The Mechanisms Of Intrathecal U0126 Attenuate Rat Bone Cancer Pain Hyperalgesia

Obstract: 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 hyperalgesia in a rat model of bone cancer pain and evaluate the role played by the ERK-CREB signal transmission pathway in the mechanism of bone cancer pain.Methods: Adult female SD rats received intra-tibial injection of syngenetic Walker256 mammary gland carcinoma cells and bone cancer pain was produced. The experiment was performed in 2 parts. In part one, in groupⅠ8 sham operated rats received a bolus of l0μg U0126 (dissolved in 5% DMSO 10μl ) i.t. respectively. 32 bone cancer pain (BCP) rats were randomly divided into 4 groups (n=8 each): In groupⅡBCP rats received a bolus of 5% DMSO 10μl i.t.; In groupⅢ,Ⅳ,ⅤBCP rats received a bolus of U0126 0.1, 1, 10μg i.t.; Mechanical paw withdrawal latencies, thermal withdrawal latencies and weight bearing different were measured before and every other day after bone cancer pain was produced and at 1, 3, 6, 9 and 24 h after intrathecal administration. In part two 25 animals were randomly divided into 5 groups (n=5 each): in group S sham operated animals served as blank control: in group M animals produced bone cancer pain only; in groupT1-T3 BCP rats were killed at 1, 6, 24 h after intrathecal administration of U0126 10μg respectively. L4-6 segments of spinal cord were removed.The expression of pCREB was assessed by immunohistochemical analysis.Result: MWT was significantly decreased and WBD was increased from 7 days after the intra-tibial injection of Walker256 cells, and intrathecal U0126 1μg and 10μg significantly reversed the mechanical hyperalgesia induced by bone cancer pain. No significant differences in TWL were found at all time points between any two of these groups. The activation of pCREB in bone cancer pain rats is much more obviously than normal ones; Intrathecal U0126 10μg significantly attenuated the activation of pCREB in the spinal cord dorsal horn induced by BCP and the effects lasted for at least 6 h.Conclusion: This study shows that ERK-CREB signal cascade might be involved in the mechanism of bone cancer pain.