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，是已知的最有效的疼痛缓解药物，但其临床用途受到危险和潜在致命副作用的限制，以及耐受性和身体依赖性与相关成瘾倾向的发展。我们实验室最近的研究首次确定了哺乳动物大脑中的一种机制，通过这种机制，阿片类药物的疼痛缓解作用可以通过独立调节与阿片类药物改变的生物化学过程不同的药物大大增强。开发这些机制对于开发新的药物疗法以有效缓解疼痛并使副作用最小化具有巨大潜力。这些协同机制似乎对脊髓中的疼痛缓解至少与脑中的疼痛缓解一样重要，因此拟议的研究将首先检查与阿片类药物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，在拟议的工作中要研究的机制是关键的发展衰弱，慢性疼痛的条件，涉及高度敏感性的疼痛刺激和疼痛的反应，通常无害的刺激，如轻触。这种异常反应在最初的组织损伤恢复后可以持续很长时间。已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。更好地理解这些病理过程的基础将导致更好的策略来延缓或预防慢性疼痛状况的发展。

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.