Nociception in Diabetic Neuropathy: Role of Endothelins

描述（由申请人提供）：糖尿病神经病变是糖尿病的主要并发症之一。糖尿病性神经病变的两种不同临床表现包括患有疼痛性对称性多发性神经病变的患者和患有不敏感、无痛性足部神经病变的患者。形态计量学分析表明，在糖尿病神经病变的过程中，小的感觉纤维神经元退化早，突出。与小纤维变性相关的体征和症状从痛觉过敏到疼痛和温度感觉丧失不等。内皮素（endothelins，IET）是一类血管活性肽家族，与不同受体亚型相互作用，调节血流、细胞增殖、肌肉收缩或舒张。最近在正常大鼠中的观察已经证明了A型和B型内皮素受体（分别为ETAR和ETBR）在小的无髓鞘感觉纤维及其卫星雪旺细胞（SC）中的主要定位，在那里它们似乎调节神经性疼痛和炎性疼痛。这些受体对疼痛的调节似乎是相互的，因为ETBR激动剂的给药抵消了ETAR介导的伤害感受器的兴奋。我们最近已经证明，糖尿病，通过ETBR，调节培养的SC的增殖和表型，并观察到ETBR在糖尿病神经的表达减少。基于这些信息，我们假设在实验性糖尿病中，机械性痛觉过敏和触觉异常性疼痛的发展反映了神经胶质细胞中ETBR表达的减少和/或伤害性感受纤维神经元中ETAR表达的增加。为了验证这一假设，我们提出：1）比较正常和糖尿病大鼠神经和背根神经节细胞中ET-1和ETR的表达和定位。2）研究ETBR激动剂和ETAR拮抗剂对正常和糖尿病大鼠伤害性反应的影响。并将对照大鼠中的伤害性反应与缺乏ETBR表达的大鼠中观察到的伤害性反应进行比较。预计将大大推进我们对糖尿病疼痛中的作用的理解，目前糖尿病疼痛仍处于早期发展阶段。

DESCRIPTION (provided by applicant): Diabetic neuropathy is one of the major complications of diabetes mellitus. Two distinct clinical manifestations of: the diabetic neuropathy include patients suffering from painful symmetrical polyneuropathy and those with insensitive, painless, feet. Morphometrical analysis shows that small sensory fiber neurons degenerate early and prominently during the course of diabetic neuropathy. Signs and symptoms associated with degeneration of small fibers vary from hyperalgesia to loss of pain and temperature sensation. The endothelins (lETs) constitute a family of vasoactive peptides interacting with different receptor subtypes to regulate blood flow, cell proliferation, muscle contraction or relaxation. Recent observations in normal rats have demonstrated the predominant localization of type A and type B endotbelin receptors (ETAR and ETBR, respectively) in small non-myelinated sensory fibers and their satellite Schwann cells (SC), where they appear to regulate neuropathic and inflammatory pain. The regulation of pain by these receptors seems to be reciprocal, since administration of ETBR agonists counteracts ETAR-mediated excitation of nociceptors. We have recently demonstrated that ETs, acting through the ETBR, modulate the proliferation and phenotype of cultured SC, and have observed a decreased expression of ETBR in diabetic nerves. Based on this information, we hypothesize that in experimental diabetes, the development of mechanical hyperalgesia and tactile allodynia reflects a decreased expression of ETBR in glial cells and/or an increased expression of ETAR in neurons from nociceptive fibers. To test this hypothesis we propose: 1) To compare the expression and localization of ET-1 and ETR in nerves and dorsal root ganglia cells isolated from normal and diabetic rats 2) To study the effect of ETBR agonists and ETAR antagonists on the nociceptive responses in normal and diabetic rats, and to compare the nociceptive responses in control rats with those observed in rats lacking expression of ETBR This short-term exploratory project (R21) is expected to significantly advance our understanding of the role of ETs in diabetic pain, which is currently in early stages of development.