Inhibition of intracellular signaling pathways NF-κB and MEK1/2 attenuates neuropathic pain development and enhances morphine analgesia

Pharmacol Rep. 2014 Oct;66(5):845-51. doi: 10.1016/j.pharep.2014.05.001. Epub 2014 May 19.


Background: Neuropathic pain is clinically challenging because it is resistant to alleviation by morphine. The nuclear factor κB (NF-κB) and mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathways may be involved in the development of neuropathic pain. The aim of our study was to examine the influence of a chronic, intrathecal administration of parthenolide (PTL, inhibitor of NF-κB) and U0126 (inhibitor of MEK1/2) on nociception and morphine effectiveness in a rat model of neuropathy.

Methods: The chronic constriction injury of the sciatic nerve in Wistar rats was performed. PTL and U0126 were injected chronic intrathecally and morphine was injected once at day 7. To evaluate allodynia and hyperalgesia, the von Frey and cold plate tests were used, respectively. The experiments were carried out according to IASP rules. Using qRT-PCR we analyzed mRNAs of μ-(mor), δ-(dor) and κ-(kor)-opioid receptors in the lumbar spinal cord after drugs administration.

Results: The administration of PTL and U0126 decreased allodynia and hyperalgesia and significantly potentiated morphine effect. The mor, dor and kor mRNAs were down-regulated 7 days after injury in the ipsilateral spinal cord. The PTL and U0126 significantly up-regulated the mRNA levels of all opioid receptors. The levels of mor and dor mRNAs were much higher compared to those in naïve, but only the kor levels returned to control values.

Conclusions: These results indicate that the inhibition of the NF-κB pathway has better analgesic effects. Both inhibitors similarly potentiate morphine analgesia, which parallels the up-regulation of both mor and dor mRNAs expression spinal levels of the model of neuropathy.

Keywords: Morphine; Neuropathic pain; Opioid receptors; Parthenolide; U0126.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analgesics / pharmacology*
  • Analgesics, Opioid / pharmacology
  • Animals
  • Butadienes / pharmacology*
  • Disease Models, Animal
  • Drug Synergism
  • Hyperalgesia / drug therapy
  • MAP Kinase Kinase 1 / antagonists & inhibitors
  • MAP Kinase Kinase 1 / metabolism
  • MAP Kinase Kinase 2 / antagonists & inhibitors
  • MAP Kinase Kinase 2 / metabolism
  • Male
  • Morphine / pharmacology
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / metabolism
  • Neuralgia / drug therapy*
  • Neuralgia / physiopathology
  • Nitriles / pharmacology*
  • Rats
  • Rats, Wistar
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sciatic Nerve / injuries
  • Sesquiterpenes / pharmacology*
  • Signal Transduction / drug effects


  • Analgesics
  • Analgesics, Opioid
  • Butadienes
  • NF-kappa B
  • Nitriles
  • Sesquiterpenes
  • U 0126
  • parthenolide
  • Morphine
  • MAP Kinase Kinase 1
  • MAP Kinase Kinase 2