Imidazoline I2 receptors as targets for the treatment of pain

咪唑啉 I2 受体作为治疗疼痛的靶标

• 批准号: 8528168
• 负责人: Jun-Xu Li
• 金额: $ 33.38万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 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/8528168
• 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' s Adjuvant; Goals; Grant; 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; novel; painful neuropathy; programs; public health relevance; receptor; research study

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）：慢性疼痛是一个全球性的卫生保健挑战，现有的治疗策略控制不佳。这一医学现实促使开发更安全、更有效的镇痛药。一种方法是确定新的镇痛靶点。我们最近的研究表明，咪唑啉I2受体作为一种新的药物靶点的急性伤害，虽然它在慢性疼痛的作用还不清楚。由于许多慢性疼痛病症的病因是多方面的，因此通过整合多种镇痛作用机制，联合治疗可能对慢性疼痛特别有效。虽然类阿片是最有效的镇痛剂，但由于担心滥用以及在长期服用期间产生耐受性和依赖性，其使用受到限制。因此，将阿片类药物与其他镇痛药（如I2受体激动剂）联合使用可能会获得更好的镇痛效果，同时减少阿片类药物的一些不良反应。基于令人兴奋的初步发现，本申请中描述的研究将检查I2受体激动剂的抗伤害性和不需要的（耐受性和滥用倾向）作用，并测试吗啡和I2受体激动剂组合对抗慢性疼痛的可行性。机械和热痛觉过敏的措施将被用来表征I2受体激动剂和吗啡，单独或组合，在完全弗氏佐剂诱导的炎性疼痛和慢性压迫性损伤诱导的神经性疼痛（目的I）的模型中的抗伤害性作用。将使用相同的程序进行单独使用I2受体激动剂或与吗啡联合使用的重复治疗，以研究抗伤害性耐受的发展（目的II）。将使用静脉内自我给药程序来评估单独的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的和非常重要的问题：（1）I2受体激动剂是否代表了一类新的有效和安全的慢性疼痛镇痛药和（2）I2受体激动剂与吗啡的组合是否增加疼痛缓解，而不增加或可能减少滥用倾向和耐受性的发展。