Time-dependent protective effects of morphine against behavioral and morphological deficits in an animal model of posttraumatic stress disorder

Post-traumatic stress disorder (PTSD) arises after an individual has experienced a major traumatic event. Recent evidence suggests that acute morphine treatment may serve as a strategy to reduce PTSD development. In the present study, we investigated the time-dependent effects of morphine on behavioral and morphological deficits induced by the single prolonged stress (SPS), an experimental model of PTSD, in adult male rats. The rats were exposed to SPS (restraint for 2 h, forced swimming for 20 min, and ether anesthesia), and kept undistributed for 11 days. Morphine was injected immediately, 6, 12 and 24 h after SPS. Anxiety profile was evaluated using the elevated plus maze11 days after SPS. Then, animals were conditioned in a fear conditioning task and extinction training was performed on days 1, 2, 3, 4 and 11 after fear conditioning which followed by morphological assessments in the medial prefrontal cortex (mPFC). SPS rats showed increased anxiety levels and impaired contextual fear extinction retention. SPS also decreased dendritic length in the infra-limbic (IL) and dendritic spines in the IL and pre-limbic (PL) regions of the mPFC. Conversely, morphine treatment 6, 12 and 24 h but not immediately after SPS significantly improved anxiety-like behaviors, fear extinction, increased dendritic length, and spines in the mPFC. Morphine-induced much stronger response when injected 24 h after the SPS, and this effect was blocked by naloxone. Our findings show that morphine within a restricted time window selectively reversed the SPS-induced deficits in anxiety profile, fear extinction, and dendritic morphology in the mPFC. Finally, these findings suggest that the time point of morphine injection following a traumatic event is an important determinant of the full therapeutic effect of morphine against PTSD.