Although mechanisms of LTP at C-fibers synapses remain unclear, there is evidence for a postsynaptic, Ca
2+-dependent form of LTP induction in lamina I neurons of the SC. Induction of LTP requires co-activation of neurokinin 1 (NK1) and neurokinin 2 (NK2) receptors [
4], opening of T-type voltage-gated calcium channels [
8,
13], and activation of group I metabotropic glutamate receptors [
34]. Activation of NK1 receptor by substance P (SP) may directly enhance single NMDA channel opening [
35] and NMDA receptor mediated currents in lamina I neurons [
13]. All of these may lead to substantial rise in postsynaptic [Ca
2+]
i, which is essential for LTP induction. In addition, Ca
2+ influx through Ca
2+-permeable a-amino-3-ydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors may also be required for LTP induction in pain pathways [
36,
37]. Signal transduction of LTP involves Ca
2+-dependent pathways including PKC, CaMKII, PKA, NOS and members of MAPK including ERK [
6,
8,
13‐
15,
29]. The potential mechanisms of LTP at synapses between C-fibers and SC projection neurons were recently reviewed by Sandkühler [
3]. According to this model, LTP can be prevented if release of glutamate and/or SP is inhibited, or if opening of voltage sensitive and Ca
2+ permeable ion channels is blocked. LTP deficits or de-potentiation could result from de-phosphorylation of synaptic proteins, changes in receptor trafficking or degradation of synaptic proteins [
3]. Studies have shown that in the rat DH this synaptic plasticity is sensitive to inhibitors of iNOS, glial cell metabolism [
38], group I mGluR [
34], glial glutamate transporters [
39,
40] and protein synthesis [
41].
This study presents the first description of the time course of HFS-induced phosphorylation of CaMKII, ERK and CREB and altered expression of c-Fos in the SC of mice and rats. Note that the transient, peak phosphorylation of both CaMKII and ERK occured within 5–10 min of HFS, while phosphorylation of CREB reached its peak approximately 2–3 h after HFS. Increased expression of c-Fos was first increased at 2 h and reached peak at 3 h after HFS. Our results also showed obvious differences in the HFS-induced c-Fos expression in mice and rats, 1) the peak expression of c-Fos in the mouse DH was detected at 3 h, whereas it was markedly increased in the DH of rats at 2 h [
40]; and 2) the Fos-immunoreactive neurons were seen distributed across all of the mouse DH, while it distributed mainly in the superficial layers of rats DH [
40] (and the present analysis, data not shown).