NEW APPROACHES TO C NOCICEPTORS IN DIABETIC NEUROPATHY

糖尿病神经病变中 C 伤害感受器的新方法

• 批准号: 6529411
• 负责人: JOSE L OCHOA
• 金额: $ 36.52万
• 依托单位: LEGACY EMANUEL HOSPITAL AND HEALTH CENTER
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-30 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6529411
• 关键词: C fiber; action potentials; adolescence (12-20); adult human (21+); capsaicin; catecholamines; chemoreceptors; clinical research; diabetic neuropathy; human subject; hyperalgesia; irritation /irritant; membrane channels; receptor sensitivity; thermoreceptors; voltage gated channel

Diabetic neuropathy causes pain. C nociceptors are neural instruments for reception of noxious stimuli and for transmission of impulses decoded as pain sensation in the brain. They also mediate antidromic inflammation. C nociceptor dysfunction is a main cause of spontaneous pain, hyperalgesia for mechanical or thermal stimuli, and neurogenic inflammation. Following discovery of hyperexcitable C nociceptors in patients, these units have become a focus for investigation in painful neuropathy. Recent scientific advances enlighten understanding of nociceptor function and disease, and provide new methods for their investigation in man. These include: a) biophysical differentiation of subtypes of human C units, b) identification of specific voltage and heat sensitive ion channels, and their blockers, in the excitable membranes of C nociceptor neurons (animals), c) discovery of an insensitive nociceptor subtype, d) characterization of receptor properties of C nociceptors from human muscle, e) objective measurement through skin microdialysis or thermography of vascular responses to C antidromic excitation, f) recognition of abnormal catecholamine sensitivity of surviving nociceptor axons in (animal) neuropathy, and g) discovery of secondary central neuronal windup and sensitization (animals). Upgrading our research on pain, we will apply a fresh paradigm to investigate nociceptor status in diabetic neuropathy patients and normal volunteer controls. We propose a) to further characterize subtypes of C units serving skin, and also muscle, through in vivo biophysical and physiological measurements in patients and volunteers. b) We will measure baseline excitability of C nociceptor subtypes in diabetic neuropathy patients, particularly in those with the ABC syndrome of nociceptor sensitization, compared to experimentally sensitized (capsaicin) nociceptor subtypes in volunteers. c) We will study the effects of catecholamines upon excitability or subtypes of C nociceptors in patients and in areas of hyperalgesia in sensitized volunteers. d) Finally, we will indirectly test central neurons of diabetics and volunteers with sensitized nociceptors for presence of secondary sensitization hypothetically maintained by the primary nociceptor source.

糖尿病神经病变会引起疼痛。 C伤害感受器是用于接收有害刺激和在大脑中传递解码为疼痛感觉的脉冲的神经仪器。 它们还介导抗炎症。 C 伤害感受器功能障碍是自发性疼痛、机械或热刺激痛觉过敏以及神经源性炎症的主要原因。 在发现患者体内存在过度兴奋的 C 伤害感受器后，这些单位已成为疼痛性神经病研究的焦点。 最近的科学进展启发了对伤害感受器功能和疾病的理解，并为人类研究提供了新方法。 这些包括：a) 人类 C 单位亚型的生物物理分化，b) 识别 C 伤害感受器神经元（动物）的可兴奋膜中的特定电压和热敏感离子通道及其阻断剂，c) 发现不敏感的伤害感受器亚型，d）表征来自人体肌肉的 C 伤害感受器的受体特性，e）通过皮肤微透析或热成像对血管对 C 逆向激发的反应进行客观测量，f）识别异常（动物）神经病中幸存伤害感受器轴突的儿茶酚胺敏感性，以及g）继发性中枢神经元饱和和敏化（动物）的发现。升级我们对疼痛的研究，我们将应用一种新的范式来研究糖尿病神经病变患者和正常志愿者对照的伤害感受器状态。 我们建议a)通过对患者和志愿者进行体内生物物理和生理测量，进一步表征服务于皮肤和肌肉的C单元的亚型。 b) 我们将测量糖尿病神经病变患者中 C 伤害感受器亚型的基线兴奋性，特别是患有伤害感受器敏化 ABC 综合征的患者，与志愿者中实验致敏（辣椒素）伤害感受器亚型进行比较。 c) 我们将研究儿茶酚胺对患者和致敏志愿者痛觉过敏区域的 C 伤害感受器兴奋性或亚型的影响。 d）最后，我们将间接测试糖尿病患者和具有致敏伤害感受器的志愿者的中枢神经元是否存在假设由主要伤害感受器源维持的次级致敏作用。