Peripheral and central sensitization in remote spinal cord regions contribute to central neuropathic pain after spinal cord injury.
Central neuropathic pain (CNP) developing after spinal cord injury (SCI) is described by the region affected: above-level, at-level and below-level pain occurs in dermatomes rostral, at/near, or below the SCI level, respectively. People with SCI and rodent models of SCI develop above-level pain characterized by mechanical allodynia and thermal hyperalgesia. Mechanisms underlying this pain are unknown and the goals of this study were to elucidate components contributing to the generation of above-level CNP. Following a thoracic (T10) contusion, forelimb nociceptors had enhanced spontaneous activity and were sensitized to mechanical and thermal stimulation of the forepaws 35 days post-injury. Cervical dorsal horn neurons showed enhanced responses to non-noxious and noxious mechanical stimulation as well as thermal stimulation of receptive fields. Immunostaining dorsal root ganglion (DRG) cells and cord segments with activating transcription factor 3 (ATF3, a marker for neuronal injury) ruled out neuronal damage as a cause for above-level sensitization since few C8 DRG cells expressed AFT3 and cervical cord segments had few to no ATF3-labeled cells. Finally, activated microglia and astrocytes were present in thoracic and cervical cord at 35 days post-SCI, indicating a rostral spread of glial activation from the injury site. Based on these data, we conclude that peripheral and central sensitization as well as reactive glia in the uninjured cervical cord contribute to CNP. We hypothesize that reactive glia in the cervical cord release pro-inflammatory substances which drive chronic CNP. Thus a complex cascade of events spanning many cord segments underlies above-level CNP.
Department of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, TX 77555-1069, USA. smcarlto@utmb.edu
Susan M
SM
Carlton
Junhui
J
Du
Huai Yu
HY
Tan
Olivera
O
Nesic
Gregory L
GL
Hargett
Anne C
AC
Bopp
Ammar
A
Yamani
Qing
Q
Lin
William D
WD
Willis
Claire E
CE
Hulsebosch
D000200:Action Potentials / Q000502:physiology; D051700:Activating Transcription Factor 3 / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal; D002452:Cell Count / Q000379:methods; D004195:Disease Models, Animal; D005552:Forelimb / Q000503:physiopathology; D005727:Ganglia, Spinal / Q000378:metabolism / Q000502:physiology; D006930:Hyperalgesia / Q000503:physiopathology; D066298:In Vitro Techniques; D008297:Male; D009437:Neuralgia / Q000209:etiology*; D009619:Nociceptors / Q000473:pathology / Q000502:physiology; D017288:Pain Threshold / Q000502:physiology*; D010812:Physical Stimulation / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D011984:Sensory Receptor Cells / Q000502:physiology; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D013119:Spinal Cord Injuries / Q000150:complications* / Q000378:metabolism / Q000473:pathology*; D018709:Statistics, Nonparametric
D051700:Activating Transcription Factor 3; C497108:Atf3 protein, rat