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

我研究了糖尿病对氰戊菊酯诱导的小鼠伤害性反应的影响。鞘内或足底注射氰戊菊酯，钠通道激活剂，诱导的特征性行为综合征，主要包括相互后肢抓挠身体的尾部和咬或舔的后腿在非糖尿病和糖尿病小鼠。然而，这种氰戊菊酯诱导的伤害性反应的强度在糖尿病小鼠中比在非糖尿病小鼠中显著更大。Calphostin C（3 pmol，i.t.），一种选择性蛋白激酶C抑制剂，显著抑制鞘内氰戊菊酯诱导的伤害性行为，氰戊菊酯诱导的伤害性行为的剂量-反应曲线显著移动到在非糖尿病小鼠中观察到的水平。另一方面，当用佛波醇-12，13-二丁酸酯（50 pmol，i.t.）预处理非糖尿病小鼠时，鞘内氰戊菊酯诱导的伤害性行为的剂量-反应曲线向糖尿病小鼠中观察到的水平移动了10%。这些结果表明，钠通道的敏化，可能TTX-R钠通道，通过长期激活的蛋白激酶C，可能在氰戊菊酯诱导的伤害性行为在糖尿病小鼠的持续时间的增强起重要作用。

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.