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Astrocyte sigma-1 receptors modulate connexin 43 expression leading to the induction of below-level mechanical allodynia in spinal cord injured mice.
Neuropharmacology. 2016 12; 111:34-46.N

Abstract

We have previously shown using a spinal cord injury (SCI) model that gap junctions contribute to the early spread of astrocyte activation in the lumbar spinal cord and that this astrocyte communication plays critical role in the induction of central neuropathic pain. Sigma-1 receptors (Sig-1Rs) have been implicated in spinal astrocyte activation and the development of peripheral neuropathic pain, yet their contribution to central neuropathic pain remains unknown. Thus, we investigated whether SCI upregulates spinal Sig-1Rs, which in turn increase the expression of the astrocytic gap junction protein, connexin 43 (Cx43) leading to the induction of central neuropathic pain. A thoracic spinal cord hemisection significantly increased both astrocyte activation and Cx43 expression in lumbar dorsal horn. Sig-1Rs were also increased in lumbar dorsal horn astrocytes, but not neurons or microglia. Intrathecal injection of an astrocyte metabolic inhibitor (fluorocitrate); a gap junction/hemichannel blocker (carbenoxolone); or a Cx43 mimetic peptide (43Gap26) significantly reduced SCI-induced bilateral below-level mechanical allodynia. Blockade of Sig-1Rs with BD1047 during the induction phase of pain significantly suppressed the SCI-induced development of mechanical allodynia, astrocyte activation, increased expression of Cx43 in both total and membrane levels, and increased association of Cx43 with Sig-1R. However, SCI did not change the expression of oligodendrocyte (Cx32) or neuronal (Cx36) gap junction proteins. These findings demonstrate that SCI activates astrocyte Sig-1Rs leading to increases in the expression of the gap junction protein, Cx43 and astrocyte activation in the lumbar dorsal horn, and ultimately contribute to the induction of bilateral below-level mechanical allodynia.

Authors+Show Affiliations

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 08826, Republic of Korea.Department of Maxillofacial Tissue Regeneration and Research Center for Tooth and Periodontal Tissue Regeneration, School of Dentistry, Kyung Hee University, Seoul 02447, Republic of Korea.Pain Cognitive Function Research Center, Department of Brain and Cognitive Sciences, College of Natural Sciences, Seoul National University, Seoul 08826, Republic of Korea.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 08826, Republic of Korea.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 08826, Republic of Korea.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 08826, Republic of Korea.Department of Veterinary and Biomedical Sciences, College of Veterinary Medicine, University of Minnesota, St Paul, MN 55108, USA.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 08826, Republic of Korea. Electronic address: jhl1101@snu.ac.kr.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

27567941

Citation

Choi, Sheu-Ran, et al. "Astrocyte Sigma-1 Receptors Modulate Connexin 43 Expression Leading to the Induction of Below-level Mechanical Allodynia in Spinal Cord Injured Mice." Neuropharmacology, vol. 111, 2016, pp. 34-46.
Choi SR, Roh DH, Yoon SY, et al. Astrocyte sigma-1 receptors modulate connexin 43 expression leading to the induction of below-level mechanical allodynia in spinal cord injured mice. Neuropharmacology. 2016;111:34-46.
Choi, S. R., Roh, D. H., Yoon, S. Y., Kwon, S. G., Choi, H. S., Han, H. J., Beitz, A. J., & Lee, J. H. (2016). Astrocyte sigma-1 receptors modulate connexin 43 expression leading to the induction of below-level mechanical allodynia in spinal cord injured mice. Neuropharmacology, 111, 34-46. https://doi.org/10.1016/j.neuropharm.2016.08.027
Choi SR, et al. Astrocyte Sigma-1 Receptors Modulate Connexin 43 Expression Leading to the Induction of Below-level Mechanical Allodynia in Spinal Cord Injured Mice. Neuropharmacology. 2016;111:34-46. PubMed PMID: 27567941.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Astrocyte sigma-1 receptors modulate connexin 43 expression leading to the induction of below-level mechanical allodynia in spinal cord injured mice. AU - Choi,Sheu-Ran, AU - Roh,Dae-Hyun, AU - Yoon,Seo-Yeon, AU - Kwon,Soon-Gu, AU - Choi,Hoon-Seong, AU - Han,Ho-Jae, AU - Beitz,Alvin J, AU - Lee,Jang-Hern, Y1 - 2016/08/24/ PY - 2016/05/03/received PY - 2016/08/21/revised PY - 2016/08/23/accepted PY - 2016/8/29/pubmed PY - 2017/7/14/medline PY - 2016/8/29/entrez KW - (43)Gap26 (PubChem CID: 25088334) KW - Astrocytes KW - BD1047 (PubChem CID: 188914) KW - Below-level mechanical allodynia KW - Carbenoxolone disodium salt (PubChem CID: 6419769) KW - Connexin 43 KW - DL-Fluorocitric acid barium salt (PubChem CID: 16219377) KW - PRE084 (PubChem CID: 126402) KW - Sigma-1 receptors KW - Spinal cord injury SP - 34 EP - 46 JF - Neuropharmacology JO - Neuropharmacology VL - 111 N2 - We have previously shown using a spinal cord injury (SCI) model that gap junctions contribute to the early spread of astrocyte activation in the lumbar spinal cord and that this astrocyte communication plays critical role in the induction of central neuropathic pain. Sigma-1 receptors (Sig-1Rs) have been implicated in spinal astrocyte activation and the development of peripheral neuropathic pain, yet their contribution to central neuropathic pain remains unknown. Thus, we investigated whether SCI upregulates spinal Sig-1Rs, which in turn increase the expression of the astrocytic gap junction protein, connexin 43 (Cx43) leading to the induction of central neuropathic pain. A thoracic spinal cord hemisection significantly increased both astrocyte activation and Cx43 expression in lumbar dorsal horn. Sig-1Rs were also increased in lumbar dorsal horn astrocytes, but not neurons or microglia. Intrathecal injection of an astrocyte metabolic inhibitor (fluorocitrate); a gap junction/hemichannel blocker (carbenoxolone); or a Cx43 mimetic peptide (43Gap26) significantly reduced SCI-induced bilateral below-level mechanical allodynia. Blockade of Sig-1Rs with BD1047 during the induction phase of pain significantly suppressed the SCI-induced development of mechanical allodynia, astrocyte activation, increased expression of Cx43 in both total and membrane levels, and increased association of Cx43 with Sig-1R. However, SCI did not change the expression of oligodendrocyte (Cx32) or neuronal (Cx36) gap junction proteins. These findings demonstrate that SCI activates astrocyte Sig-1Rs leading to increases in the expression of the gap junction protein, Cx43 and astrocyte activation in the lumbar dorsal horn, and ultimately contribute to the induction of bilateral below-level mechanical allodynia. SN - 1873-7064 UR - https://www.unboundmedicine.com/medline/citation/27567941/Astrocyte_sigma_1_receptors_modulate_connexin_43_expression_leading_to_the_induction_of_below_level_mechanical_allodynia_in_spinal_cord_injured_mice_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0028-3908(16)30363-X DB - PRIME DP - Unbound Medicine ER -