Tumor necrosis factor-alpha and its inducer inhibit morphine-induced rewarding effects and sensitization.
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.
Niwa
Minae
M
Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya 466-8560, Japan.
Nitta
Atsumi
A
Yamada
Yuichiro
Y
Nakajima
Akira
A
Saito
Kuniaki
K
Seishima
Mitsuru
M
Noda
Yukihiro
Y
Nabeshima
Toshitaka
T
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003216:Conditioning, Operant / Q000187:drug effects; D004151:Dipeptides / Q000494:pharmacology* / Q000627:therapeutic use; D006185:Habituation, Psychophysiologic / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009020:Morphine / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D009021:Morphine Dependence / Q000188:drug therapy / Q000523:psychology*; D009043:Motor Activity / Q000187:drug effects; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009294:Narcotics / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D012201:Reward; D013037:Spatial Behavior / Q000187:drug effects; D013375:Substance Withdrawal Syndrome / Q000209:etiology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology* / Q000627:therapeutic use
D004151:Dipeptides; D009292:Narcotic Antagonists; D009294:Narcotics; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C492946:leucyl-isoleucyl; D009270:Naloxone; D009020:Morphine