title: Astrocytic CX43 hemichannels and gap junctions play a crucial role in development of chronic neuropathic pain following spinal cord injury.
abstract: Chronic neuropathic pain is a frequent consequence of spinal cord injury (SCI). Yet despite recent advances, upstream releasing mechanisms and effective therapeutic options remain elusive. Previous studies have demonstrated that SCI results in excessive ATP release to the peritraumatic regions and that purinergic signaling, among glial cells, likely plays an essential role in facilitating inflammatory responses and nociceptive sensitization. We sought to assess the role of connexin 43 (Cx43) as a mediator of CNS inflammation and chronic pain. To determine the extent of Cx43 involvement in chronic pain, a weight-drop SCI was performed on transgenic mice with Cx43/Cx30 deletions. SCI induced robust and persistent neuropathic pain including heat hyperalgesia and mechanical allodynia in wild-type control mice, which developed after 4 weeks and was maintained after 8 weeks. Notably, SCI-induced heat hyperalgesia and mechanical allodynia were prevented in transgenic mice with Cx43/Cx30 deletions, but fully developed in transgenic mice with only Cx30 deletion. SCI-induced gliosis, detected as upregulation of glial fibrillary acidic protein in the spinal cord astrocytes at different stages of the injury, was also reduced in the knockout mice with Cx43/Cx30 deletions, when compared with littermate controls. In comparison, a standard regimen of post-SCI treatment of minocycline attenuated neuropathic pain to a significantly lesser degree than Cx43 deletion. These findings suggest Cx43 is critically linked to the development of central neuropathic pain following acute SCI. Since Cx43/Cx30 is expressed by astrocytes, these findings also support an important role of astrocytes in the development of chronic pain.
authors.affiliation: Department of Neurosurgery, Center for Translational Neuromedicine, University of Rochester Medical School, Rochester, New York, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Chen
authors.forename: Benjamin
authors.initials: B
authors.lastname: Kress
authors.forename: Xiaoning
authors.initials: X
authors.lastname: Han
authors.forename: Katherine
authors.initials: K
authors.lastname: Moll
authors.forename: Weiguo
authors.initials: W
authors.lastname: Peng
authors.forename: Ru-Rong
authors.initials: RR
authors.lastname: Ji
authors.forename: Maiken
authors.initials: M
authors.lastname: Nedergaard
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D018031:Connexin 43 / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D017629:Gap Junctions / Q000378:metabolism*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006930:Hyperalgesia / Q000209:etiology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009437:Neuralgia / Q000209:etiology / Q000378:metabolism*; D010147:Pain Measurement; D017288:Pain Threshold / Q000502:physiology; D013116:Spinal Cord / Q000378:metabolism*; D013119:Spinal Cord Injuries / Q000150:complications / Q000378:metabolism*
chemical_list: D018031:Connexin 43; D005904:Glial Fibrillary Acidic Protein