T-type calcium channel inhibitors and alpha lipoic acid as novel therapies for treating pain post-surgery

背根神经节和背角的痛觉感觉神经元可被敏化 (极度兴奋)对组织损伤的反应。因为对这些机制的了解还不够 这种敏感化，目前对术后疼痛的治疗仅限于某种程度上的非特异性全身性。 有显著副作用或可能被滥用的药物(类阿片)。我们实验室最近的研究表明 建立了CaV3.2(T型)钙通道电压门控性钙通道 通过增强外周伤害性感受器的兴奋性对疼痛反应敏化的未知贡献 在外科手术引起的组织损伤的背景下。尽管CaV3.2通道在 疼痛反应外周敏化的发病机制，多种亚型T通道的作用(CaV3.1， CaV3.2和CaV3.3)在中枢(脊髓)敏化疼痛反应中的作用还没有得到很好的研究。我们之前展示了 内源性化合物和饮食对伤害性背根神经节神经元CaV3.2电流的阻断 补充硫辛酸(ALA)是其强大的外周抗伤害作用的基础。我们的新数据表明 ALA在爪部皮肤切开引起的手术后疼痛的大鼠模型中表现出良好的止痛作用，以及 T通道的CaV3.1亚型对小鼠痛觉过敏的发生也很重要。 爪子切开。因此，我们认为ALA可能是一类更安全的止痛药，具有理想的止痛剂。 通过靶向疼痛通路中的T通道以及能够减少 阿片成瘾的风险。 在目标1中，我们将通过临床实验研究CaV3.1和CaV3.2通道在丙氨酸镇痛中的作用。 相关皮肤和深部组织切开的啮齿动物模型。 在目标2中，我们将确定ALA在调节突触传递和神经元兴奋性中的作用。 伤害性感觉的双氢叶酸能神经元。在这一目标中，我们还将测试ALA可能逆转脑内过度兴奋的假设 大鼠足底皮肤切开后的伤害性感觉神经元。这些研究将定义 ALA在主要伤害性感受通路中的全细胞神经生理学作用。最后，我们还将使用电子 用显微镜观察CaV3.1和CaV3.2通道在伤害性DH中的细胞和亚细胞定位 神经元。这项拟议的工作具有创新性和医学意义，因为我们预计我们的临床前研究 研究将确定围术期疼痛的新疗法，这些疗法可能会极大地减少麻醉药物和 有滥用药物的可能。

Pain-sensing sensory neurons of the dorsal root ganglion (DRG) and dorsal horn (DH) can become sensitized (hyperexcitable) in response to the tissue injury. Because of insufficient knowledge about the mechanisms for this sensitization, current treatment for postoperative pain has been limited to somewhat non-specific systemic drugs (opioids) having significant side effects or potential for abuse. Recent studies in our laboratory have established that CaV3.2 (T-type) calcium-channels voltage-gated calcium channels make a previously unrecognized contribution to sensitization of pain responses by enhancing excitability of peripheral nociceptors in the setting of surgically induced tissue injury. Despite the established role of CaV3.2 channels in the pathogenesis of peripheral sensitization of pain responses, the role of multiple isoforms of T-channels (CaV3.1, CaV3.2 and CaV3.3) in central (spinal) sensitization of pain responses is not well studied. We previously showed that the blockade of CaV3.2 currents in nociceptive DRG neurons by an endogenous compound and dietary supplement a lipoic acid (ALA) underlies its potent peripheral anti-nociceptive effects. Our new data demonstrate that ALA displays excellent analgesia in a rat model of post-surgical pain resulting from paw skin incisions, and that CaV3.1 isoform of T-channels is also important for the development of hyperalgesia in a mouse model of paw incision. Thus, we propose that ALA may represent a safer class of analgesics having desirable analgesic properties in post-operative period by targeting T-channels in pain pathway, as well as being able to reduce the risk for the opioid addiction. In Aim 1, we will study the roles of CaV3.1 and CaV3.2 channels in ALA-induced analgesia using a clinically relevant rodent model of skin and deep tissue incision. In Aim 2, we will define the role of ALA in modulating synaptic transmission and neuronal excitability of nociceptive DH neurons. In this Aim, we will also test the hypothesis that ALA may reverse hyperexcitability in the identified nociceptive DH neurons in the rats following plantar skin incision. These studies will define the whole-cell neurophysiological effects of ALA in the major nociceptive pathway. Finally, we will also use electron microscopy to study cellular and subcellular localization of CaV3.1 and CaV3.2 channels in nociceptive DH neurons. The proposed work is innovative and medically significant because we anticipate that our preclinical studies will identify novel therapies for perioperative pain that may greatly decrease the need for narcotics and potential for drug abuse.