Mechanism of intrathecal Contulakin-G induced analgesia without motor block

鞘内Contulakin-G诱导无运动阻滞镇痛机制

基本信息

批准号：
9927707
负责人：
Amol M Patwardhan
金额：
$ 19.76万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-15 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9927707
关键词：
Absence of pain sensation Acute Acute Pain Address Affective Afferent Neurons Agonist Amino Acids Analgesics Animals Behavioral Assay Biological Assay Breakthrough Pain CRISPR/Cas technology Calcium Calcium Channel Cells Characteristics Chronic Clinical Clinical Trials Coupled Data Development Dose Drug Delivery Systems Drug Kinetics Drug usage Educational Intervention Electrophysiology (science)Exhibits Fiber Funding G-Protein-Coupled Receptors GTP-Binding Protein alpha Subunits, Gs Goals Granuloma Human Image Implant In Vitro Infusion procedures Intractable Pain Laboratories Lead Life Ligation Local Anesthetics Mediating Mentors Methods Molecular Molecular Target Motor Motor Neurons Neurons Neurotensin Neurotensin Receptors Opioid Oral Pain Pain quality Paralysed Patients Peptides Pharmaceutical Preparations Pharmacodynamics Pharmacology Pharmacotherapy Physicians Postoperative Pain Psychotic Disorders Publishing Pump Rattus Receptor Signaling Research Resistance Rodent Model Route Scientist Secondary to Sensory Signal Pathway Site Snail Venoms Specificity Spinal Spinal Cord Spinal cord injury Spine pain Testing Therapeutic Toxicology United States National Institutes of Health absorption analog career development chronic pain chronic pain patient chronic painful condition daily pain dorsal horn effective therapy experimental study genetic pedigree in vivo innovation motor behavior non-opioid analgesic novel nuclease pain model pain patient pain processing pain relief painful neuropathy patch clamp patient population prototype receptor remote control response reuptake side effect social tool voltage ziconotide

项目摘要

Effective treatment of high-impact pain patients is one the major stated goals of the National Pain Strategy. Although implanted intrathecal drug delivery system that takes advantage of spinal pain processing mechanisms is highly effective in most intractable pain patients, their use is limited primarily because of the side effects such as tolerance, psychosis and motor block associated with drugs used in them (opioids, ziconotide, local anesthetics). Novel analgesics that take advantage of spinal pain processing, are safe to use in humans and have minimal motor block and tolerance can be revolutionary in the management of high-impact pain. Contulakin-G (CGX) is a snail venom derived peptide that has homology with mammalian neurotensin has been shown to be safe in humans and a small, pilot Phase1A study demonstrated its analgesic effect. Prior published studies and our preliminary data demonstrate that intrathecal CGX is analgesic in various intractable pain conditions with minimal tolerance and motor block. However, the mechanism behind the analgesia without motor block and the receptor signaling pathway elicited by CGX is not known. Our preliminary data suggest that CGX activates neurotensin receptor 2 (NT2) to inhibit the R-type voltage gated calcium channels (VGCC). Interestingly, although NT2 is present in both sensory and motor neurons, R-type VGCC expression is more selective in pain neurons and possibly some motor neurons. In this project, we propose to test an innovative hypothesis that spinal CGX produces analgesia without motor block is secondary to CGX activation of neurotensin receptor 2 (NT2) leading to inhibition of R-type VGCC in sensory but not motor neurons. We propose to study the central hypothesis both in vitro (SA1) and in vivo (SA2). We incorporate cutting edge scientific tools such as CRISPR-Cas9 editing and proximity ligation assay coupled with highly validated in vitro and in vivo assays to address these questions. The proposed studies test a novel hypothesis with high translational significance and they also serve as a career development mechanism for a highly trained, interventional pain physician and pharmacologist who is mentored by accomplished pain scientists with a strong pedigree of successful mentees. Data from these studies will not only form the basis of a subsequent R01 application and allow the applicant to be an independently funded clinician scientist but have the potential to lead to clinical advancement of a nonopioid drug in a patient population that desperately needs relief.

对高影响疼痛患者的有效治疗是国家疼痛战略的主要既定目标之一。尽管利用脊柱疼痛处理机制的植入式鞘内给药系统对大多数顽固性疼痛患者非常有效，但其使用受到限制，主要是因为与所用药物（阿片类药物、阿片类药物、齐考诺肽、局部麻醉剂）。新型镇痛药利用脊柱疼痛处理，可安全用于人类，并且具有最小的运动阻滞和耐受性，可以在高强度疼痛的治疗中具有革命性的意义。 Contulakin-G (CGX) 是一种蜗牛毒液衍生肽，与哺乳动物神经降压素具有同源性，已被证明对人类是安全的，一项小型试点 1A 期研究证明了其镇痛作用。之前发表的研究和我们的初步数据表明，鞘内 CGX 对各种顽固性疼痛具有镇痛作用，且耐受性和运动阻滞极小。然而，无运动阻滞镇痛背后的机制以及 CGX 引发的受体信号通路尚不清楚。我们的初步数据表明，CGX 激活神经降压素受体 2 (NT2)，从而抑制 R 型电压门控钙通道 (VGCC)。有趣的是，虽然 NT2 存在于感觉神经元和运动神经元中，但 R 型 VGCC 表达在疼痛神经元和可能的一些运动神经元中更具选择性。在这个项目中，我们建议测试一个创新的假设，即脊髓 CGX 在不产生运动阻滞的情况下产生镇痛，是继发于 CGX 激活神经降压素受体 2 (NT2) 导致感觉神经元而非运动神经元中 R 型 VGCC 的抑制。我们建议在体外（SA1）和体内（SA2）研究中心假设。我们将 CRISPR-Cas9 编辑和邻近连接测定等尖端科学工具与经过高度验证的体外和体内测定相结合来解决这些问题。拟议的研究测试了具有高度转化意义的新假设，并且它们还为训练有素的介入疼痛医师和药理学家提供了职业发展机制，这些医师和药理学家由具有丰富成功学员血统的资深疼痛科学家指导。这些研究的数据不仅将构成后续 R01 申请的基础，并使申请人成为一名独立资助的临床科学家，而且有可能在迫切需要缓解的患者群体中推动非阿片类药物的临床进展。