MECHANISMS OF TUMOR-NECROSIS-FACTOR-ALPHA (TNF-ALPHA) HYPERALGESIA

Activation of immune cells by pathogens induces the release of a varie ty of proinflammatory cytokines, including IL-1 beta and TNF-alpha. Pr evious studies using IL-1 beta have demonstrated that this cytokine ca n alter brain function, resulting in a variety of 'illness responses' including increased sleep, decreased food intake, fever, etc. We have recently demonstrated that i.p. IL-1 beta also produces hyperalgesia a nd that this hyperalgesia (as well as most illness responses) is media ted via activation of subdiaphragmatic vagal afferents. The present se ries of studies were designed to provide an initial examination of the generality of proinflammatory cytokine-induced hyperalgesia by examin ing the effects of i.p. TNF-alpha on pain responsivity. These studies demonstrate that: (a) i.p. TNF-alpha produces dose-dependent hyperalge sia as measured by the tailflick test, (b) this hyperalgesia is mediat ed via the induced release of IL-1 beta, (c) hyperalgesia is mediated via activation of subdiaphragmatic vagal afferents, and (d) the effect s of subdiaphragmatic vagotomy cannot be explained by a generalized de pression of neural excitability.