We recently reported that micro-opioid receptor agonist morphine failed to induce its rewarding effects in rodents with sciatic nerve injury. In the present study, we investigated whether a state of neuropathic pain induced by sciatic nerve ligation could change the activities of the extracellular signal-regulated kinase (ERK) and p38 in the mouse lower midbrain area including the ventral tegmental area (VTA), and these changes could directly affect the development of the morphine-induced rewarding effect in mice. The sciatic nerve ligation caused a long-lasting and profound thermal hyperalgesia. A dose-dependent place preference induced by s.c. administration of morphine was observed in sham-operated mice, but not in sciatic nerve-ligated mice. We found here for the first time that nerve injury produces a sustained and significant reduction in protein levels of phosphorylated-ERK and -p38 in cytosolic preparations of the mouse lower midbrain. The inhibition of ERK activity by i.c.v. pre-treatment with either PD98059 or U0126 impaired the morphine-induced place preference. In contrast, i.c.v. treatment with a specific inhibitor of p38, SB203580, did not interfere with the morphine-induced rewarding effect. Immunohistochemical study showed a drastic reduction in phosphorylated-ERK immunoreactivity within tyrosine hydroxylase-positive cells of the VTA. These results suggest that a sustained reduction in the ERK-dependent signalling pathway in dopamine cells of the VTA may be implicated in the suppression of the morphine-induced rewarding effect under neuropathic pain.