NEW APPROACHES TO C NOCICEPTORS IN DIABETIC NEUROPATHY

糖尿病神经病变引起疼痛。痛觉感受器是一种神经工具，用于接收有害刺激，并在大脑中传输解码为痛觉的脉冲。它们还能介导反激炎症。痛觉感受器功能障碍是自发性疼痛、机械或热刺激引起的痛觉过敏和神经源性炎症的主要原因。在患者中发现超兴奋C伤害感受器后，这些单位已成为疼痛性神经病变研究的焦点。近年来的科学进展启发了人们对伤害感受器功能和疾病的认识，并为人类伤害感受器的研究提供了新的方法。这些包括:a)人类C单元亚型的生物物理分化，b)在C伤害感受器神经元（动物）的可兴奋膜中特定电压和热敏离子通道及其阻滞剂的鉴定，C)发现一种不敏感的伤害感受器亚型，d)人体肌肉中C伤害感受器受体特性的表征，e)通过皮肤微透析或热成像客观测量血管对C反激兴奋的反应。F)识别（动物）神经病变中幸存的伤害感受器轴突的异常儿茶酚胺敏感性，g)发现继发性中枢神经元卷曲和致敏（动物）。为了进一步提升我们对疼痛的研究，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单位亚型。b)与实验致敏的（辣椒素）伤害感受器亚型志愿者相比，我们将测量糖尿病神经病变患者C伤害感受器亚型的基线兴奋性，特别是那些具有伤害感受器致敏ABC综合征的患者。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兴奋性或c伤害感受器亚型的影响。d)最后，我们将用致敏的伤害感受器间接测试糖尿病患者和志愿者的中枢神经元是否存在次生致敏，假设是由初级伤害感受器来源维持的。

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.