IMIDAZOLINE I2 RECEPTORS AS TARGETS FOR THE TREATMENT OF PAIN

咪唑啉 I2 受体作为治疗疼痛的靶点

基本信息

批准号：
9170057
负责人：
Jun-Xu Li
金额：
$ 1.86万
依托单位：
STATE UNIVERSITY OF NEW YORK AT BUFFALO
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-03-01 至 2017-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9170057
关键词：
Absence of pain sensation Acute Acute Pain Address Adult Adverse effects Affect Agonist Analgesics Animal Model Animals Behavior Chronic Clinical Combined Modality Therapy Dependence Development Dose Drug Targeting Effectiveness Etiology Female Freund&apos s Adjuvant Goals Grant Health Healthcare Infusion procedures Intravenous Investigation Measures Mechanics Mediating Medical Mission Modeling Morphine Nociception Opioid Outcome Pain Pain management Patients Pharmaceutical Preparations Pharmacotherapy Procedures Rattus Research Role Self Administration Self-Administered Testing Therapeutic Thermal Hyperalgesias United States United States National Institutes of Health base burden of illness chronic constriction injury chronic pain cost disability drug discovery global health imidazoline receptor 2 inflammatory neuropathic pain inflammatory pain male new therapeutic target novel painful neuropathy programs receptor research study

项目摘要

DESCRIPTION (provided by applicant): Chronic pain is a global health care challenge and is poorly controlled by existing therapeutic strategies. This medical reality urges the development of safer and more effective analgesics. One approach is to identify novel analgesic targets. Our recent studies have suggested imidazoline I2 receptors as a novel drug target for acute nociception, although its role in chronic pain is less clear. As the etiology of many chronic pain conditions is multifaceted, combination therapy may be particularly effective against chronic pain by integrating multiple analgesic mechanisms of action. Although opioids are the most effective analgesics, their use is limited by concerns about abuse and the development of tolerance and dependence during chronic administration. Thus, combining opioids with other analgesics such as I2 receptor agonists may achieve better analgesic effects while decreasing some adverse effects of opioids. Building on exciting preliminary findings, studies described in this application will examine the antinociceptive and unwanted (tolerance and abuse liability) effects of I2 receptor agonists and test the feasibility of combining morphine and I2 receptor agonists against chronic pain. Mechanical and thermal hyperalgesia measures will be used to characterize the antinociceptive effects of I2 receptor agonists and morphine, alone or in combination, in models of complete Freund's adjuvant-induced inflammatory pain and chronic constriction injury-induced neuropathic pain (Aim I). Repeated treatment with I2 receptor agonists alone or combined with morphine will be performed to investigate the development of antinociceptive tolerance using the same procedures (Aim II). An intravenous self-administration procedure will be used to assess the reinforcing effects of I2 receptor agonists alone and how I2 receptor agonists modify the reinforcing effects of morphine (Aim III). Collectively, these experiments address two related and highly significant questions: (1) Do I2 receptor agonists represent a novel class of effective and safe analgesics for chronic pain and (2) Does the combination of I2 receptor agonists with morphine increase pain relief without increasing, or possibly decreasing, the abuse liability and development of tolerance.

描述（由申请人提供）：慢性疼痛是一项全球医疗挑战，受现有治疗策略的控制不佳。这种医学现实敦促发展更安全，更有效的镇痛药。一种方法是确定新颖的镇痛靶标。我们最近的研究表明，咪唑啉I2受体是急性伤害感受的新型药物，尽管其在慢性疼痛中的作用尚不清楚。由于许多慢性疼痛状况的病因是多方面的，因此联合疗法通过整合多种镇痛作用机制，可能特别有效地抵抗慢性疼痛。尽管阿片类药物是最有效的镇痛药，但它们的使用受到对虐待以及在慢性施用期间的耐受性和依赖性的发展的限制。因此，将阿片类药物与其他镇痛药（例如I2受体激动剂）结合起来可能会产生更好的镇痛作用，同时减少阿片类药物的某些不良反应。基于令人兴奋的初步发现，本应用程序中描述的研究将检查I2受体激动剂的抗伤害感受和不需要的（耐受性和滥用责任）的影响，并测试将吗啡和I2受体激动剂结合慢性疼痛的可行性。机械和热痛觉过敏措施将用于表征I2受体激动剂和吗啡的抗伤害感受作用，单独或组合中，在完全弗洛伦德辅助诱导的炎症性疼痛以及慢性收缩损伤引起的神经性疼痛的模型中（AIM I）。仅用I2受体激动剂或与吗啡结合的重复治疗将使用相同的程序研究抗伤害感受耐受性的发展（AIM II）。静脉内的自我给药程序将用于评估仅I2受体激动剂的增强作用，以及I2受体激动剂如何改变吗啡的增强作用（AIM III）。总的来说，这些实验解决了两个相关和非常重要的问题：（1）I2受体激动剂是否代表了一类新型的有效和安全的镇痛药，以缓解慢性疼痛，（2）（2）是否将I2受体激动剂与吗啡的组合增加吗啡疼痛缓解疼痛，而不会增加，或者可能会增加，或者可能减少，滥用责任和耐受性的发展。