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

描述（由申请人提供）：难治性疼痛对生活质量有显著的不良影响，没有一种现有的治疗方法可以完全逆转这些症状。此外，目前可用的疼痛疗法往往伴有严重的副作用。近年来的研究表明，t型钙通道（t -channel）在急性和慢性伤害感受加工中起着信号放大器的作用。我们证明，在早期疼痛性链脲霉素诱导的糖尿病周围神经病变（PDN）大鼠的伤害性背根神经节（DRG）神经元亚群中，CaV3.2 T-电流选择性上调。此外，选择性地在体内沉默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感觉的影响较小。重要的是，缺乏CaV3.2通道的小鼠没有出现PDN的早期痛觉过敏。这些结果首次有力地表明t通道作为治疗疼痛性PDN的靶点的潜在价值。将对糖尿病大鼠的DRG神经元进行体外生物物理、药理学和建模研究，以及对整个动物的疼痛研究。据推测，DRG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，从而逆转伤害感受器增加的细胞兴奋性，并比健康动物更有效地影响糖尿病患者的疼痛阈值。因此，降低药物在体内的剂量可以大大降低不良副作用的风险。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和更安全的治疗方法。希望这种方法可以大大减少患者对麻醉品的使用需求，并减少顽固性神经性疼痛患者滥用药物的可能性。

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.