Imidazoline I2 receptors as targets for the treatment of pain

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，现有的治疗策略很难控制。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受体是急性伤害感觉的一个新的药物靶点，尽管它在慢性疼痛中的作用尚不清楚。由于许多慢性疼痛的病因是多方面的，通过整合多种镇痛机制，联合治疗可能对慢性疼痛特别有效。虽然阿片类药物是最有效的镇痛药，但由于担心滥用和长期给药过程中产生耐受性和依赖性，它们的使用受到限制。因此，阿片类药物与其他镇痛药物如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。在令人兴奋的初步发现的基础上，本申请中描述的研究将检查I2受体激动剂的抗痛感和不良（耐受性和滥用倾向）效应，并测试吗啡和I2受体激动剂联合治疗慢性疼痛的可行性。机械和热痛觉过敏措施将用于表征I2受体激动剂和吗啡单独或联合在完全弗氏佐剂诱导的炎症性疼痛和慢性收缩性损伤诱导的神经性疼痛模型中的抗痛觉作用（Aim I）。将使用I2受体激动剂单独或联合吗啡进行重复治疗，以研究使用相同程序的抗痛感耐受性的发展（Aim II）。静脉内自我给药程序将用于评估I2受体激动剂单独的强化作用以及I2受体激动剂如何改变吗啡的强化作用（Aim III）。总的来说，这些实验解决了两个相关且非常重要的问题：(1)I2受体激动剂是否代表了一种新型的有效和安全的慢性疼痛镇痛药；(2)I2受体激动剂与吗啡的联合使用是否增加了疼痛缓解，而不会增加或可能减少滥用倾向和耐受性的发展。

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.