A novel finding on the sex-dependent role of BDNF and GSK-3beta in the medial prefrontal cortex in pain threshold changes in a rat model of fear conditioning with respect to the effect of extinction and the time period after conditioning.

Evidence has shown a wide range of changes in pain perception in posttraumatic stress disorder (PTSD). The present study aimed to explore changes in thermal pain threshold in both sexes of rats exposed to electrical footshocks in different periods after fear conditioning. Fear conditioning (PTSD-like model) was induced by three footshocks (0.8 mA, 3 s) paired with sounds (75 dB, 3 s). Extinction was performed using twenty sounds (75 dB, 3 s) with no footshocks, 1 h after footshocks. Freezing and pain threshold were measured 2 h, 2 days, 7 days, or 30 days after PTSD or extinction (there was not any recall session). The results showed freezing behavior showed a downward trend over time in males, while an upward trend over time in females. Extinction slightly decreased freezing behavior in males, while significantly decreased it in females. Pain threshold was increased in male PTSD rats, while after 30days, there was no change in pain perception. In females, pain threshold was restored in both PTSD-7d and - 30d groups. Extinction decreased pain threshold in males, with stronger effect in females. BDNF was decreased and GSK-3beta was increased in male PTSD rats, except PTSD-30d only for BDNF. In females, BDNF level was restored in both PTSD-7d and - 30d, and also, increased in PTSD-2d group, while GSK-3beta was increased. In conclusion, significant sex differences were observed in freezing behavior, pain threshold, and BDNF. Notably, it seems that GSK-3beta may be involved in freezing and pain perception changes only in females exposed to extinction session.