Immobilization stress-induced oral opioid self-administration and withdrawal in rats: role of conditioning factors and the effect of stress on "relapse" to opioid drugs.

The effect of 15 min/day of immobilization (IM) stress on oral self-administration (SA) of morphine (0.5 mg/ml) or fentanyl (25 micrograms/ml) and withdrawal was examined in rats. In addition, the role of conditioning factors in these effects was assessed. For each drug, four groups of subjects were exposed for 50 days to IM stress prior to the drug SA period [Paired-Stress (P-S) groups], to IM stress prior to the drug SA period on half of the days and after the drug SA period on the rest of the days [Partial Paired-Stress (PP-S) groups], to IM stress several hours after the drug SA period [Unpaired-Stress (UP-S) groups], or to no IM stress [Control (C) groups]. The P-S and PP-S groups increased their drug SA during choice days in which both the opioid solution and water were available, and tended to manifest a more severe withdrawal syndrome after a naloxone challenge compared with the UP-S and C groups. Reinstatement of the opioid SA under conditions of paired-stress or no stress was further examined after 3 weeks without exposure to either stress or drugs. The paired stress animals had higher levels of drug SA and manifested a more severe withdrawal syndrome than those tested without stress. These results indicate that the learned association between exposure to stress and the drug availability may mediate, in part, the stress-induced enhancement of opioid SA and withdrawal effects.