Novel neurosteroid anesthetics and perioperative analgesia

新型神经类固醇麻醉剂和围手术期镇痛

基本信息

批准号：
9333664
负责人：
Vesna Jevtovic-Todorovic
金额：
$ 35.62万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2021-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9333664
关键词：
Absence of pain sensation Acute Acute Pain Adverse effects Afferent Neurons Analgesics Androstanols Anesthetics Biophysical Process Calcium Calcium Channel Calcium Channel Blockers Cells Chronic Cocaine Constipation Data Disease Dose Drug abuse Electron Microscopy Future General anesthetic drugs Goals Heroin Homeostasis Human Immunohistochemistry Impaired cognition In Vitro Injectable Injury Knockout Mice Knowledge Laboratories Lead Mediating Medical Modality Modeling Mus Narcotics Neurons Nociception Nociceptors Operative Surgical Procedures Opioid Opioid Analgesics Outcome Pain Pain management Pathway interactions Perioperative Peripheral Pharmaceutical Preparations Pharmacology Posterior Horn Cells Postoperative Pain Postoperative Period Preparation Presynaptic Terminals Property Rattus Recombinants Research Rodent Model Role Sensory Motor Performances Site Skin Slice Spinal Spinal Cord Spinal Ganglia Spinal cord posterior horn Steroids Structure-Activity Relationship Surgical incisions Synapses Synaptic Transmission Synaptic Vesicles T-Type Calcium Channels Testing Tissues United States United States National Center for Health Statistics Urinary Retention Ventilatory Depression Work addiction chronic pain clinically relevant cognitive function design dorsal horn expectation experimental study ganglion cell hypnotic in vivo inhibitor/antagonist innovation neuronal excitability neurophysiology neurosteroids novel novel therapeutics opioid abuse overdose death patch clamp response soft tissue steroid analog voltage

项目摘要

Project Summary Pain-sensing sensory neurons of the dorsal root ganglion (DRG) and dorsal horn (DH) can become sensitized (hyperexcitable) in response to surgically induced peripheral 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 and CaV2.3 (R-type) voltage- gated calcium channels make a previously unrecognized contribution to sensitization of pain responses by enhancing excitability of peripheral nociceptors and controlling excitatory synaptic transmission in the DH of the spinal cord. We previously showed that the blockade of CaV3.2 currents in nociceptive DRG neurons by 5β-reduced neuroactive steroids underlies their potent peripheral anti-nociceptive effects. Our new data demonstrate that one such steroid, 3β-OH [(3β,5β,17β)-3-hydroxyandrostane-17-carbonitrile], in addition to hypnotic properties, also displays excellent spinally-mediated analgesia. We also found that 3β-OH inhibits recombinant CaV2.3 currents. This finding has led us to hypothesize that: inhibition of neuronal CaV3.2 and CaV2.3 currents in pain pathways with the novel anesthetic 3β-OH and related neuroactive steroids underlies effective analgesia. In Aim 1, we will study analgesic potency of neuroactive steroids using a clinically relevant rodent model of skin and deep tissue incision. In Aim 2, we will define the role of neuroactive steroids in modulating synaptic transmission and neuronal excitability of nociceptive DH neurons. These studies will define the whole-cell neurophysiological effects of test compounds in the major nociceptive pathway. We will also use electron microscopy to study cellular and subcellular localization of CaV2.3 and CaV3.2 channels in nociceptive DH neurons. In Aim 3, we will study mechanisms and structure-activity relationships of steroid inhibition of recombinant and native CaV2.3 currents in the nociceptive DRG neurons. The main goal of this aim is to expand the limited information currently available with the expectation that the information obtained will be important for the design of more potent and selective inhibitors of CaV2.3 channels that can be important in developing novel and safer anesthetics and analgesics. The proposed work is innovative and medically significant because we anticipate that our studies will identify novel therapies for perioperative pain that may greatly decrease the need for narcotics and potential for drug abuse.β

项目概要背根神经节 (DRG) 和背角 (DH) 的疼痛感觉神经元可能变得敏感（过度兴奋）对手术引起的周围组织损伤的反应由于知识不足。关于这种致敏机制，目前术后疼痛的治疗仅限于具有显着副作用或滥用可能性的非特异性全身药物（阿片类药物）。我们实验室的研究已确定 CaV3.2（T 型）钙通道和 CaV2.3（R 型）电压- 门控钙通道对疼痛反应的敏化做出了以前未被认识到的贡献增强外周伤害感受器的兴奋性并控制 DH 中的兴奋性突触传递我们之前表明，伤害性 DRG 神经元中的 CaV3.2 电流的阻断是通过我们的新数据表明，5β-减少的神经活性类固醇具有强大的外周抗伤害作用。证明这样一种类固醇，3β-OH [(3β,5β,17β)-3-羟基雄甾烷-17-甲腈]，除了催眠特性，还表现出出色的脊髓介导的镇痛作用，我们还发现 3β-OH 具有抑制作用。重组 CaV2.3 电流这一发现使我们得出这样的结论：抑制神经元 CaV3.2 和新型麻醉剂 3β-OH 和相关神经活性类固醇在疼痛通路中的 CaV2.3 电流在目标 1 中，我们将使用临床相关研究神经活性类固醇的镇痛效力。在目标 2 中，我们将定义神经活性类固醇在皮肤和深层组织切口的啮齿动物模型中的作用。这些研究将调节伤害性 DH 神经元的突触传递和神经元兴奋性。我们将定义测试化合物在主要伤害感受途径中的全细胞神经生理学作用。还使用电子显微镜研究 CaV2.3 和 CaV3.2 通道的细胞和亚细胞定位在目标 3 中，我们将研究类固醇的机制和构效关系。抑制伤害性 DRG 神经元中的重组和天然 CaV2.3 电流这是其主要目标。目的是扩展目前可获得的有限信息，并期望获得的信息对于设计更有效和更具选择性的 CaV2.3 通道抑制剂非常重要对于开发新型、更安全的麻醉剂和镇痛剂非常重要。拟议的工作具有创新性和实用性。具有医学意义，因为我们预计我们的研究将确定围手术期疼痛的新疗法这可能会大大减少对麻醉品的需求和药物滥用的可能性。β