Inflammatory pain-induced signaling events following a conditional deletion of the N-methyl-D-aspartate receptor in spinal cord dorsal horn.
The N-methyl-d-aspartate (NMDA) receptor in the spinal cord dorsal horn (SCDH) is one of the mechanisms involved in central sensitization during chronic pain. Previously, this laboratory created a spatio-temporal knockout (KO) of the N-methyl-d-aspartate receptor I (NR1) subunit in the mouse SCDH. The NR1 KO completely blocks NR1 gene and subsequent NMDA receptor expression and function in SCDH neurons. In the NR1 KO mice, the mechanical and cold allodynia induced at 24 h after complete Freund's adjuvant (CFA) was reduced. However, the protective effects of KO were transient and were not seen at 48 h after CFA. These observations suggest the presence of NMDA-independent pathways that contribute to CFA-induced pain. CFA induces the activation of several signaling cascades in the SCDH, including protein kinase C (PKC)gamma and extracellular signal-regulated kinases (ERK1/2). The phosphorylation of PKCgamma and ERK1/2 was inhibited in the SCDH of NR1 KO mice up to 48 h after CFA treatment, suggesting that these pathways are NMDA receptor-dependent. Interestingly, neuronal cyclooxygenase (COX) -2 expression and microglial p38 phosphorylation were induced in the SCDH of the NR1 KO at 48 h after CFA. Our findings provide evidence that inflammatory reactions are responsible for the recurrence of pain after NR1 KO in the SCDH.
Cheng
H T
HT
Department of Pharmacology, Weill Medical College, Cornell University, New York, NY 10065, USA. chengt@umich.edu
Suzuki
M
M
Hegarty
D M
DM
Xu
Q
Q
Weyerbacher
A R
AR
South
S M
SM
Ohata
M
M
Inturrisi
C E
CE
D000704:Analysis of Variance; D000818:Animals; D051546:Cyclooxygenase 2 / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005620:Freund's Adjuvant / Q000009:adverse effects; D015971:Gene Expression Regulation, Enzymologic; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006930:Hyperalgesia / Q000503:physiopathology; D051379:Mice; D008822:Mice, Transgenic; D010146:Pain / Q000139:chemically induced / Q000473:pathology*; D017288:Pain Threshold / Q000502:physiology; D010766:Phosphorylation / Q000187:drug effects; D010812:Physical Stimulation; D020671:Posterior Horn Cells / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000172:deficiency*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013116:Spinal Cord / Q000473:pathology*; D013997:Time Factors
C409466:NR1 NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D049452:Green Fluorescent Proteins; D005620:Freund's Adjuvant; D051546:Cyclooxygenase 2; C087857:protein kinase C gamma; D011493:Protein Kinase C; D048049:Extracellular Signal-Regulated MAP Kinases