选择性咪唑啉I2受体配体的镇痛效应及滥用潜力研究

Chronic pain is a global health care challenge and is poorly controlled by existing therapeutic strategies. This medical reality urges the development of better 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. 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. 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. 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. Collectively, these experiments address two related and highly significant questions: (1) Do I2 receptor agonists represent a novel class of analgesics for chronic pain and (2) Does the combination of I2 receptor agonists with morphine increase pain relief without increasing, or possibly decreasing, some adverse effects.

慢性疼痛是一个重要的临床问题，我们现有的治疗手段远远无法满足临床需要。因此，新型镇痛药的开发一直是一个药学研究的重要问题。我们实验室的研究发现咪唑啉I2受体可能是一个治疗疼痛的新靶点。本申请在我们现有实验结果的基础上计划系统研究I2受体配体急性和慢性给药时对于两种慢性疼痛（完全福氏佐剂引起的炎性痛和坐骨神经结扎引起的神经痛）以及与吗啡合用时的镇痛作用。此外，我们初步实验结果发现I2受体配体能够增强吗啡的镇痛作用，提示两药可以组合给药。因此我们还将研究I2受体配体与吗啡合用时对吗啡镇痛耐受性产生以及吗啡滥用潜力的影响。这一系列研究的顺利完成将会大大增加我们对于I2受体这一全新镇痛药物作用靶点的了解，并会确定基于这一靶点的镇痛先导药物，为后续新型镇痛药的开发奠定坚实的基础，具有重要理论和临床意义。

疼痛尤其是慢性疼痛是一个重要的临床挑战。本项目系统研究了咪唑啉2受体激动剂作为慢性疼痛新型治疗药物的可能性，并就其与阿片类药物联合用药的镇痛作用和成瘾性进行了系统研究。我们的研究发现，咪唑啉2受体激动剂（2-BFI, CR4056, phenyzoline）急性给药在完全弗氏佐剂（CFA）造成的炎性疼痛与坐骨神经结扎(CCI)造成的慢性神经痛具有显著镇痛作用，且重复多次给药后不产生显著镇痛耐受性。咪唑啉2受体激动剂与阿片类药物联合使用时产生相加或者协同镇痛作用，且慢性使用后可以延缓耐受性的产生。此外，咪唑啉2受体激动剂本身在大鼠自我给药模型中不具有维持自身给药的效应，且能够显著降低吗啡自我给药行为。在吗啡药物辨别实验中，咪唑啉2受体激动剂显著抑制吗啡的辨别刺激效应。这些结果强烈提示咪唑啉2受体激动剂具有很好的临床治疗慢性疼痛的应用前景，且可以作为辅助药物与阿片类药物联合使用进行疼痛治疗。