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

阿片类药物如吗啡具有很强的止痛作用，对消除顽固性疼痛具有重要的治疗价值。因此，阿片类药物成为提高疼痛患者生活质量不可缺少的药物。然而，阿片耐受和依赖是与阿片治疗和阿片成瘾相关的难题。遗憾的是，基于其潜在机制的有效预防止痛耐受的方法尚未被开发出来。我们以前已经表明，缺乏R型电压依赖钙通道的小鼠表现出增强的吗啡镇痛作用，但也表现出对吗啡耐受的抵抗。为了确定与改变的镇痛反应有关的分子，我们利用脑干组织进行了基因芯片分析，发现了几个与改变的吗啡反应有关的候选基因。一些药理、生化和免疫组织化学实验的结果表明，在脑干区吗啡耐受的发展过程中存在新的信号转导机制。我们还指出，通过对肠道中存在的类似信号转导进行药理操作，有可能诱导对吗啡诱导的便秘的耐受。

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.