title: Spinal sigma-1 receptor activation increases the production of D-serine in astrocytes which contributes to the development of mechanical allodynia in a mouse model of neuropathic pain.
abstract: We have previously demonstrated that activation of the spinal sigma-1 receptor (Sig-1R) plays an important role in the development of mechanical allodynia (MA) via secondary activation of the N-methyl-d-aspartate (NMDA) receptor. Sig-1Rs have been shown to localize to astrocytes, and blockade of Sig-1Rs inhibits the pathologic activation of astrocytes in neuropathic mice. However, the mechanism by which Sig-1R activation in astrocytes modulates NMDA receptors in neurons is currently unknown. d-serine, synthesized from l-serine by serine racemase (Srr) in astrocytes, is an endogenous co-agonist for the NMDA receptor glycine site and can control NMDA receptor activity. Here, we investigated the role of d-serine in the development of MA induced by spinal Sig-1R activation in chronic constriction injury (CCI) mice. The production of d-serine and Srr expression were both significantly increased in the spinal cord dorsal horn post-CCI surgery. Srr and d-serine were only localized to astrocytes in the superficial dorsal horn, while d-serine was also localized to neurons in the deep dorsal horn. Moreover, we found that Srr exists in astrocytes that express Sig-1Rs. The CCI-induced increase in the levels of d-serine and Srr was attenuated by sustained intrathecal treatment with the Sig-1R antagonist, BD-1047 during the induction phase of neuropathic pain. In behavioral experiments, degradation of endogenous d-serine with DAAO, or selective blockade of Srr by LSOS, effectively reduced the development of MA, but not thermal hyperalgesia in CCI mice. Finally, BD-1047 administration inhibited the development of MA and this inhibition was reversed by intrathecal treatment with exogenous d-serine. These findings demonstrate for the first time that the activation of Sig-1Rs increases the expression of Srr and d-serine in astrocytes. The increased production of d-serine induced by CCI ultimately affects dorsal horn neurons that are involved in the development of MA in neuropathic mice.
authors: KM Fundamental Research Division, Korea Institute of Oriental Medicine, Daejeon 305-811, Republic of Korea.
authors: Ji-Young
authors: JY
authors: Moon
authors: Department of Veterinary Physiology, BK21 PLUS Program for Creative Veterinary Science Research, Research Institute for Veterinary Science and College of Veterinary Medicine, Seoul National University, Seoul 151-742, Republic of Korea.
authors: Sheu-Ran
authors: SR
authors: Choi
authors: Department of Maxillofacial Tissue Regeneration, Kyung Hee University School of Dentistry, Seoul 130-701, Republic of Korea.
authors: Dae-Hyun
authors: DH
authors: Roh
authors: Pain Cognitive Function Research Center, Department of Brain and Cognitive Sciences College of Natural Sciences, Dental Research Institute and Department of Neurobiology and Physiology, School of Dentistry, Seoul National University, Seoul 110-749, Republic of Korea.
authors: Seo-Yeon
authors: SY
authors: Yoon
authors: Department of Veterinary Physiology, BK21 PLUS Program for Creative Veterinary Science Research, Research Institute for Veterinary Science and College of Veterinary Medicine, Seoul National University, Seoul 151-742, Republic of Korea.
authors: Soon-Gu
authors: SG
authors: Kwon
authors: Department of Veterinary Physiology, BK21 PLUS Program for Creative Veterinary Science Research, Research Institute for Veterinary Science and College of Veterinary Medicine, Seoul National University, Seoul 151-742, Republic of Korea.
authors: Hoon-Seong
authors: HS
authors: Choi
authors: KM Fundamental Research Division, Korea Institute of Oriental Medicine, Daejeon 305-811, Republic of Korea.
authors: Suk-Yun
authors: SY
authors: Kang
authors: Department of Veterinary Physiology, BK21 PLUS Program for Creative Veterinary Science Research, Research Institute for Veterinary Science and College of Veterinary Medicine, Seoul National University, Seoul 151-742, Republic of Korea.
authors: Ho-Jae
authors: HJ
authors: Han
authors: Department of Physiology, Institute of Brain Research, Chungnam National University Medical School, Daejeon 301-747, Republic of Korea.
authors: Hyun-Woo
authors: HW
authors: Kim
authors: Department of Veterinary and Biomedical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, MN 55108, USA.
authors: Alvin J
authors: AJ
authors: Beitz
authors: Pain Cognitive Function Research Center, Department of Brain and Cognitive Sciences College of Natural Sciences, Dental Research Institute and Department of Neurobiology and Physiology, School of Dentistry, Seoul National University, Seoul 110-749, Republic of Korea.
authors: Seog-Bae
authors: SB
authors: Oh
authors: Department of Veterinary Physiology, BK21 PLUS Program for Creative Veterinary Science Research, Research Institute for Veterinary Science and College of Veterinary Medicine, Seoul National University, Seoul 151-742, Republic of Korea. Electronic address: jhl1101@snu.ac.kr.
authors: Jang-Hern
authors: JH
authors: Lee
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D004195:Disease Models, Animal; D005029:Ethylenediamines / Q000494:pharmacology; D006930:Hyperalgesia / Q000378:metabolism*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009437:Neuralgia / Q000378:metabolism*; D020671:Posterior Horn Cells / Q000378:metabolism; D019998:Racemases and Epimerases / Q000378:metabolism; D017480:Receptors, sigma / Q000378:metabolism*; D012694:Serine / Q000378:metabolism*; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism; D000097605:Sigma-1 Receptor; D000099300:Serine Racemase
chemical_list: D005029:Ethylenediamines; D019998:Racemases and Epimerases; D017480:Receptors, sigma; D012694:Serine; D000097605:Sigma-1 Receptor; D000099300:Serine Racemase; C097963:N-(2-(3,4-Dichlorphenyl)ethyl)-N,N',N'-trimethyl-1,2-ethandiamin
keywords: Astrocyte; Mechanical allodynia; N-[2-(3,4-dichlorophenyl) ethyl]-N-methyl-2-(dimethylamino) ethylamine dihydro-bromide (PubChem CID: 188,914); Neuropathic pain; Sig-1R; d-serine; d-serine (PubChem CID: 71,077); l-serine O-sulfate potassium salt (PubChem CID: 5951)