Altered vulnerability to acute opiate withdrawal following stress: roles of N-methyl-D-aspartate and glucocorticoid receptors.

Five experiments studied the modulation of acute opiate withdrawal by restraint stress. Rats were subjected to a 2-hr restraint stress, and 1, 3, or 7 days later they received a single injection of morphine followed by injection of naloxone. Naloxone precipitated a withdrawal syndrome. This syndrome was enhanced when it occurred 1 day after stress but was reduced when it occurred 7 days after stress. The enhancement of withdrawal by restraint stress was prevented by treatment with the N-methyl-d-aspartate (NMDA) receptor antagonist MK801 or the glucocorticoid receptor antagonist RU486 prior to stress. Together these experiments show that restraint stress alters vulnerability to opiate withdrawal and identify activation of NMDA and glucocorticoid receptors as causal to this vulnerability.