Chemokine-mediated Modulaton of Opioid-induced Pain

描述(申请人提供)：吗啡目前是治疗剧烈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会导致需要不断增加的剂量来维持止痛，也称为止痛耐受。与止痛耐受相关的机制被认为是由于吗啡诱导的细胞适应，产生高度疼痛或痛敏状态。最近的研究表明，阿片类药物通过Mu-阿片受体作用，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/受体中的一些已经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、趋化因子信号和止痛耐受之间可能存在联系的证据，我们提出了阿片剂诱导的趋化因子信号在止痛耐受中起中心作用的假说。我们的具体目标包括1)表征与阿片类药物诱导的痛敏相关的细胞/信号事件的时间序列；2)探索吗啡诱导背根神经节趋化因子/受体表达的机制；3)研究慢性吗啡治疗增强趋化因子信号转导的细胞/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抗阿片类有害物质诱导的细胞适应并有效降低止痛耐受性的药物提供必要的框架。公共卫生意义：对于癌症和非癌症疼痛，吗啡是一种强有力的止痛剂，但也是一种有效的耐受性诱导剂。阿片耐受性是指接触阿片剂导致止痛效果(缓解疼痛)减弱的一种现象。对吗啡止痛效果的耐受是一种鲜为人知的现象，显然会给一些患者带来主要的管理困难。更好地了解与耐受性形成相关的事件可能为设计有效降低止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.