Direct evidence for the involvement of endogenous beta-endorphin in the suppression of the morphine-induced rewarding effect under a neuropathic pain-like state

Neurosci Lett. 2008 Apr 25;435(3):257-62. doi: 10.1016/j.neulet.2008.02.059. Epub 2008 Mar 4.


Recent clinical studies have demonstrated that when opioids are used to control pain, psychological dependence is not a major problem. In this study, we further investigated the mechanisms that underlie the suppression of opioid reward under neuropathic pain in rodents. Sciatic nerve ligation suppressed a place preference induced by the selective mu-opioid receptor agonist [d-Ala(2), N-MePhe(4), Gly-ol(5)] enkephalin (DAMGO) and reduced both the increase in the level of extracellular dopamine by s.c. morphine in the nucleus accumbens and guanosine-5'-o-(3-[(35)S]thio) triphosphate ([(35)S]GTPgammaS) binding to membranes of the ventral tegmental area (VTA) induced by DAMGO. These effects were eliminated in mice that lacked the beta-endorphin gene. Furthermore, intra-VTA injection of a specific antibody to the endogenous mu-opioid peptide beta-endorphin reversed the suppression of the DAMGO-induced rewarding effect by sciatic nerve ligation in rats. These results provide molecular evidence that nerve injury results in the continuous release of endogenous beta-endorphin to cause the dysfunction of mu-opioid receptors in the VTA. This phenomenon could explain the mechanism that underlies the suppression of opioid reward under a neuropathic pain-like state.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Behavior, Animal / drug effects
  • Conditioning, Operant / drug effects
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / therapeutic use
  • Female
  • Guanosine 5'-O-(3-Thiotriphosphate) / metabolism
  • Male
  • Mice
  • Mice, Knockout
  • Morphine / administration & dosage*
  • Narcotics / administration & dosage*
  • Pain Measurement
  • Protein Binding / drug effects
  • Reaction Time / drug effects
  • Reward*
  • Sciatica / drug therapy*
  • Sciatica / genetics
  • Sciatica / psychology*
  • Time Factors
  • Tyrosine 3-Monooxygenase / metabolism
  • beta-Endorphin / deficiency
  • beta-Endorphin / physiology*


  • Narcotics
  • Enkephalin, Ala(2)-MePhe(4)-Gly(5)-
  • Guanosine 5'-O-(3-Thiotriphosphate)
  • beta-Endorphin
  • Morphine
  • Tyrosine 3-Monooxygenase