Upregulation of tumor necrosis factor-alpha in nucleus accumbens attenuates morphine-induced rewarding in a neuropathic pain model

Biochem Biophys Res Commun. 2014 Jul 11;449(4):502-7. doi: 10.1016/j.bbrc.2014.05.025. Epub 2014 May 17.


Treatment of neuropathic pain with opioid analgesics remains controversial and a major concern is the risk of addiction. Here, we investigated this issue with spared nerve injury (SNI) model of neuropathic pain in rats and mice. SNI prevented conditioned place preference (CPP) induced by low dose (3.5mg/kg) of morphine (MOR), which was effective for anti-allodynia, but not by high dose (⩾5.0 mg/kg) of MOR. Tumor necrosis factor-alpha (TNF-α) was upregulated in nucleus accumbens (NAcc) following SNI. The inhibitory effect of SNI on MOR-induced CPP was blocked by either genetic deletion of TNF receptor 1 (TNFR1) or microinjection of anti-TNF-α into the NAcc and was mimicked by intra-NAcc injection of TNF-α in sham rats. Furthermore, SNI reduced dopamine (DA) level and upregulated dopamine transporter (DAT) in the NAcc, but did not affect total tyrosine hydroxylase (TH) or phospho-TH (p-TH), a rate-limiting enzyme of catecholamine biosynthesis, in ventral tegmental area (VTA). Accordingly, the increase in DA reuptake but not decrease in its synthesis may lead to the reduction of DA level. Finally, the upregulation of DAT in the NAcc of SNI animals was again blocked by either genetic deletion of TNFR1 or NAcc injection of anti-TNF-α, and was mimicked by NAcc injection of TNF-α in sham animals. Thus, our data provided novel evidence that upregulation of TNF-α in NAcc may attenuate MOR-induced rewarding by upregulation of DAT in NAcc under neuropathic pain condition.

Keywords: Dopamine transporter; Morphine; Neuropathic pain; Nucleus accumbens; Rewarding; Tumor necrosis factor-alpha.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Conditioning, Operant / drug effects
  • Dopamine / metabolism
  • Dopamine Plasma Membrane Transport Proteins / biosynthesis
  • Hyperalgesia / drug therapy
  • Male
  • Mice
  • Morphine / administration & dosage*
  • Neuralgia / drug therapy*
  • Nucleus Accumbens / drug effects
  • Nucleus Accumbens / metabolism*
  • Rats
  • Reward
  • Tumor Necrosis Factor-alpha / biosynthesis*
  • Tyrosine 3-Monooxygenase
  • Up-Regulation


  • Dopamine Plasma Membrane Transport Proteins
  • Tumor Necrosis Factor-alpha
  • Morphine
  • Tyrosine 3-Monooxygenase
  • Dopamine