We have investigated the effect of chronic lithium (Li+) treatment on stress-induced hypoalgesia, a phenomenon known to be dependent on the activation and sensitization of the central opioid system. Adult female Wistar rats received either 20 mM LiCl in the drinking water (serum level of 0.5 mEq/l, N = 110) or tap water (controls, N = 113) for 28 days. The rats were divided into three subgroups and were trained either by receiving 60 inescapable 1-mA footshocks (IS) while yoked to an escapable (ES) group, or by confinement (NS) to the shock box. As a control for the activation of the opioid system, we included rats injected with 0.9% saline (N = 24) or morphine (4 mg/kg, sc, N = 20) before confinement. Twenty-four hours later, the rats (N = 187) were either submitted to five inescapable (1 s, 0.6 mA) footshocks (shock reexposure) or received no shocks over the same period (N = 80). The pain threshold was estimated using a tail-flick apparatus after the training session and immediately after the shock reexposure. ANOVA followed by Duncan's test indicated that hypoalgesia was produced soon after the training session in the morphine and shocked groups and persisted in the Li+-IS group for up to three days. Hypoalgesia was reinstated in the control IS and morphine groups by reexposure to the shocks, but was not modified in the Li+-IS groups. We conclude that Li+ treatment prolongs the hypoalgesia induced by inescapable shocks.287791799