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医疗保健挑战，现有的治疗策略控制不佳。这一医学现实促使人们开发更安全、更有效的止痛药。一种方法是寻找新的止痛药靶点。我们最近的研究表明，咪唑啉I2受体是治疗急性伤害性感觉的一种新的药物靶点，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，通过整合多种止痛作用机制，联合疗法可能对慢性疼痛特别有效。尽管阿片类药物是最有效的止痛剂，但由于担心长期给药过程中滥用以及耐受性和依赖性的形成，阿片类药物的使用受到限制。因此，阿片类药物与其他镇痛剂如I2受体激动剂联合使用可能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受体激动剂的抗伤害性和不受欢迎的(耐受性和滥用倾向)效果，并测试将吗啡和I2受体激动剂联合用于治疗慢性疼痛的可行性。在完全弗氏佐剂诱导的炎症性疼痛和慢性收缩损伤诱导的神经病理性疼痛(AIM I)模型中，将使用机械和热痛敏措施来表征I2受体激动剂和吗啡单独或联合使用的抗伤害性效应。重复使用I2受体激动剂或与吗啡联合治疗，将使用相同的程序来研究抗伤害耐受性的发展(AIM II)。将使用静脉自我给药程序来评估单独使用I2受体激动剂的增强效果以及I2受体激动剂如何改变吗啡的增强效果(目标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类治疗慢性疼痛的新的有效和安全的止痛剂；(2)I2受体激动剂与吗啡的结合是否在不增加或可能减少滥用可能性和耐受性的情况下增加了疼痛缓解。

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.