Effects of various Ca2+ channel antagonists on morphine analgesia, tolerance and dependence, and on blood pressure in the rat.

Following the finding that nifedipine enhances morphine analgesia and prevents the development of dependence, we have now compared the effect of nifedipine with these of other L-type Ca2+ channel antagonists, nimodipine (a dihydropyridine) and verapamil (a phenylethylalkylamine). Male Wistar rats received the antagonist 20 min before each injection of morphine. Analgesia was measured in a hot-plate test, and the development of dependence was assessed in the naloxone precipitation test after 13 days of morphine (20-30 mg/kg i.p.) administration. L-type Ca2+ channels were assayed in the cerebral cortex as [3H]nitrendipine binding sites. Blood pressure was monitored from the tail by a non-invasive method. We found that all three Ca2+ antagonists enhanced the analgesia, and prevented development of the naloxone-precipitated withdrawal syndrome, although they differed in their efficacy. Nifedipine and verapamil effectively blocked the development of tolerance. While chronic morphine up-regulated L-type Ca2+ channels, co-administration of the antagonists completely prevented this effect. The effects of Ca2+ channel antagonists cannot be ascribed to their potential circulatory effects as, at the dose used, none affected significantly the arterial blood pressure.