Synergism between opioids and other agents at central primary afferent synapses

阿片类药物，如可待因、哌替啶和吗啡，是已知的最有效的止痛药物，但它们的临床应用受到危险和潜在致命副作用的限制，以及与成瘾相关的耐受性和身体依赖的发展。我们实验室最近的研究首次在哺乳动物大脑中发现了一种机制，通过这种机制，阿片类药物的镇痛作用可以通过独立调节与阿片类药物不同的生化过程的药物大大增强。利用这些机制对开发新的药物疗法具有很大的潜力，可以有效地减轻疼痛，并将副作用降到最低。这些协同机制似乎对脊髓疼痛的缓解至少与大脑疼痛的缓解一样重要，因此拟议的研究将首先检查阿片介导的脊髓疼痛缓解协同作用的基础。也有强有力的证据表明，在提议的工作中研究的机制在衰弱的发展中是关键的，慢性疼痛条件涉及对疼痛刺激的高度敏感性和或对通常无害的刺激（如轻触）的疼痛反应。这种异常反应可以在最初的组织损伤恢复后持续很长时间。众所周知，阿片类药物可以在一定程度上限制诱导这些异常反应的初始步骤，但所涉及的机制尚不清楚。拟议的研究将有助于解决这些机制。更好地了解这些病理过程的基础将导致更好的策略，以延缓或预防慢性疼痛条件的发展。

Opioids, such as codeine, pethidine and morphine, are the most effective pain relieving drugs known but their clinical utility is limited by hazardous and potentially lethal side effects, as well as the development of tolerance and physical dependence with associated addiction liability. Recent research in our laboratory has identified for the first time a mechanism in the mammalian brain by which the pain relieving actions of opioids can be greatly enhanced by drugs that independently modulate biochemical processes distinct from those altered by opioids. Exploitation of these mechanisms has great potential for the development of new pharmacotherapies for effective pain relief with minimised side effects. These synergistic mechanisms appear to be at least as important for pain relief in the spinal cord as in brain, so the proposed studies will first examine the basis for synergism with opioid mediated pain relief in spinal cord. There is also strong evidence that the mechanisms to be studied in the proposed work are pivotal in the development of debilitating, chronic pain conditions that involve heightened sensitivity to painful stimuli and-or painful responses to normally innocuous stimuli such as light touch. Such aberrant responses can persist long after initial tissue damage has recovered. It is known that opioids can limit somewhat the initial steps in the induction of these abnormal responses but the mechanisms involved are unknown. The proposed studies will contribute to resolution of these mechanisms. Better understanding of the basis of these pathological processes will lead to better strategies for retarding or preventing the development of chronic pain conditions.