title: Involvement of Spinal PKMζ Expression and Phosphorylation in Remifentanil-Induced Long-Term Hyperalgesia in Rats.
abstract: 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-1min-1for 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-L6segments 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.
authors.affiliation: Department of Anesthesiology, Tianjin Medical University General Hospital, Tianjin, 300052, China.|Tianjin Research Institute of Anesthesiology, Tianjin, 300052, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhao
authors.affiliation: Department of Anesthesiology, Tianjin Medical University General Hospital, Tianjin, 300052, China.|Tianjin Research Institute of Anesthesiology, Tianjin, 300052, China.
authors.forename: Linlin
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Anesthesiology, Tianjin Medical University General Hospital, Tianjin, 300052, China.|Tianjin Research Institute of Anesthesiology, Tianjin, 300052, China.
authors.forename: Ruichen
authors.initials: R
authors.lastname: Shu
authors.affiliation: Department of Anesthesiology, Tianjin Medical University General Hospital, Tianjin, 300052, China.|Tianjin Research Institute of Anesthesiology, Tianjin, 300052, China.
authors.forename: Chunyan
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Anesthesiology, Tianjin Medical University General Hospital, Tianjin, 300052, China.|Tianjin Research Institute of Anesthesiology, Tianjin, 300052, China.
authors.forename: Yonghao
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Department of Anesthesiology, Tianjin Medical University General Hospital, Tianjin, 300052, China.|Tianjin Research Institute of Anesthesiology, Tianjin, 300052, China.
authors.forename: Haiyun
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Anesthesiology, Tianjin Medical University General Hospital, Tianjin, 300052, China. 1277619382@qq.com.|Tianjin Research Institute of Anesthesiology, Tianjin, 300052, China. 1277619382@qq.com.
authors.forename: Guolin
authors.initials: G
authors.lastname: Wang
mesh_terms: D000818:Animals; D006930:Hyperalgesia / Q000139:chemically induced / Q000378:metabolism*; D057567:Memory, Long-Term / Q000187:drug effects; D009437:Neuralgia / Q000188:drug therapy* / Q000378:metabolism; D010766:Phosphorylation; D010880:Piperidines / Q000494:pharmacology*; D020671:Posterior Horn Cells / Q000187:drug effects; D011493:Protein Kinase C / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D000077208:Remifentanil; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D000099221:Protein Kinase C zeta
chemical_list: D010880:Piperidines; D011493:Protein Kinase C; D016194:Receptors, N-Methyl-D-Aspartate; D000077208:Remifentanil; D000099221:Protein Kinase C zeta
keywords: Hyperalgesia; N-methyl-D-aspartate; PKMζ; Remifentanil; ZIP