title: Sigma-1 receptor-induced increase in murine spinal NR1 phosphorylation is mediated by the PKCalpha and epsilon, but not the PKCzeta, isoforms.
abstract: Our previous studies have demonstrated that intrathecal (i.t.) administration of a sigma-1 receptor agonist facilitated peripheral nociception via calcium-dependent second messenger cascades including protein kinase C (PKC). We also showed that activation of spinal sigma-1 receptors increased the phosphorylation of the NMDA receptor NR1 subunit (pNR1) in the spinal cord dorsal horn, which resulted in the potentiation of NMDA receptor function. The present study was designed to examine the effect of different PKC isoform inhibitors on sigma-1 receptor-mediated pain facilitation and increased spinal pNR1 expression in mice. The intrathecal injection of the sigma-1 receptor agonist, PRE-084 (PRE, 3nmol/5mul) increased the frequency of paw withdrawal responses to mechanical stimuli (0.6g) and the number of spinal pNR1-immunoreactive (ir) cells. Intrathecal pretreatment with inhibitors (Go6976, PKCepsilonV1-2 or PKC zetapseudosubstrate) of the PKCalpha, epsilon or zeta isoforms significantly reduced the PRE-induced pain facilitatory effect. On the other hand, the PRE-induced increase in the number of spinal pNR1-ir neurons was only blocked by inhibitors of the PKCalpha and PKCepsilon isoforms, but not the PKCzeta isoform. These findings demonstrate that the sigma-1 receptor-induced increase in spinal pNR1 expression is mediated by the PKCalpha and PKC epsilon isoforms, which in turn contribute to the pain facilitation phenomenon. Conversely, the sigma-1 receptor activation of the PKCzeta isoform appears to be involved in a pain signaling pathway that is independent of spinal pNR1 modulation.
authors.affiliation: Biotherapy Human Resources Center, College of Veterinary Medicine, Chonnam National University, Gwangju, Republic of Korea.
authors.forename: Dae-Hyun
authors.initials: DH
authors.lastname: Roh
authors.forename: Seo-Yeon
authors.initials: SY
authors.lastname: Yoon
authors.forename: Hyoung-Sig
authors.initials: HS
authors.lastname: Seo
authors.forename: Suk-Yun
authors.initials: SY
authors.lastname: Kang
authors.forename: Ji-Young
authors.initials: JY
authors.lastname: Moon
authors.forename: Sunok
authors.initials: S
authors.lastname: Song
authors.forename: Alvin J
authors.initials: AJ
authors.lastname: Beitz
authors.forename: Jang-Hern
authors.initials: JH
authors.lastname: Lee
mesh_terms: D000818:Animals; D007278:Injections, Spinal; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000502:physiology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009474:Neurons / Q000378:metabolism; D010146:Pain / Q000201:enzymology / Q000503:physiopathology; D010766:Phosphorylation; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology*; D051571:Protein Kinase C-alpha / Q000037:antagonists & inhibitors / Q000502:physiology*; D051744:Protein Kinase C-epsilon / Q000037:antagonists & inhibitors / Q000502:physiology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D017480:Receptors, sigma / Q000502:physiology*; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism*; D000097605:Sigma-1 Receptor; D000099221:Protein Kinase C zeta
chemical_list: D007527:Isoenzymes; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha; D051744:Protein Kinase C-epsilon; D016194:Receptors, N-Methyl-D-Aspartate; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor; D000099221:Protein Kinase C zeta; C409466:NR1 NMDA receptor