Mechanical allodynia but not thermal hyperalgesia is impaired in mice deficient for ERK2 in the central nervous system.
Extracellular signal-regulated kinase (ERK) plays critical roles in pain plasticity. However, the specific contribution of ERK2 isoforms to pain plasticity is not necessarily elucidated. Here we investigate the function of ERK2 in mouse pain models. We used the Cre-loxP system to cause a conditional, region-specific, genetic deletion of Erk2. To induce recombination in the central nervous system, Erk2-floxed mice were crossed with nestin promoter-driven cre transgenic mice. In the spinal cord of resultant Erk2 conditional knockout (CKO) mice, ERK2 expression was abrogated in neurons and astrocytes, but indistinguishable in microglia compared to controls. Although Erk2 CKO mice showed a normal baseline paw withdrawal threshold to mechanical stimuli, these mice had a reduced nociceptive response following a formalin injection to the hind paw. In a partial sciatic nerve ligation model, Erk2 CKO mice showed partially restored mechanical allodynia compared to control mice. Interestingly, thermal hyperalgesia was indistinguishable between Erk2 CKO and control mice in this model. In contrast to Erk2 CKO mice, mice with a targeted deletion of ERK1 did not exhibit prominent anomalies in these pain models. In Erk2 CKO mice, compensatory hyperphosphorylation of ERK1 was detected in the spinal cord. However, ERK1 did not appear to influence nociceptive processing because the additional inhibition of ERK1 phosphorylation using MEK (MAPK/ERK kinase) inhibitor SL327 did not produce additional changes in formalin-induced spontaneous behaviors in Erk2 CKO mice. Together, these results indicate that ERK2 plays a predominant and/or specific role in pain plasticity, while the contribution of ERK1 is limited.
Department of Anesthesiology, National Defense Medical College, Tokorozawa 359-8513, Japan Department of Anesthesiology, Tokyo Medical and Dental University Graduate School, Tokyo 113-8510, Japan Institute of Developmental Biology and Cancer Research, University of Nice Sophia-Antipolis, Centre National de la Recherche Scientifique, Unité mixte de Recherche 6543, Centre Antoine Lacassagne, Nice 06189, France Aging Regulation Research Team, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, Tokyo 173-0015, Japan.
Yukiko
Y
Otsubo
Yasushi
Y
Satoh
Mitsuyoshi
M
Kodama
Yoshiyuki
Y
Araki
Maiko
M
Satomoto
Eiji
E
Sakamoto
Gilles
G
Pagès
Jacques
J
Pouysségur
Shogo
S
Endo
Tomiei
T
Kazama
D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D006930:Hyperalgesia / Q000378:metabolism / Q000503:physiopathology*; D020935:MAP Kinase Signaling System / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D048052:Mitogen-Activated Protein Kinase 3 / Q000172:deficiency* / Q000235:genetics
C535148:Mapk1 protein, mouse; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3