Validation of voltage-dependent T-channel blockers in treatment of neuropathic pa

描述（由申请人提供）：顽固性疼痛对生活质量指标有显著的不良影响，现有的治疗方法都不能完全逆转这些症状。此外，目前可用的疼痛疗法通常与严重的副作用有关。最近的研究表明，T型钙通道（T通道）在急性和慢性伤害性信息处理中起着信号放大器的作用。我们证明，CaV3.2 T-电流选择性上调的伤害性背根神经节（DRG）神经元的大鼠早期疼痛链脲佐菌素诱导的周围糖尿病神经病变（PDN）的亚群。此外，在DRG神经元中的CaV3.2通道的选择性体内沉默完全逆转了PDN大鼠中的痛觉过敏，而对健康大鼠中的伤害性感受具有较小的影响。重要的是，缺乏CaV3.2通道的小鼠不会发生PDN的早期痛觉过敏。这些结果首次强烈表明T通道作为治疗疼痛性PDN的靶点的潜在价值。将在体外对糖尿病大鼠的DRG神经元进行生物物理学、药理学和建模研究，并对整个动物进行疼痛研究。据推测，背根神经节神经元中T通道可用性的增加将增强电压依赖性阻滞剂与这些通道相互作用的能力，从而逆转伤害性感受器增加的细胞兴奋性，并更有效地影响糖尿病患者的痛阈比健康动物。因此，降低体内药物剂量可以大大降低不希望的副作用的风险。预计这种方法可能最终导致糖尿病患者疼痛感觉改变的更好，更安全的治疗方法。希望这种方法可以大大减少对使用麻醉剂的需求和患有难治性神经性疼痛的患者群体中药物滥用的可能性。 公共卫生相关性：顽固性疼痛对生活质量指标有显著的不良影响，目前可用的治疗方法不能完全逆转这些症状，而且往往伴有严重的副作用。这项拟议的研究将研究T型钙通道的电压依赖性阻滞剂在逆转与疼痛性糖尿病神经病变相关的感觉神经元兴奋性增强中的作用。我们预计，这种方法将最终导致更好的治疗糖尿病患者的顽固性神经病理性疼痛。希望这种方法可以大大减少对使用麻醉剂的需求和患有难治性神经性疼痛的患者群体中药物滥用的可能性。

DESCRIPTION (provided by applicant): Intractable pain has significant adverse effects on quality of life measures, and none of the available treatments can completely reverse these symptoms. Furthermore, currently available pain therapies are often associated with serious side effects. Recent studies indicate that T-type calcium channels (T-channels) function as signal amplifiers in acute and chronic nociceptive processing. We demonstrated that CaV3.2 T- currents are selectively up-regulated in a subpopulation of nociceptive dorsal root ganglion (DRG) neurons of rats with early painful streptozocin-induced peripheral diabetic neuropathy (PDN). Also, selective in vivo silencing of CaV3.2 channels in DRG neurons completely reversed hyperalgesia in rats with PDN, while having a smaller effect on nociception in healthy rats. Importantly, mice lacking CaV3.2 channels did not develop early hyperalgesia of PDN. These results for the first time strongly indicate the potential value of T-channels as a target for the treatment of painful PDN. Biophysical, pharmacological and modeling studies will be performed with DRG neurons from diabetic rats in vitro, as well as pain studies with whole animals. It is hypothesized that an increase in the availability of T-channels in DRG neurons will enhance the ability of voltage-dependent blockers to interact with these channels and thus reverse the increased cellular excitability of nociceptors and more potently affect pain thresholds in diabetic than healthy animals. Thus, lowering the dosage of drugs in vivo may greatly decrease risk of unwanted side effects. It is anticipated that this approach may ultimately lead to better and safer therapies for altered pain sensation in patients with diabetes. It is hoped that this approach may greatly decrease need for the use of narcotics and potential for drug abuse in patient populations suffering from intractable neuropathic pain. PUBLIC HEALTH RELEVANCE: Intractable pain has significant adverse effects on quality of life measures, and currently available treatments can not completely reverse these symptoms and are often associated with serious side effects. This proposed research will study the role of voltage-dependent blockers of T-type calcium channels in reversing enhanced excitability of sensory neurons associated with painful diabetic neuropathy. We anticipate that this approach will ultimately lead to better treatments for intractable neuropathic pain in patients with diabetes. It is hoped that this approach may greatly decrease need for the use of narcotics and potential for drug abuse in patient populations suffering from intractable neuropathic pain.