The role of the N-methyl-d-aspartate receptor NR1 subunit in peripheral nerve injury-induced mechanical allodynia, glial activation and chemokine expression in the mouse
Section snippets
NR1 knock down mice
The knockdown founder mice were generated by microinjecting NR1 constructs into C57BL/6×CBA-fertilized eggs. These mice had the normal NR1 gene knocked down and express a modified NR1 gene at a low level (NR±) (Iwasato et al., 1997, Li et al., 1994). The genotyped knockdown NR1± mice were backcrossed seven to eight times to C57BL/6. B6 were used for the initial mating with founder mice and all other breedings. The transgene is transmitted through the germ line. The generation of NR1 transgenic
Mechanical allodynia
All mice exhibited mechanical allodynia following L5 spinal nerve transection. However, the behavioral response of the NR1 knock down was significantly decreased (P<0.001) in comparison to the wild type mice. The difference in allodynic response was sustained over the postoperative period, for both the 0.008 (results not shown) and 0.015 (Fig. 1) gram von Frey filaments. A sham surgery group was not included in this study since it has been extensively shown in both mice and rats that the sham
Discussion
Using a unique genetically modified mouse model, we confirmed a vital role of NMDA signaling in the pathogenesis of tactile allodynia induced by peripheral nerve injury. The NR1± mice demonstrated a reduced behavioral hypersensitivity but the sensitivity was still present after the L5 spinal nerve transection. These data can be interpreted in two ways: 1) the NR1 deletion resulted in a 50–60% reduction of NR1 protein and thus, NMDAR can still signal glutamate transmission, albeit at a reduced
Acknowledgements
The authors would like to thank Tracy Wynkoop for editorial assistance; Dr. William F. Hickey for monoclonal antibodies and glial expertise; and the following for grant support: National Institute of Drug Abuse grant DA11276 (J.A.D.) and DA 05969 (S.M.S.); the National Institute of Arthritis and Musculoskeletal and Skin Diseases grant AR44757 (J.A.D.), Bristol-Myers Squibb/Zimmer Orthopaedic Foundation (J.A.D.).
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