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： 阿片类药物、齐考诺肽和局部麻醉剂等镇痛药的硬膜外/脊髓给药对某些患者具有深远的疗效。 最棘手的疼痛状况，例如背部手术失败后的严重神经性疼痛、癌症疼痛和术后疼痛 主要腹部/胸部手术后的疼痛。尽管它们具有深远的功效，但它们的使用受到限制主要是因为副作用 诸如耐受性、肉芽肿、精神病和运动障碍等影响。新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，我们建议根据我们的机制研究来验证一种新的脊髓镇痛靶标——神经降压素受体 2 (NTSR2) Contulakin-G (CGX)，已显示出对患有最难治疗的神经病之一的人类的初步疗效 疼痛状况-脊髓损伤相关的疼痛。 CGX 是一种源自蜗牛毒液的肽，与哺乳动物神经降压素具有同源性，并被证明对人类是安全的。一个 小型试点 1A 期研究证明了对一些脊髓损伤相关疼痛患者的镇痛作用。虽然， CGX 不具有良好的药代动力学特性，这些研究表明有可能成为一种新型非阿片类镇痛药 在人类中活跃的机制。我们的初步研究表明 CGX 通过激活脊髓产生镇痛作用 神经降压素受体 2 (NTSR2) 以及随后对电压门控钙通道的抑制。 NTSR2 高表达于 啮齿动物中的小/中型感觉神经元并与电压门控钙通道共表达。转录组学 证实了 NTSR2 在人类背根神经节感觉神经元中的表达。重要的是，我们的试点研究表明 NTSR2 CGX 的激活可产生深度镇痛作用，并且不会引起不必要的副作用，例如快速耐受或 机动封锁。因此，初步数据支持脊髓 NTSR2 在疼痛调节中的作用，但验证该受体作为 镇痛目标尚未完成。 在这个项目中，我们建议利用三种物种对脊髓 NTSR2 作为镇痛靶点进行强有力的验证。 性别（大鼠、小鼠和人类）、两种模型（神经性疼痛和术后疼痛）、药理学 (SA1) 和现有技术 CRISPR-Cas9 编辑 (SA2) 等遗传工具以及疼痛的感觉和情感测量评估。此外，我们 提出在多中心临床试验后设计的严格的两中心平行确认研究（SA3），以进一步验证脊柱 NTSR2作为镇痛靶点。 如果成功，拟议的研究可能会导致开发具有高转化潜力的非阿片类脊髓镇痛药。