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

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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.