The roles of neuronal calcium channels on the physiological functions of opioid analgesics

吗啡等阿片类药物具有较强的镇痛作用，对消除顽固性疼痛具有重要的治疗价值。阿片类药物成为改善疼痛患者生活质量不可缺少的药物。然而，阿片类药物的耐受性和依赖性是阿片类药物治疗和阿片类药物成瘾相关的难题。不幸的是，目前还没有基于潜在机制的有效方法来预防镇痛耐受性。我们之前已经证明，缺乏r型电压依赖性Ca^<2+>通道的小鼠表现出增强的吗啡镇痛，但也表现出对吗啡耐受性的抵抗。为了确定导致镇痛反应改变的分子，我们利用脑干组织进行了cDNA微阵列分析，发现了几个与吗啡反应改变有关的候选基因。多项药理、生化和免疫组化实验结果提示脑干区域吗啡耐受的发生存在新的信号转导机制。我们还指出，可能通过药理学上操纵肠道中存在的类似信号转导来诱导对吗啡引起的便秘的耐受性。

Opioids like morphine exert strong analgesic effects and have essential therapeutic values to eliminate intractable pain. Thus opioid drugs became indispensable medicine to improve the quality of life of pain patient. However, opioid tolerance and dependence are difficult problems associated with the opioid therapy and opioid addiction. Unfortunately, efficient method to prevent analgesic tolerance based on the underlying mechanism has not been developed yet. We have shown previously that mice lacking R-type voltage-dependent Ca^<2+> channel showed enhanced morphine analgesia but also showed resistance to morphine tolerance. To identify molecules responsible for the altered analgesic responses, we have conducted cDNA microarray analysis using brainstem tissues and found several candidate genes involved in the altered morphine responses. The results from several pharmacological, biochemical and immunohistochemical experiments suggested the existence of new signal transduction mechanisms in the development of morphine tolerance in the brainstem area. We have also indicated that it might be possible to induce tolerance against morphine-evoked constipation by manipulating pharmacologically the similar signal transduction existed in the intestine.