We have previously demonstrated that intrathecal pretreatment with dextro-morphine or morphine attenuates the morphine-produced antinociception. The phenomenon has been defined as antianalgesia, which is mediated by a non-opioid receptor [Wu, H., Thompson, J., Sun, H., Terashvili, M., Tseng, L.F., 2005. Antianalgesia: stereo-selective action of dextro-morphine over levo-morphine on glia in the mouse spinal cord. J. Pharmacol. Exp. Ther. 314, 1101-1108]. To determine if p38 mitogen-activated protein kinase (MAPK) is involved in the antianalgesia, the effects of p38 MAPK inhibitor 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)-1H-imidazole (SB203580) on the attenuation of the morphine-produced tail-flick inhibition induced by dextro-morphine or morphine were studied in male CD-1 mice. Intrathecal pretreatment with SB203580 (24.2 nmol) reversed the attenuation of the morphine-produced tail-flick inhibition induced by dextro-morphine (33 fmol) or morphine (0.3 nmol) pretreatment. The finding indicates that the antianalgesia induced by dextro-morphine or morphine is mediated by the activation of p38 MAPK in the mouse spinal cord.