Validation of Spinal Neurotensin Receptor 2 as an Analgesic Target

脊髓神经降压素受体 2 作为镇痛靶点的验证

• 批准号: 9976792
• 负责人: Amol M Patwardhan
• 金额: $ 16.41万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2022-07-05
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9976792
• 关键词: Abdomen; Absence of pain sensation; Acute; Affective; Afferent Neurons; Affinity; Agonist; Amino Acids; Analgesics; Animals; Arizona; Back; Baclofen; Binding; Blinded; Bolus Infusion; Breakthrough Pain; CRISPR/Cas technology; Calcium Channel; Caliber; Canis familiaris; Clinical; Clinical Research; Clonidine; Clustered Regularly Interspaced Short Palindromic Repeats; Conotoxin; Data; Development; Dissection; Dose; Drug Delivery Systems; Drug Kinetics; Electrophysiology (science); Epidural Analgesia; Female; Genetic; Granuloma; Human; Intractable Pain; Laboratories; Lead; Local Anesthetics; Malignant Neoplasms; Measures; Mechanics; Mediating; Methods; Modeling; Motor; Mouse Strains; Multi-Institutional Clinical Trial; Mus; Neuropathy; Neurotensin; Neurotensin Receptors; Operative Surgical Procedures; Opioid; Opioid Analgesics; Pain; Pain management; Pain quality; Paralysed; Patients; Peptides; Pharmaceutical Preparations; Pharmacology; Pilot Projects; Postoperative Pain; Property; Protocols documentation; Psychotic Disorders; Rattus; Research Design; Resistance; Risk; Rodent; Rodent Model; Role; Route; Sensory; Sensory Thresholds; Site; Snail Venoms; Specificity; Spinal; Spinal Ganglia; Spinal cord injury; Sprague-Dawley Rats; Stimulus; Tachyphylaxis; Testing; Therapeutic; Thoracic Surgical Procedures; Universities; Utah; Validation; Ventilatory Depression; Viral Vector; base; cancer pain; chronic neuropathic pain; clinical effect; dorsal horn; drug discovery; ganglion cell; genetic approach; hemodynamics; improved; in vivo; knockout animal; male; non-opioid analgesic; novel; pain model; painful neuropathy; power analysis; pre-clinical; preference; presynaptic; receptor; remote control; response; sex; side effect; therapeutic development; tool; transcriptomics; translational study; voltage; ziconotide

Project Summary: Epidural/spinal administration of analgesics such as opioids, ziconotide and local anesthetics have profound efficacy in some of the most intractable pain conditions such as severe neuropathic pain after failed back surgery, cancer pain and post-operative pain after major abdominal/thoracic surgeries. Despite their profound efficacy, their use is limited primarily because of the side effects such as tolerance, granuloma, psychosis and motor block. Discovery and validation of new spinal analgesic targets for development of therapeutics is urgently needed. Here we propose to validate a novel spinal analgesic target, neurotensin receptor 2 (NTSR2), based upon our mechanistic studies of Contulakin-G (CGX), that has shown preliminary efficacy in humans suffering from one of the hardest to treat neuropathic pain condition-spinal cord injury associated pain. CGX is a snail venom derived peptide that has homology with mammalian neurotensin and was shown to be safe in humans. A small, pilot Phase1A study demonstrated analgesic effect in some patients with spinal cord injury-associated pain. Although, CGX does not have favorable pharmacokinetic properties, these studies suggested a possibility of a novel, non-opioid, analgesic mechanism that is active in humans. Our preliminary studies suggest CGX produces its analgesic actions via activation of spinal neurotensin receptor 2 (NTSR2) and subsequent inhibition of voltage-gated calcium channels. NTSR2 is highly expressed in small/medium size sensory neurons in rodents and co-expressed with voltage gated calcium channels. Transcriptomics confirmed NTSR2 expression in human dorsal root ganglia sensory neurons. Importantly, our pilot studies show that NTSR2 activation by CGX produces profound analgesia and is not associated with unwarranted side effects such as rapid tolerance or motor blockade. Preliminary data thus support a role of spinal NTSR2 in pain modulation, but validation of this receptor as an analgesic target has not been done. In this project, we propose to perform a robust validation of spinal NTSR2 as an analgesic target utilizing three species of both sexes (rat, mice and human), two models (neuropathic pain and post-surgical pain), pharmacological (SA1) and state of the art genetic tools such as CRISPR-Cas9 editing (SA2) and assessment of both sensory and affective measures of pain. Moreover, we propose a rigorous, two-site parallel confirmation study (SA3) designed after multisite clinical trials to further authenticate spinal NTSR2 as an analgesic target. If successful, proposed studies could lead to a development of non-opioid spinal analgesic that has high translational potential.

项目概要： 镇痛剂如阿片类、齐考诺肽和局部麻醉剂的硬膜外/脊髓给药在一些患者中具有显著的疗效。 最难治的疼痛状况，如背部手术失败后的严重神经性疼痛、癌症疼痛和手术后疼痛， 腹部/胸部大手术后的疼痛。尽管它们具有深刻的功效，但它们的使用受到限制，主要是因为它们的副作用。 影响，如耐受性，肉芽肿，精神病和运动阻滞。新的脊髓镇痛靶点的发现和验证 迫切需要开发治疗方法。 在这里，我们提出验证一个新的脊髓镇痛靶点，神经降压素受体2（NTSR 2），基于我们的机制研究 Contulakin-G（CGX），已在患有最难治疗的神经性疾病之一的人类中显示出初步疗效。 疼痛状况-脊髓损伤相关的疼痛。 CGX是一种蜗牛毒衍生肽，与哺乳动物神经降压素具有同源性，并显示在人体内是安全的。一 一项小型、先导性1A期研究证实了在一些脊髓损伤相关疼痛患者中的镇痛作用。不过， CGX不具有有利的药代动力学特性，这些研究表明了一种新型非阿片类镇痛剂的可能性 这是一种活跃在人类身上的机制。我们的初步研究表明，CGX通过激活脊髓背角神经元产生镇痛作用。 神经降压素受体2（NTSR 2）和随后的电压门控钙通道抑制。NTSR 2在哺乳动物中高度表达， 啮齿类动物中的小/中型感觉神经元，并与电压门控钙通道共表达。转录组 证实NTSR 2在人背根神经节感觉神经元中表达。重要的是，我们的初步研究表明，NTSR 2 CGX激活产生深度镇痛，并且与不必要的副作用如快速耐受或 运动神经阻滞因此，初步数据支持脊髓NTSR 2在疼痛调节中的作用，但验证这种受体作为一种神经递质， 镇痛目标尚未完成。 在这个项目中，我们建议利用三种两种动物对脊髓NTSR 2作为镇痛靶点进行稳健的验证。 性别（大鼠、小鼠和人）、两种模型（神经性疼痛和术后疼痛）、药理学（SA 1）和最新技术水平 基因工具，如CRISPR-Cas9编辑（SA 2）和评估疼痛的感觉和情感测量。而且我们 建议在多中心临床试验后设计一项严格的两中心平行确认研究（SA 3），以进一步验证脊柱 NTSR 2作为镇痛靶点。 如果成功，拟议的研究可能导致开发具有高转化潜力的非阿片类脊髓镇痛药。