Sensory SystemResearch PaperMKK3, an upstream activator of p38, contributes to formalin phase 2 and late allodynia in mice
Section snippets
Animals
Mice (20–30 g, male) were gang housed on a 12-h light/dark cycle and fed food and water ad libitum. Knockout (KO) mice for MKK3 and MKK6 were originally generated at Yale University, New Haven, CT, USA (Lu et al 1999, Tanaka et al 2002) where they were backcrossed onto a C57BL/6 line obtained from Charles River Laboratories (Wilmington, MA, USA). MKK3-/- and MKK6-/- mice were bred at UCSD and genotyped according to standard protocols available at the Jackson Laboratories web site: //www.jax.org/imr/supp_proto.html
Thermal and mechanical stimuli
Mean thermal latency and mechanical withdrawal threshold for MKK3-/- and MKK6-/- mice did not differ from that of WT mice (Table 1). Also, no differences were seen between right and left paws (data not shown). Thus, escape responses to acute nociceptive stimulation were unaffected by either MKK3 or MKK6 deficiency.
Formalin response phase 1
The phase 1 response (1–9 min postinjection) is the acute behavioral response to intraplantar formalin and, to a great extent, reflects the degree of primary afferent fiber activity (
Discussion
These studies explored whether the kinases that regulate p38 play contribute to pain behavior in mice. Our major findings are (1) MKK3 and MKK6 do not participate in acute pain; (2) MKK3, but not MKK6, participates in the initiation of formalin phase 2 behavior and the subsequent prolonged allodynia and its phosphorylation correlates with phase 2 activity; (3) lack of P-MKK3 reduces and delays spinal p38 phosphorylation post-injury; and (4) P-MKK3/6 in mice is expressed in astrocytes.
Activation
Acknowledgments
This work was supported by National Institutes of Health grant NS048563 (L.S.S. and G.S.F.) and 5R01AI070555 (G.S.F.). We thank Dr. Camilla Svensson for many valuable discussions concerning the data.
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