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

神经元钙通道对阿片类镇痛药生理功能的影响

• 批准号: 19603002
• 负责人: KURIHARA Takashi
• 金额: $ 2.91万
• 依托单位: Tokyo Medical and Dental University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2007
• 资助国家: 日本
• 起止时间: 2007 至 2009
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-19603002/
• 关键词: オピオイド; モルヒネ; 電位依存性カルシウムチャネル; 鎮痛; 鎮痛耐性; cDNAマイクロアレイ; 消化管運動抑制

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.

如吗啡等阿片类药物具有强大的镇痛作用，并具有必不可少的治疗值以消除可怕的疼痛。因此，阿片类药物成为必不可少的药物，以改善疼痛患者的生活质量。但是，阿片类药物的耐受性和依赖性是与阿片类药物疗法和阿片类药物成瘾相关的困难问题。不幸的是，尚未开发出基于潜在机制的预防镇痛耐受性的有效方法。我们先前已经表明，缺乏R型电压依赖性Ca^<2+>通道的小鼠显示出增强的吗啡镇痛，但也显示出对吗啡耐受性的抗性。为了确定负责改变镇痛反应的分子，我们使用脑干组织进行了cDNA微阵列分析，并发现了涉及吗啡反应改变的几个候选基因。来自几种药理，生化和免疫组织化学实验的结果表明，在脑干地区吗啡耐受性的发展中存在新的信号转导机制。我们还指出，通过操纵药理学，肠道中存在相似的信号转导，可能会诱导对吗啡诱发的便秘的耐受性。