Astrocyte sigma-1 receptors modulate connexin 43 expression leading to the induction of below-level mechanical allodynia in spinal cord injured mice.

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: Sheu-Ran Choi, Dae-Hyun Roh, Seo-Yeon Yoon, Soon-Gu Kwon, Hoon-Seong Choi, Ho-Jae Han, Alvin J Beitz, Jang-Hern Lee
• Journal: Neuropharmacology (Neuropharmacology) Vol. 111 Pg. 34-46 (12 2016) ISSN: 1873-7064 [Electronic] England
• PMID: 27567941 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2016 Elsevier Ltd. All rights reserved.

Chemical References

• Connexin 43
• Ethylenediamines
• Receptors, sigma
• sigma-1 receptor
• N-(2-(3,4-Dichlorphenyl)ethyl)-N,N',N'-trimethyl-1,2-ethandiamin

Topics

• Animals
• Astrocytes (metabolism)
• Connexin 43 (metabolism, physiology)
• Disease Models, Animal
• Ethylenediamines (administration & dosage)
• Hyperalgesia (complications, metabolism)
• Male
• Mice
• Mice, Inbred ICR
• Neuralgia (complications, metabolism)
• Receptors, sigma (antagonists & inhibitors, metabolism)
• Spinal Cord Dorsal Horn (metabolism)
• Spinal Cord Injuries (complications)