Objective To investigate the effects of intrathecally (i.t.) administered U0126 (MAPK kinase inhibitor) on the expression
of phosphorylated cAMP response element binding protein (pCREB) in the dorsal horn of spinal cord and changes in mechanical and thermal hyperalgesia in a rat model of
neuropathic pain and evaluate the role played by the ERK-CREB signal transmission pathway in the mechanism of neuropathic pain.Methods Adult male SD rats weighing 220-300 g were used. Neuropathic pain was produced by chronic constrictive injury (CCI). Four loose ligatures were placed on left sciatic nerve at 1 mm intervals according to the method described by Bennett. The experiment was performed in 2 parts. In part one 48 SD rats were randomly divided into 6 groups (n = 8 each): In group Ⅰ normal rats received a bolus of U0126 5.0 μg i.t. ; in group Ⅱ CCI rats received a bolus of 5% DMSO 10μli.t. ; in group Ⅲ-Ⅳ CCI rats received a bolus of 0.2, 0.5, 1 and 5 μg U0126 (dissolved in 5% DMSO 10 μl) i.t. respectively. Thermal and mechanical paw withdrawal latencies were measured before and at 0.5, 2, 6, 12 and 24 h after
intrathecal injection. In part two 60 animals were randomly divided into 6 groups ( n = 10 each): in group Ⅰ normal animals served as blank control; in groupⅡanimals received CCI only; in group Ⅲ-Ⅳ CCI rats were killed at 0.5, 2, 6 and 12 h after intrathecal administration of U0126 5 μg respectively. L4,5 segments of spinal cord were removed. The expression of pCREB was assessed by Western blot analysis ( n = 4) and immunohistochemical analysis ( n = 6). Results Intrathecal U0126 1 μg and 5 μg significantly reversed the mechanical and thermal hyperalgesia induced by CCI of sciatic nerve. Intrathecal U0126 5 μg significantly attenuated the activation of pCREB in the spinal cord dorsal horn induced by CCI and the effects lasted for at least 6 h. Conclusion This study shows that ERK-CREB signal cascade is involved in the mechanism of neuropathic pain.