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

• 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
• 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

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.

有效治疗高影响力疼痛患者是国家疼痛策略的主要目标之一。尽管利用脊柱疼痛加工机制的植入鞘内药物输送系统在大多数棘手的疼痛患者中非常有效，但其使用主要是因为其副作用，例如耐受性，精神病和与使用药物相关的运动阻滞（阿片类药物，Ziconotide，Ziconotide，局部麻醉药）。利用脊柱疼痛处理的新型镇痛药可以安全地用于人类，并且具有最小的运动障碍和耐受性在高影响力疼痛的管理中可能具有革命性。 Contulakin-G（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，已证明在人类中是安全的，而一项小型的，Pilot phise1a研究表明其镇痛作用。事先发表的研究和我们的初步数据表明，鞘内CGX在各种棘手的疼痛条件下具有镇痛作用，具有最小的耐受性和运动阻滞。但是，尚不清楚没有运动阻滞的镇痛和受体信号通路的镇痛机制尚不清楚。我们的初步数据表明，CGX激活神经素受体2（NT2）以抑制R型电压门控钙通道（VGCC）。有趣的是，尽管在感觉神经元和运动神经元中都存在NT2，但R型VGCC表达在疼痛神经元中更具选择性，可能是一些运动神经元。在这个项目中，我们建议检验一个创新的假设，即脊柱CGX在没有运动障碍的情况下产生镇痛作用，是CGX激活神经素受体2（NT2）的继发性，从而导致抑制感官中R型VGCC，而不是运动神经元。我们建议在体外（SA1）和体内研究中心假设（SA2）。我们结合了尖端的科学工具，例如CRISPR-CAS9编辑和接近连接测定法，再加上经过高度验证的体外和体内测定法，以解决这些问题。拟议的研究检验了一个具有高转化意义的新假设，它们还可以作为训练有素，介入的疼痛医师和药物学家的职业发展机制，该机制受到了良好的疼痛科学家的指导，并具有强大的成功受训者的谱系。这些研究的数据不仅将构成随后的R01应用的基础，并允许申请人成为一名独立资助的临床医生，而且有可能导致在迫切需要缓解的患者人群中非阿片类药物的临床进步。