Inflammation-induced upregulation of AMPA receptor subunit expression in brain stem pain modulatory circuitry.
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.
Guan
Yun
Y
Program in Neuroscience, University of Maryland, Baltimore, MD 21201-1586, USA.
Guo
Wei
W
Zou
Shi-Ping
SP
Dubner
Ronald
R
Ren
Ke
K
D000818:Animals; D001933:Brain Stem / Q000737:chemistry / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000235:genetics; D007249:Inflammation / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D009434:Neural Pathways / Q000378:metabolism; D010146:Pain / Q000378:metabolism*; D021122:Protein Subunits / Q000096:biosynthesis* / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000032:analysis / Q000096:biosynthesis* / Q000235:genetics; D015854:Up-Regulation / Q000502:physiology
D021122:Protein Subunits; D018091:Receptors, AMPA; C104722:glutamate receptor ionotropic, AMPA 2