Up-regulation of GluN2B-containing
N-methyl-D-aspartate receptors (NMDARs) expression and trafficking is the key mechanism for
remifentanil-induced
hyperalgesia (RIH), nevertheless, the signaling pathway and pivotal
proteins involved in RIH remain equivocal. PKMζ, an
isoform of
protein kinase C (PKC), maintains
pain memory storage in
neuropathic pain and inflammatory
pain, which plays a parallel role regulated by NMDARs in long-term memory trace. In the present study, Zeta Inhibitory
Peptide (ZIP), a PKMζ inhibitor, and a selective GluN2B antagonist Ro-256981 are injected intrathecally before
remifentanil infusion (1 μg kg-1 min-1 for 1 h, iv) in order to detect whether GluN2B contributes to RIH through affecting synthesis and activity of PKMζ in spinal dorsal horn. Nociceptive tests are measured by Paw withdrawal mechanical threshold (PWT) and paw withdrawal thermal latency (PWL). The L4-L6 segments of dorsal horn taken from rats with RIH are for determining expression of PKMζ and pPKMζ by Western blot and immunohistochemistry. Our data suggest that
remifentanil infusion causes an increase of PKMζ in expression and phosphorylation in rats with nociceptive sensitization, beginning at 2 h, peaked at 2 days, and returned to basal level at 7 days. ZIP (10 ng) could block behavioral sensitization induced by
remifentanil. Ro25-6981 dosage-dependently attenuated mechanical and
thermal hyperalgesia and reversed expression of PKMζ and pPKMζ, indicating that GluN2B-containing
NMDA receptor facilitates development of RIH through mediating expression and activity of spinal PKMζ in rats. Although detailed mechanisms require further comprehensive study, the preventive role of Ro25-6981 and ZIP provide novel options for the effective precaution of RIH in clinics.