Recent clinical studies have demonstrated that when opioids are used to control pain, psychological dependence is not a major problem. In this study, we further investigated the mechanisms that underlie the suppression of opioid reward under neuropathic pain in rodents. Sciatic nerve ligation suppressed a place preference induced by the selective μ-opioid receptor agonist d-Ala2, N-MePhe4, Gly-ol5 enkephalin (DAMGO) and reduced both the increase in the level of extracellular dopamine by s.c. morphine in the nucleus accumbens and guanosine-5′-o-(3-35Sthio) triphosphate (35SGTPγS) binding to membranes of the ventral tegmental area (VTA) induced by DAMGO. These effects were eliminated in mice that lacked the β-endorphin gene. Furthermore, intra-VTA injection of a specific antibody to the endogenous μ-opioid peptide β-endorphin reversed the suppression of the DAMGO-induced rewarding effect by sciatic nerve ligation in rats. These results provide molecular evidence that nerve injury results in the continuous release of endogenous β-endorphin to cause the dysfunction of μ-opioid receptors in the VTA. This phenomenon could explain the mechanism that underlies the suppression of opioid reward under a neuropathic pain-like state.