Background: Tumor necrosis factor-α (TNF-α) is emerging as an important modulator of the function of the central nervous system (CNS). We have demonstrated that TNF-α or Leu-Ile, a TNF-α inducer, inhibits methamphetamine-induced rewarding effects and sensitization. In this study, we investigated the effects of TNF-α or Leu-Ile on morphine (MOR)-induced rewarding effects and sensitization. Methods: Levels of TNF-α messenger RNA (mRNA) and protein were determined by real-time reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemistry. Effects of TNF-α or Leu-Ile on MOR-induced rewarding effects and sensitization were investigated by conditioned place preference and locomotor activity tests. Extracellular dopamine levels were examined using in vivo microdialysis. Effects of TNF-α or Leu-Ile on MOR-induced antinociceptive effect and withdrawal symptoms were examined by hot plate test and naloxone-preciptated withdrawal. Results: Morphine induced TNF-α mRNA expression via dopamine and opioid receptors. Posttreatment with TNF-α or Leu-Ile attenuated the MOR-induced place preference and sensitization even after their development, as well as pretreatment with TNF-α or Leu-Ile blocked them. An inhibitory effect of Leu-Ile on MOR-induced place preference was not observed in TNF-α knockout mice. Tumor necrosis factor-α or Leu-Ile inhibited the increase in extracellular dopamine levels in the nucleus accumbens induced by repeated MOR treatment. Conclusions: These results suggest that TNF-α inhibits MOR-induced rewarding effect and sensitization by regulating extracellular dopamine levels, and Leu-Ile inhibits them via the induction of TNF-α. © 2007 Society of Biological Psychiatry.