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

T型钙通道抑制剂和α硫辛酸作为治疗术后疼痛的新疗法

• 批准号: 10454791
• 负责人: Slobodan M. Todorovic
• 金额: --
• 依托单位: VA EASTERN COLORADO HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10454791
• 关键词: Absence of pain sensation; Acute; Acute Pain; Adult; Analgesics; Animals; Attenuated; Calcium Channel; Cells; Chronic; Clinical; Cocaine; Complement; Conduction Anesthesia; Constipation; Dangerousness; Data; Development; Disease; Dose; Drug abuse; Electron Microscopy; Electrophysiology (science); Exposure to; Family; General Population; General anesthetic drugs; Heroin; Hyperalgesia; Impaired cognition; Knockout Mice; Knowledge; Laboratories; Lead; Local Anesthetics; Mediating; Medical; Modality; Modeling; Mus; Narcotics; Neuraxis; Neurologic; Neurons; Nociception; Nociceptors; Numbness; Operative Surgical Procedures; Opiate Addiction; Opioid; Opioid Analgesics; Outcome; Pain; Pain management; Pathogenesis; Pathologic; Pathway interactions; Patients; Perioperative; Peripheral; Persons; Pharmaceutical Preparations; Pharmacology; Physiological; Population; Posterior Horn Cells; Postoperative Pain; Postoperative Period; Preparation; Presynaptic Terminals; Property; Protein Isoforms; Publishing; Rattus; Research; Risk; Rodent Model; Role; Sensory Motor Performances; Site; Skin; Slice; Spinal; Spinal Cord; Spinal Ganglia; Surgical incisions; Synapses; Synaptic Transmission; Synaptic Vesicles; T-Type Calcium Channels; Testing; Thioctic Acid; Tissues; Translating; United States; United States National Center for Health Statistics; Urinary Retention; Ventilatory Depression; Veterans; Work; abuse liability; addiction; addiction liability; base; chronic pain; clinically relevant; cognitive function; dietary supplements; dorsal horn; in vivo; in vivo Model; inhibitor; innovation; member; military veteran; mouse model; neuronal excitability; neurophysiology; novel therapeutics; opioid abuse; overdose death; pain model; pain processing; preclinical study; prevent; response; side effect; tissue injury; transmission process; voltage

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.

背根神经节（DRG）和背角（DH）的痛觉神经元可被致敏 （过度兴奋的）响应于组织损伤。由于缺乏对这一机制的了解， 这种致敏，目前对术后疼痛的治疗仅限于某种非特异性的全身性疼痛， 具有显著副作用或滥用可能性的药物（阿片类药物）。我们实验室最近的研究表明， 建立了CaV3.2（T型）钙通道电压门控钙通道使先前的 通过增强外周伤害感受器的兴奋性对疼痛反应致敏的未被认识的贡献 在手术引起的组织损伤的情况下。尽管CaV3.2通道在细胞内的作用已经确定， 疼痛反应的外周致敏的发病机制，T-通道的多种同种型（CaV3.1， CaV3.2和CaV3.3）在疼痛反应的中枢（脊髓）敏化中的作用尚未得到充分研究。We previously showed 内源性化合物和饮食对伤害性DRG神经元CaV3.2电流的阻断 补充硫辛酸（ALA）是其有效的外周抗伤害感受作用的基础。我们的新数据表明 ALA在由爪皮肤切口引起的术后疼痛的大鼠模型中显示出优异的镇痛作用，并且 CaV3.1亚型的T-通道也是重要的发展痛觉过敏的小鼠模型， 爪切口。因此，我们认为ALA可能是一类安全的镇痛药， 通过靶向疼痛通路中的T通道，以及能够减少 阿片类药物成瘾的风险。 在目的1中，我们将研究CaV3.1和CaV3.2通道在ALA诱导的镇痛中的作用。 皮肤和深部组织切口的相关啮齿动物模型。 在目标2中，我们将定义ALA在调节突触传递和神经元兴奋性中的作用， 伤害感受性DH神经元。在本研究中，我们还将检验ALA可能逆转高血压患者的过度兴奋性的假设。 大鼠足底皮肤切口后鉴定的伤害性DH神经元。这些研究将确定 ALA在主要伤害性通路中的全细胞神经生理学作用。最后，我们还将使用电子 显微镜下研究伤害感受性DH中CaV3.1和CaV3.2通道的细胞和亚细胞定位 神经元这项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将在2020年完成。 研究将确定新的治疗围手术期疼痛的方法，可能会大大减少对麻醉剂的需求， 可能滥用药物。