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Spinal D-Serine Increases PKC-Dependent GluN1 Phosphorylation Contributing to the Sigma-1 Receptor-Induced Development of Mechanical Allodynia in a Mouse Model of Neuropathic Pain

  • Sheu-Ran Choi
    Affiliations
    Department of Veterinary Physiology, BK21 PLUS Program for Creative Veterinary Science Research, Research Institute for Veterinary Science and College of Veterinary Medicine, Seoul, Republic of Korea
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  • Ji-Young Moon
    Affiliations
    KM Fundamental Research Division, Korea Institute of Oriental Medicine, Daejeon, Republic of Korea
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  • Dae-Hyun Roh
    Affiliations
    Department of Maxillofacial Tissue Regeneration and Research Center for Tooth and Periodontal Tissue Regeneration, School of Dentistry, Kyung Hee University, Seoul, Republic of Korea
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  • Seo-Yeon Yoon
    Affiliations
    Pain Cognitive Function Research Center, Department of Brain and Cognitive Sciences, College of Natural Sciences, Seoul National University, Seoul, Republic of Korea
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  • Soon-Gu Kwon
    Affiliations
    Department of Maxillofacial Tissue Regeneration and Research Center for Tooth and Periodontal Tissue Regeneration, School of Dentistry, Kyung Hee University, Seoul, Republic of Korea
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  • Hoon-Seong Choi
    Affiliations
    Department of Veterinary Physiology, BK21 PLUS Program for Creative Veterinary Science Research, Research Institute for Veterinary Science and College of Veterinary Medicine, Seoul, Republic of Korea
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  • Suk-Yun Kang
    Affiliations
    KM Fundamental Research Division, Korea Institute of Oriental Medicine, Daejeon, Republic of Korea
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  • Ho-Jae Han
    Affiliations
    Department of Veterinary Physiology, BK21 PLUS Program for Creative Veterinary Science Research, Research Institute for Veterinary Science and College of Veterinary Medicine, Seoul, Republic of Korea
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  • Alvin J. Beitz
    Affiliations
    Department of Veterinary and Biomedical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, Minnesota
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  • Jang-Hern Lee
    Correspondence
    Address reprint requests to Jang-Hern Lee, DVM, PhD, Department of Veterinary Physiology, College of Veterinary Medicine, Seoul National University, Seoul 08826, Republic of Korea.
    Affiliations
    Department of Veterinary Physiology, BK21 PLUS Program for Creative Veterinary Science Research, Research Institute for Veterinary Science and College of Veterinary Medicine, Seoul, Republic of Korea
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Published:December 13, 2016DOI:https://doi.org/10.1016/j.jpain.2016.12.002

      Highlights

      • Spinal N-methyl-D-aspartate receptors play a key role in the development of central sensitization.
      • D-serine modulated spinal protein kinase C-dependent (Ser896) phosphorylation of GluN1 subunit.
      • D-serine mediated the effects of spinal sigma-1 receptors on phosphorylated GluN1 and nociception.
      • D-serine contributed to the development of mechanical allodynia after peripheral nerve injury.

      Abstract

      We have recently shown that spinal sigma-1 receptor (Sig-1R) activation facilitates nociception via an increase in phosphorylation of the N-methyl-D-aspartate (NMDA) receptor GluN1 subunit (pGluN1). The present study was designed to examine whether the Sig-1R-induced facilitative effect on NMDA-induced nociception is mediated by D-serine, and whether D-serine modulates spinal pGluN1 expression and the development of neuropathic pain after chronic constriction injury (CCI) of the sciatic nerve. Intrathecal administration of the D-serine degrading enzyme, D-amino acid oxidase attenuated the facilitation of NMDA-induced nociception induced by the Sig-1R agonist, 2-(4-morpholinethyl)1-phenylcyclohexane carboxylate. Exogenous D-serine increased protein kinase C (PKC)-dependent (Ser896) pGluN1 expression and facilitated NMDA-induced nociception, which was attenuated by preteatment with the PKC inhibitor, chelerythrine. In CCI mice, administration of the serine racemase inhibitor, L-serine O-sulfate potassium salt or D-amino acid oxidase on postoperative days 0 to 3 suppressed CCI-induced mechanical allodynia (MA) and pGluN1 expression on day 3 after CCI surgery. Intrathecal administration of D-serine restored MA as well as the GluN1 phosphorylation on day 3 after surgery that was suppressed by the Sig-1R antagonist, N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino)ethylamine dihydrobromide or the astrocyte inhibitor, fluorocitrate. In contrast, D-serine had no effect on CCI-induced thermal hyperalgesia or GluN1 expression. These results indicate that spinal D-serine: 1) mediates the facilitative effect of Sig-1R on NMDA-induced nociception, 2) modulates PKC-dependent pGluN1 expression, and 3) ultimately contributes to the induction of MA after peripheral nerve injury.

      Perspective

      This report shows that reducing D-serine suppresses central sensitization and significantly alleviates peripheral nerve injury-induced chronic neuropathic pain and that this process is modulated by spinal Sig-1Rs. This preclinical evidence provides a strong rationale for using D-serine antagonists to treat peripheral nerve injury-induced neuropathy.

      Key words

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