Inflammation-induced upregulation of AMPA receptor subunit expression in brain stem pain modulatory circuitry

Pain. 2003 Jul;104(1-2):401-13. doi: 10.1016/s0304-3959(03)00048-4.


Our previous study demonstrated an increase in alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor sensitivity in the rostral ventromedial medulla (RVM) associated with enhanced net descending inhibition after inflammatory hyperalgesia. The present study further studied the time-dependent changes in AMPA-produced inhibition after inflammation and the underlying molecular mechanisms. Inflammation was induced by intraplantar injection of complete Freund's adjuvant (CFA, 0.2ml). There was a significant increase in AMPA-produced inhibition at 5h that was further enhanced at 24h (P<0.05), as compared to that at 3h post-inflammation. The AMPA-produced inhibition returned to the control level at 14 days post-inflammation. We analyzed mRNA and protein levels of the GluR1 and GluR2 AMPA receptor subunits in the RVM at 2h to 14 days post-inflammation. AMPA receptor subunits exist in the two 'flip' and 'flop' isoforms that differentially affect the desensitization properties of the receptor. Reverse transcription-polymerase chain reaction analysis indicated that there was a significant upregulation of mRNAs encoding the GluR1-flip (5-24h), GluR2-flip (24h) and GluR2-flop (24h) isoforms in the RVM after inflammation, whereas the levels of GluR1-flop mRNAs showed no significant change. Western blots demonstrated that the GluR1 protein levels were significantly upregulated at 24h-3 days (P<0.05) post-inflammation, compared to that of naive animals. GluR2 protein levels remained unchanged. Immunohistochemistry further demonstrated an increase in GluR1-like immunoreactivity localized to the RVM at 24h post-inflammation. These findings suggest that AMPA receptors in the RVM undergo selective transcriptional and translational modulation following inflammation and may contribute to activity-dependent plasticity in descending pain modulatory systems after prolonged noxious input.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Brain Stem / chemistry
  • Brain Stem / metabolism*
  • Gene Expression Regulation / genetics
  • Inflammation / metabolism
  • Inflammation / physiopathology*
  • Male
  • Neural Pathways / metabolism
  • Pain / metabolism*
  • Protein Subunits / biosynthesis*
  • Protein Subunits / genetics
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, AMPA / analysis
  • Receptors, AMPA / biosynthesis*
  • Receptors, AMPA / genetics
  • Up-Regulation* / physiology


  • Protein Subunits
  • Receptors, AMPA
  • glutamate receptor ionotropic, AMPA 2
  • glutamate receptor ionotropic, AMPA 1