Effects of Etanercept and Minocycline in a rat model of spinal cord injury.
Loss of function is usually considered the major consequence of spinal cord injury (SCI). However, pain severely compromises the quality of life in nearly 70% of SCI patients. The principal aim of this study was to assess the contribution of Tumor necrosis factor alpha (TNF-alpha) to SCI pain. TNF-alpha blockers have already been successfully used to treat inflammatory disorders but there are few studies on its effect on neuropathic pain, especially following SCI. Following T13 spinal cord hemisection, we examined the effects on mechanical allodynia and microglial activation of immediate and delayed chronic intrathecal treatment with etanercept, a fusion protein blocker of TNF-alpha. Immediate treatment (starting at the time of injury) with etanercept resulted in markedly reduced mechanical allodynia 1, 2, 3 and 4 weeks after SCI. Delayed treatment had no effect. Immediate etanercept treatment also reduced spinal microglial activation assessed by OX-42 immunostaining, a putative marker of activated microglia. To assess whether the effects of etanercept were mediated via decreased microglial activation, we examined the effects of the microglial inhibitor, minocycline which significantly reduced the development of pain behaviours at 1 and 2 weeks after SCI compared to saline treatment. Minocycline also significantly reduced microglial OX-42 expression. Furthermore, minocycline decreased the expression of noxious-stimulation-induced c-Fos, suggesting an effect on evoked neuronal activity. This study demonstrates that TNF-alpha plays an important role in the establishment of neuropathic pain following SCI, seemingly dependent on microglial activation. Pharmacological targeting of TNF-alpha may offer therapeutic opportunities for treating SCI pain.
Neurorestoration Group, King's College London, Wolfson Wing, Wolfson Centre for Age Related Diseases, Hodgkin Building, Guy's Campus, London SE1 1UL, United Kingdom.
Fabien
F
Marchand
Christoforos
C
Tsantoulas
Dalbinder
D
Singh
John
J
Grist
Anna K
AK
Clark
Elizabeth J
EJ
Bradbury
Stephen B
SB
McMahon
D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D002452:Cell Count; D000068800:Etanercept; D007839:Functional Laterality / Q000502:physiology; D006358:Hot Temperature; D007074:Immunoglobulin G / Q000627:therapeutic use*; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007278:Injections, Spinal; D008297:Male; D017628:Microglia / Q000187:drug effects / Q000502:physiology; D008911:Minocycline / Q000627:therapeutic use*; D010146:Pain / Q000188:drug therapy* / Q000209:etiology*; D010812:Physical Stimulation; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018124:Receptors, Tumor Necrosis Factor / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects; D013119:Spinal Cord Injuries / Q000150:complications* / Q000188:drug therapy*; D048069:Tumor Necrosis Factors / Q000502:physiology
D000900:Anti-Bacterial Agents; D007074:Immunoglobulin G; D007166:Immunosuppressive Agents; D016760:Proto-Oncogene Proteins c-fos; D018124:Receptors, Tumor Necrosis Factor; D048069:Tumor Necrosis Factors; D008911:Minocycline; D000068800:Etanercept