Chemokine-mediated Modulaton of Opioid-induced Pain

描述（由申请人提供）：吗啡目前是治疗严重疼痛和慢性疼痛状态的最佳选择。阿片类药物的长期使用往往会产生对不断增加剂量的需求，以维持疼痛缓解，也被称为镇痛耐受。与镇痛耐受相关的机制被认为是由于吗啡诱导的细胞适应性，其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表明，这些相同的趋化因子/受体中的一些已被证明在慢性疼痛状态中发挥核心作用。为了揭示慢性吗啡治疗，趋化因子信号和镇痛耐受之间可能存在联系的证据，我们提出了阿片诱导的趋化因子信号是镇痛耐受的核心的假设。我们的具体目标包括：1）与阿片类药物诱导的痛觉过敏相关的细胞/信号事件的时序特征; 2）探索吗啡诱导背根神经节中趋化因子/受体表达的机制; 3）研究慢性吗啡治疗增强趋化因子信号传导的细胞/分子机制。更好地理解这些趋化因子/受体介导的事件可能提供必要的框架设计的药物，抵消有害的阿片诱导的细胞适应，并有效地减少镇痛耐受。公共卫生相关性：吗啡是癌症和非癌症疼痛的强效止痛药，但也是耐受性的强效诱导剂。阿片类药物耐受是指暴露于阿片类药物导致镇痛作用（疼痛缓解）减弱的现象。对吗啡镇痛作用的耐受性是一个知之甚少的现象，在某些患者中显然存在重大管理困难。更好地了解与耐受性发展相关的事件可能为设计有效降低镇痛耐受性的药物提供必要的框架。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Morphine is a powerful pain reliever for cancer and non-cancer pain, but also a potent inducer of tolerance. Opiate tolerance refers to a phenomenon in which exposure to a opiate results in the diminution of an analgesic effect (pain relief). Tolerance to the analgesic effect of morphine is a poorly understood phenomenon and can clearly present major management difficulties in some patients. Better understanding of the events associated with the development of tolerance may provide the necessary framework for the design of agents effectively reduce analgesic tolerance.