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。长期使用阿片类药物通常需要不断增加剂量以维持疼痛缓解，也称为镇痛耐受。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产生了加剧的疼痛或痛觉过敏的状态。最近的研究表明，通过 mu-阿片受体发挥作用的阿片类药物可以诱导趋化因子及其受体的表达。我们实验室之前的工作表明，其中一些相同的趋化因子/受体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、趋化因子信号传导和镇痛耐受性之间可能存在联系的证据，我们提出这样的假设：阿片类药物诱导的趋化因子信号传导对于镇痛耐受性至关重要。我们的具体目标包括 1) 表征与阿片引起的痛觉过敏相关的细胞/信号事件的时间顺序；2) 探索吗啡诱导背根神经节趋化因子/受体表达的机制；3) 检查长期吗啡治疗增强趋化因子信号传导的细胞/分子机制。更好地了解这些趋化因子/受体介导的事件可能为设计抵消有害阿片诱导的细胞适应并有效降低镇痛耐受性的药物提供必要的框架。公共健康相关性：吗啡是一种有效的癌症和非癌症疼痛缓解剂，也是一种有效的耐受性诱导剂。阿片耐受性是指接触阿片导致镇痛效果（疼痛缓解）减弱的现象。对吗啡镇痛作用的耐受性是一个人们知之甚少的现象，并且可以清楚地给某些患者带来重大的治疗困难。更好地了解与耐受性发展相关的事件可以为有效降低镇痛耐受性的药物设计提供必要的框架。

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.