Intrathecal injection of carbenoxolone, a gap junction decoupler, attenuates the induction of below-level neuropathic pain after spinal cord injury in rats.
The most common type of chronic pain following spinal cord injury (SCI) is central neuropathic pain and SCI patients typically experience mechanical allodynia and thermal hyperalgesia. The present study was designed to examine the potential role of astrocyte gap junction connectivity in the induction and maintenance of "below-level" neuropathic pain in SCI rats. We examined the effect of intrathecal treatment with carbenoxolone (CARB), a gap junction decoupler, on SCI-induced bilateral thermal hyperalgesia and mechanical allodynia during the induction phase (postoperative days 0 to 5) and the maintenance phase (days 15 to 20) following T13 spinal cord hemisection. Immunohistochemistry was performed to determine potential SCI-induced changes in spinal astrocyte activation and phosphorylation of the NMDA receptor NR1 subunit (pNR1). CARB administered during the induction period dose-dependently attenuated the development of bilateral thermal hyperalgesia and mechanical allodynia. Intrathecal CARB also significantly reduced the bilateral SCI-induced increase in GFAP-immunoreactive (ir) staining and the number of pNR1-ir cell profiles in the spinal cord dorsal horn compared to vehicle-treated rats. In contrast, CARB treatment during the maintenance phase had no effect on the established thermal hyperalgesia and mechanical allodynia nor on spinal GFAP expression or the number of pNR1-ir cell profiles. These results indicate that gap junctions play a critical role in the activation of astrocytes distant from the site of SCI and in the subsequent phosphorylation of NMDA receptors in the lumbar spinal cord. Both of these processes appear to contribute to the induction of bilateral below-level pain in SCI rats.
Biotherapy Human Resources Center, College of Veterinary Medicine, Chonnam National University, Gwangju, South Korea.
Dae-Hyun
DH
Roh
Seo-Yeon
SY
Yoon
Hyoung-Sig
HS
Seo
Suk-Yun
SY
Kang
Ho-Jae
HJ
Han
Alvin J
AJ
Beitz
Jang-Hern
JH
Lee
D000704:Analysis of Variance; D000818:Animals; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism; D002229:Carbenoxolone / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D017629:Gap Junctions / Q000187:drug effects*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D007278:Injections, Spinal; D008297:Male; D009043:Motor Activity / Q000502:physiology; D009437:Neuralgia / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D010147:Pain Measurement; D010766:Phosphorylation / Q000502:physiology; D020671:Posterior Horn Cells / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D020127:Recovery of Function / Q000187:drug effects*; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism; D013119:Spinal Cord Injuries / Q000150:complications* / Q000378:metabolism; D013904:Thoracic Vertebrae
D005904:Glial Fibrillary Acidic Protein; D016194:Receptors, N-Methyl-D-Aspartate; D002229:Carbenoxolone