Nociception in Diabetic Neuropathy: Role of Endothelins

描述(申请人提供)：糖尿病神经病变是糖尿病的主要并发症之一。两种不同的临床表现：糖尿病神经病变包括患有疼痛的对称性多发性神经病变的患者和那些感觉迟钝、无痛的足部患者。形态计量学分析表明，在糖尿病神经病变过程中，小感觉神经纤维神经元变性较早且明显。与细小纤维变性相关的体征和症状不一，从痛觉过敏到痛觉和温觉丧失。内皮素(ET)是一类与不同受体亚型相互作用的血管活性多肽，可调节血流、细胞增殖、肌肉收缩或松弛。最近在正常大鼠的观察表明，A型和B型内毒素受体(分别为ETAR和ETBR)主要分布在小的无髓鞘感觉纤维及其卫星雪旺细胞(SC)中，在那里它们似乎调节神经病理性和炎症性疼痛。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介导的伤害性感受器的兴奋。我们最近证实，ETS通过ETBR作用，调节培养的SC的增殖和表型，并观察到ETBR在糖尿病神经中的表达减少。基于这一信息，我们推测，在实验性糖尿病中，机械性痛敏和触觉异常痛的发展反映了神经胶质细胞ETBR表达减少和/或伤害性纤维神经元Etar表达增加。为了验证这一假说，我们建议：1)比较ET-1和ETR在正常和糖尿病大鼠神经和背根神经节细胞中的表达和定位；2)研究ETBR激动剂和ETR拮抗剂对正常和糖尿病大鼠伤害性反应的影响，并比较正常大鼠和缺乏ETBR表达的大鼠的伤害性反应。这个短期的探索性项目(R21)有望极大地促进我们对ETS在糖尿病疼痛中的作用的理解。

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.