Brain-derived TNF alpha mediates neuropathic pain

Neuropathic pain is a chronic pain state that develops a central component following acute nerve injury. However, the pathogenic mechanisms involved i n the expression of this central component are not completely understood. W e have investigated the role of brain-associated TNF in the evolution of hy peralgesia in the chronic constriction injury (CCI) model of neuropathic pa in. Thermal nociceptive threshold has been assessed in rats (male, Sprague- Dawley) that have undergone loose, chromic gut Ligature placement around th e sciatic nerve. Total levels of TNF in regions of the brain, spinal cord a nd plasma have been assayed (WEHI-13VAR bioassay). Bioactive TNF levels are elevated in the hippocampus. During the period of injury, hippocampal nora drenergic neurotransmission demonstrates a decrease in stimulated norepinep hrine (NE) release, concomitant with elevated hippocampal TNF levels. Conti nuous intracerebroventricular (i.c.v.) microinfusion of TNF-antibodies (Abs ) starting at four days, but not six days, following ligature placement com pletely abolishes the hyperalgesic response characteristic of this model, a s assessed by the 58 degrees C hot-plate test. Antibody infusion does not d ecrease spinal cord or plasma levels of TNF. Continuous i.c.v. microinfusio n of rrTNF alpha exacerbates the hyperalgesic response by ligatured animals , and induces a hyperalgesic response in animals not receiving Ligatures. L ikewise, field-stimulated hippocampal adrenergic neurotransmission is decre ased 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. (C) 1999 Elsevier Science B.V. All rights reserved.