Elucidation of the pathogenesis of painful diabetic neuropathy as a base of new drug development

我研究了糖尿病对小鼠氟戊酸酯诱导的伤害性反应的影响。在非糖尿病和糖尿病小鼠中，鞘内或足底注射氰戊酸钠（一种钠通道激活剂）诱导了一种特征性的行为综合征，主要包括后肢对身体尾部部位的相互抓挠和后腿的咬或舔。然而，这种由氰戊酸引起的伤害性反应的强度在糖尿病小鼠中明显大于非糖尿病小鼠。Calphostin C (3pmol, i.t)，一种选择性蛋白激酶C抑制剂，显著抑制鞘内氟氰菊酯诱导的伤害性行为，氟氰菊酯诱导的伤害性行为的剂量-反应曲线右移至非糖尿病小鼠的水平。另一方面，当非糖尿病小鼠接受phorol - 12,13 -二丁酸酯（50 pmol, i.t）预处理时，鞘内氰戊酸酯诱导的伤害性行为的剂量-反应曲线左移至糖尿病小鼠的水平。这些结果表明，长期激活蛋白激酶C对钠通道（可能是TTX-R钠通道）的致敏作用可能在延长糖尿病小鼠氟氰戊酸诱导的伤害性行为持续时间中起重要作用。

I examined the effect of diabetes on the fenvalerate-induced nociceptive response in mice. The intrathecal or intraplantar injection of fenvalerate, a sodium channel activator, induced a characteristic behavioral syndrome mainly consisting of reciprocal hind limb scratching directed towards caudal parts of the body and biting or licking of the hind legs in both non-diabetic and diabetic mice. However, the intensity of such fenvalerate-induced nociceptive responses was significantly greater in diabetic mice than in non-diabetic mice. Calphostin C (3 pmol, i.t.), a selective protein kinase C inhibitor, significantly inhibited intrathecal fenvalerate-induced nociceptive behavior with a rightward shift of the dose-response curve for fenvalerate-induced nociceptive behavior to the level those observed in non-diabetic mice. On the other hand, when non-diabetic mice were pretreated with phorbol-12, 13-dibutyrate (50 pmol, i.t.), the dose-response curve for intrathecal fenvalerate-induced nociceptive behavior was shifted leftward to the level those observed in diabetic mice. These results suggest that the sensitization of sodium channels, probably TTX-R sodium channels, by the long-term activation of protein kinase C may play an important role in the enhancement of the duration of fenvalerate-induced nociceptive behavior in diabetic mice.