The role of opioid antagonist efficacy and constitutive opioid receptor activity in the opioid withdrawal syndrome in mice.

摘要

On the basis of efficacy, opioid antagonists are classified as inverse opioid agonists (e.g. naltrexone) or neutral opioid antagonists (e.g. 6beta-naltrexol). This study examined the interaction between naltrexone and 6beta-naltrexol in the precipitated opioid withdrawal syndrome in morphine dependent mice. Furthermore, the possible contribution of constitutive opioid receptor activity to precipitated withdrawal was evaluated using increasing levels of morphine dependence. In the first experiment, low doses of 6beta-naltrexol antagonized naltrexone precipitated withdrawal while high doses acted additively. All doses of naltrexone increased 6beta-naltrexol's potency to precipitate withdrawal. The next experiment examined changes in antagonist potency to precipitate withdrawal with increasing morphine dependence. Mice were exposed to morphine for 1-6 days and then withdrawal was precipitated. Naltrexone was more potent than 6beta-naltrexol at all the time points. The ED(50) of both drugs decreased at the same rate suggesting that increased dependence produced no change in constitutive opioid receptor activity. Taken together these results indicate that the functional efficacy of 6beta-naltrexol is dose-dependent and that constitutive opioid receptor activity did not change as opioid dependence increased from 1 to 6 days.