是神经性疼痛的诊断。 初步数据表明，膀胱炎症的小鼠后爪的机械性超敏反应紧密 类似于神经损伤表型并反映了膀胱下肢灵敏度的患者经历 炎症或神经损伤。在周围神经系统中，背根神经（DRG）神经元为 在功能和支配组织中，受伤和未受伤的神经元及其周围的组织广泛多样 卫星神经胶质，受伤后会发生变化，导致疼痛。无伤膀胱之间的内脏串扰 或DRG中的躯体神经元可能会引起转介疼痛，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确认DRG可以共同建立两者 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 受伤后DRG中内脏串扰的假设导致过度可观的生理 未受伤的电路的响应，由其感觉神经元的功能变化和 用卫星神经胶质改变信号传导。为此，神经生理学实验将使用完整的DRG进行 保持神经元和卫星胶质的局部通信，包括一种新颖的体内准备， 将小鼠的感觉电路从后爪皮肤到完整的脊髓。与分子一起 蛋白质表达的测定，实验将确定驱动示踪剂标记的机制 通过探测卫星神经胶质和两个关键膜受体的激活，瞬时电位，未受伤的神经元 通道V成员1（TRPV1），也称为辣椒素受体和Purinocepter 3（P2X3），这是广泛的 研究了三磷酸腺苷受体，这两种受体在引用的疼痛中都鲜为人知 膀胱炎症或神经损伤。 AIM 1旨在调查未受伤的后爪神经元如何 丙烯醛诱导的膀胱炎后生理上改变了，这些改变是由 TRPV1或P2X3的变化。 AIM 2将探索未受伤的膀胱感官神经元如何受到幸免的影响 神经损伤，下肢神经性疼痛的强大模型。总的来说，这些数据将有助于阐明感觉 DRG中的神经元串扰是一种新的生物学机制，引用了膀胱患者的疼痛 疾病，为改进诊断和新颖，有效的治疗方法提供了一个起点。