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

描述(申请人提供)：顽固性疼痛对生活质量测量有显著的不利影响，现有的治疗方法都不能完全扭转这些症状。此外，目前可用的疼痛治疗方法往往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反应中起着信号放大器的作用。我们证明了在早期疼痛的链脲佐菌素诱导的周围糖尿病神经病变(PDN)大鼠的背根节(DRG)伤害性神经元亚群中，CaV3.2 T电流选择性上调。此外，选择性地体内沉默DRG神经元中的CaV3.2通道完全逆转了PDN大鼠的痛觉过敏，而对健康大鼠的伤害性感受影响较小。重要的是，缺乏CaV3.2通道的小鼠不会出现早期的PDN痛觉过敏。这些结果首次有力地表明了T通道作为治疗痛性PDN的靶点的潜在价值。将对糖尿病大鼠的背根节神经元进行体外生物物理、药理学和模型研究，以及对整个动物进行疼痛研究。据推测，与健康动物相比，DRG神经元中T通道可用性的增加将增强电压依赖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细胞兴奋性的增加，并更有效地影响痛阈值。因此，降低体内药物的剂量可能会大大降低不良副作用的风险。预计这种方法最终可能导致对糖尿病患者痛觉改变的更好和更安全的治疗。人们希望这种方法可以大大减少患有顽固性神经病理性疼痛的患者群体对麻醉药物的使用需求和药物滥用的可能性。 公共卫生相关性：顽固性疼痛对生活质量测量有显著的不利影响，目前可用的治疗方法不能完全逆转这些症状，而且往往与严重的副作用相关。这项拟议的研究将研究电压依赖的T型钙通道阻滞剂在逆转与痛性糖尿病神经病变相关的感觉神经元兴奋性增强方面的作用。我们预计，这种方法最终将导致对糖尿病患者顽固性神经病理性疼痛的更好治疗。人们希望这种方法可以大大减少患有顽固性神经病理性疼痛的患者群体对麻醉药物的使用需求和药物滥用的可能性。

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.