Brain-derived TNFalpha mediates neuropathic pain.
Neuropathic pain is a chronic pain state that develops a central component following acute nerve injury. However, the pathogenic mechanisms involved in the expression of this central component are not completely understood. We have investigated the role of brain-associated TNF in the evolution of hyperalgesia in the chronic constriction injury (CCI) model of neuropathic pain. Thermal nociceptive threshold has been assessed in rats (male, Sprague-Dawley) that have undergone loose, chromic gut ligature placement around the sciatic nerve. Total levels of TNF in regions of the brain, spinal cord and plasma have been assayed (WEHI-13VAR bioassay). Bioactive TNF levels are elevated in the hippocampus. During the period of injury, hippocampal noradrenergic neurotransmission demonstrates a decrease in stimulated norepinephrine (NE) release, concomitant with elevated hippocampal TNF levels. Continuous intracerebroventricular (i.c.v.) microinfusion of TNF-antibodies (Abs) starting at four days, but not six days, following ligature placement completely abolishes the hyperalgesic response characteristic of this model, as assessed by the 58 degrees C hot-plate test. Antibody infusion does not decrease spinal cord or plasma levels of TNF. Continuous i.c.v. microinfusion of rrTNF alpha exacerbates the hyperalgesic response by ligatured animals, and induces a hyperalgesic response in animals not receiving ligatures. Likewise, field-stimulated hippocampal adrenergic neurotransmission is decreased upon continuous i.c.v. microinfusion of TNF. These results indicate an important role of brain-derived TNF, both in the pathology of neuropathic pain, as well as in fundamental pain perception.
Ignatowski
T A
TA
Department of Pathology, State University of New York at Buffalo, 14214, USA.
Covey
W C
WC
Knight
P R
PR
Severin
C M
CM
Nickola
T J
TJ
Spengler
R N
RN
D000818:Animals; D001681:Biological Assay; D001921:Brain / Q000502:physiology* / Q000503:physiopathology; D002460:Cell Line; D002552:Cerebral Ventricles / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology; D004558:Electric Stimulation; D006624:Hippocampus / Q000502:physiology*; D006358:Hot Temperature; D066298:In Vitro Techniques; D007263:Infusions, Parenteral; D008297:Male; D009443:Neuritis / Q000503:physiopathology*; D009638:Norepinephrine / Q000378:metabolism*; D017288:Pain Threshold; D051381:Rats; D017207:Rats, Sprague-Dawley; D012584:Sciatic Nerve / Q000502:physiology* / Q000503:physiopathology; D013116:Spinal Cord / Q000502:physiology* / Q000503:physiopathology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000494:pharmacology* / Q000502:physiology*
D014409:Tumor Necrosis Factor-alpha; D009638:Norepinephrine