title: 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.
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.
  
  
  
  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.
authors.affiliation: 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.
authors.forename: Sheu-Ran
authors.initials: SR
authors.lastname: Choi
authors.affiliation: KM Fundamental Research Division, Korea Institute of Oriental Medicine, Daejeon, Republic of Korea.
authors.forename: Ji-Young
authors.initials: JY
authors.lastname: Moon
authors.affiliation: Department of Maxillofacial Tissue Regeneration and Research Center for Tooth and Periodontal Tissue Regeneration, School of Dentistry, Kyung Hee University, Seoul, Republic of Korea.
authors.forename: Dae-Hyun
authors.initials: DH
authors.lastname: Roh
authors.affiliation: Pain Cognitive Function Research Center, Department of Brain and Cognitive Sciences, College of Natural Sciences, Seoul National University, Seoul, Republic of Korea.
authors.forename: Seo-Yeon
authors.initials: SY
authors.lastname: Yoon
authors.affiliation: Department of Maxillofacial Tissue Regeneration and Research Center for Tooth and Periodontal Tissue Regeneration, School of Dentistry, Kyung Hee University, Seoul, Republic of Korea.
authors.forename: Soon-Gu
authors.initials: SG
authors.lastname: Kwon
authors.affiliation: 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.
authors.forename: Hoon-Seong
authors.initials: HS
authors.lastname: Choi
authors.affiliation: KM Fundamental Research Division, Korea Institute of Oriental Medicine, Daejeon, Republic of Korea.
authors.forename: Suk-Yun
authors.initials: SY
authors.lastname: Kang
authors.affiliation: 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.
authors.forename: Ho-Jae
authors.initials: HJ
authors.lastname: Han
authors.affiliation: Department of Veterinary and Biomedical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, Minnesota.
authors.forename: Alvin J
authors.initials: AJ
authors.lastname: Beitz
authors.affiliation: 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. Electronic address: jhl1101@snu.ac.kr.
authors.forename: Jang-Hern
authors.initials: JH
authors.lastname: Lee
mesh_terms: D000818:Animals; D003605:D-Amino-Acid Oxidase / Q000378:metabolism; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005029:Ethylenediamines / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006930:Hyperalgesia / Q000209:etiology*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009025:Morpholines / Q000494:pharmacology; D016202:N-Methylaspartate / Q000494:pharmacology / Q000633:toxicity; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009437:Neuralgia / Q000150:complications*; D010766:Phosphorylation / Q000187:drug effects; D010812:Physical Stimulation / Q000009:adverse effects; D011493:Protein Kinase C / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D017480:Receptors, sigma / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012694:Serine / Q000494:pharmacology*; D013116:Spinal Cord / Q000187:drug effects; D000097605:Sigma-1 Receptor
chemical_list: D003605:D-Amino-Acid Oxidase; D004791:Enzyme Inhibitors; D005029:Ethylenediamines; D018690:Excitatory Amino Acid Agonists; D009025:Morpholines; D016202:N-Methylaspartate; D009419:Nerve Tissue Proteins; D011493:Protein Kinase C; D016194:Receptors, N-Methyl-D-Aspartate; D017480:Receptors, sigma; D012694:Serine; D000097605:Sigma-1 Receptor; C121673:Gprin1 protein, mouse; C071738:2-(4-morpholino)ethyl-1-phenylcyclohexane-1-carboxylate; C097963:N-(2-(3,4-Dichlorphenyl)ethyl)-N,N',N'-trimethyl-1,2-ethandiamin
keywords: D-serine; GluN1 phosphorylation; neuropathic pain; protein kinase C; sigma-1 receptor