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

基本信息

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
项目类别：
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

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

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项目摘要

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.

项目摘要：硬膜外/脊柱给药镇痛药，例如阿片类药物，Ziconotide和局部麻醉药，在某些方面具有深远的功效在最棘手的疼痛状况中，例如背部手术失败后严重的神经性疼痛，癌症疼痛和术后疼痛大腹部/胸腔手术后的疼痛。尽管它们具有深远的功效，但它们的使用主要是因为诸如耐受性，肉芽瘤，精神病和运动阻滞等效果。发现和验证新的脊柱镇痛靶标迫切需要进行治疗的发展。在这里，我们建议根据我们的机械研究验证一种新型的脊柱镇痛靶靶神经素受体2（NTSR2） Contulakin-G（CGX），它显示出患有最难治疗神经性疗法之一的人类的初步疗效疼痛脊髓损伤与疼痛有关。 CGX是一种蜗牛毒液衍生的肽，与哺乳动物神经素具有同源性，在人类中被证明是安全的。一个小型试点1A研究表明，一些脊髓损伤相关疼痛患者的镇痛作用。虽然， CGX没有有利的药代动力学特性，这些研究表明可能有一种新型，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通过激活脊柱产生其镇痛作用神经素受体2（NTSR2）和随后抑制电压门控钙通道。 NTSR2在啮齿动物中的小/中等尺寸感觉神经元，并与电压门控钙通道共表达。转录组学确认在人背根神经节感觉神经元中的NTSR2表达。重要的是，我们的试点研究表明NTSR2 CGX激活会产生深刻的镇痛，并且与不必要的副作用无关，例如快速耐受性或电动机封锁。因此，初步数据支持脊柱NTSR2在疼痛调节中的作用，但验证该受体作为一种尚未完成镇痛靶标。在这个项目中，我们建议对脊柱NTSR2进行强有力的验证，作为一种镇痛靶标的，利用两种物种性别（大鼠，小鼠和人），两个模型（神经性疼痛和手术后疼痛），药理学（SA1）和最新状态 CRISPR-CAS9编辑（SA2）等遗传工具以及对疼痛的感觉和情感度量的评估。而且，我们提出了一项严格的，两端并联确认研究（SA3），在多站点临床试验中设计，以进一步验证脊柱 NTSR2作为镇痛靶标。如果成功，提出的研究可能会导致非阿片类脊柱镇痛药的发展，具有高转化潜力。