Chemokine-mediated Modulaton of Opioid-induced Pain

吗啡目前是治疗严重疼痛的最佳选择， 慢性疼痛状态长期使用鸦片制剂往往会产生永久的需求- 增加剂量以维持疼痛缓解，也称为镇痛耐受性。的 与镇痛耐受相关的机制被认为是由于吗啡- 诱发细胞适应，产生疼痛加剧或痛觉过敏的状态。 最近的研究表明，阿片类药物通过μ-阿片受体起作用，可以诱导 趋化因子及其受体的表达。我们实验室以前的工作 证明了这些相同的趋化因子/受体中的一些已经被证明可以发挥 在慢性疼痛状态中的核心作用。为了找到证据证明 慢性吗啡治疗，趋化因子信号传导和镇痛耐受，我们提出， 阿片诱导的趋化因子信号传导是镇痛耐受的中心的假说。 我们的具体目标包括：1）表征细胞/信号转导的时序 与阿片诱导的痛觉过敏相关的事件2）探索机制， 吗啡诱导背根神经节中的趋化因子/受体表达，以及3） 研究慢性吗啡治疗的细胞/分子机制， 增强趋化因子信号传导。更好地了解这些趋化因子/受体- 介导的事件可以为代理的设计提供必要的框架， 抵消有害的阿片诱导的细胞适应，并有效地减少 镇痛耐受

Morphine currently represents the best option for the management of severe pain and chronic pain states. Prolonged use of opiates often produces the need for ever- increasing doses to maintain pain relief, also known as analgesic tolerance. The mechanisms associated with analgesic tolerance are thought to due to morphine- induced cellular adaptations that produce a state of heightened pain or hyperalgesia. Recent studies suggest that opiates acting via the mu-opioid receptor can induce expression of chemokines and their receptors. Previous works from our laboratory demonstrate that some of these same chemokines/receptors have been shown to play central roles in chronic pain states. To uncover evidence of possible links between chronic morophine treatment, chemokine signaling and analgesic tolerance, we propose the hypothesis that opiate-induced chemokine signaling is central to analgesic tolerance. Our specific aims include 1) a characterization of the chronology of cellular/signaling events associated with opiate-induced hyperalgesia 2) explore mechanisms by which morphine induces chemokine/receptor expression in the dorsal root ganglia and 3) examine the cellular/molecular mechanisms by which chronic morphine treatment enhances chemokine signaling. Better understanding of these chemokine/receptor- mediated events may provide the necessary framework for the design of agents that counteract deleterious opiate-induced cellular adaptations and effectively reduce analgesic tolerance.