Tumor necrosis factor-alpha and its inducer inhibit morphine-induced rewarding effects and sensitization

Biol Psychiatry. 2007 Sep 15;62(6):658-68. doi: 10.1016/j.biopsych.2006.10.009. Epub 2007 Jan 9.


Background: Tumor necrosis factor-alpha (TNF-alpha) is emerging as an important modulator of the function of the central nervous system (CNS). We have demonstrated that TNF-alpha or Leu-Ile, a TNF-alpha inducer, inhibits methamphetamine-induced rewarding effects and sensitization. In this study, we investigated the effects of TNF-alpha or Leu-Ile on morphine (MOR)-induced rewarding effects and sensitization.

Methods: Levels of TNF-alpha messenger RNA (mRNA) and protein were determined by real-time reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemistry. Effects of TNF-alpha 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-alpha or Leu-Ile on MOR-induced antinociceptive effect and withdrawal symptoms were examined by hot plate test and naloxone-precipitated withdrawal.

Results: Morphine induced TNF-alpha mRNA expression via dopamine and opioid receptors. Posttreatment with TNF-alpha or Leu-Ile attenuated the MOR-induced place preference and sensitization even after their development, as well as pretreatment with TNF-alpha or Leu-Ile blocked them. An inhibitory effect of Leu-Ile on MOR-induced place preference was not observed in TNF-alpha knockout mice. Tumor necrosis factor-alpha 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-alpha inhibits MOR-induced rewarding effect and sensitization by regulating extracellular dopamine levels, and Leu-Ile inhibits them via the induction of TNF-alpha.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Behavior, Animal / drug effects
  • Conditioning, Operant / drug effects
  • Dipeptides / pharmacology*
  • Dipeptides / therapeutic use
  • Habituation, Psychophysiologic / drug effects*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Morphine / antagonists & inhibitors*
  • Morphine / pharmacology
  • Morphine Dependence / drug therapy
  • Morphine Dependence / psychology*
  • Motor Activity / drug effects
  • Naloxone / pharmacology
  • Narcotic Antagonists / pharmacology
  • Narcotics / pharmacology
  • RNA, Messenger / metabolism
  • Reward*
  • Spatial Behavior / drug effects
  • Substance Withdrawal Syndrome / etiology
  • Tumor Necrosis Factor-alpha / pharmacology*
  • Tumor Necrosis Factor-alpha / therapeutic use


  • Dipeptides
  • Narcotic Antagonists
  • Narcotics
  • RNA, Messenger
  • Tumor Necrosis Factor-alpha
  • leucyl-isoleucyl
  • Naloxone
  • Morphine