Morphine improved stress-induced amnesia and anxiety through interacting with the ventral hippocampal endocannabinoid system in rats

The present study aimed to investigate the possible role of the ventral hippocampal (VH) cannabinoid CB1 receptors in the improving effect of morphine on stress-induced memory formation impairment and anxiety. A step-through type passive avoidance task and a hole-board test were used to measure memory formation and anxiety-like exploratory behavior, respectively. The results showed that the exposure to 10-min stress immediately after the successful training phase impaired memory formation and also produced anxiogenic-like exploratory behaviour in adult male Wistar rats. Moreover, morphine administration before stress exposure improved the adverse effects of stress on memory formation and exploratory behaviour. After training, intra-VH microinjection of cannabinoid CB1/CB2 receptor agonist, WIN 55,212-2 (0.01-0.05 μg/rat) enhanced the response of an ineffective dose of morphine (0.5 mg/kg for memory; 5 mg/kg for anxiety, i.p.) on memory impairment and anxiogenic-like exploratory behaviour induced by acute stress. Intra-VH microinjection of the higher dose of WIN 55,212-2 alone impaired memory formation. Post-training microinjection of a cannabinoid CB1 receptor antagonist/inverse agonist, AM-251 (100-150 ng/rat) into the VH attenuated the response of an effective dose of morphine (5 mg/kg for memory; 6 mg/kg for anxiety, i.p.) in stress-exposed rats. Taken together, the present results showed that morphine administration could improve stress-induced memory impairment and anxiety in the rats exposed to the inescapable acute stress. Interestingly, the improving effect of morphine on the adverse effect of stress on memory formation and anxiety-like exploratory behaviour may be mediated through the VH endocannabinoid CB1/CB2 receptors mechanism.