Mechanisms of tumor necrosis factor-alpha (TNF-alpha) hyperalgesia.
Activation of immune cells by pathogens induces the release of a variety of proinflammatory cytokines, including IL-1 beta and TNF-alpha. Previous studies using IL-1 beta have demonstrated that this cytokine can 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 and that this hyperalgesia (as well as most illness responses) is mediated via activation of subdiaphragmatic vagal afferents. The present series of studies were designed to provide an initial examination of the generality of proinflammatory cytokine-induced hyperalgesia by examining the effects of i.p. TNF-alpha on pain responsivity. These studies demonstrate that: (a) i.p. TNF-alpha produces dose-dependent hyperalgesia as measured by the tailflick test, (b) this hyperalgesia is mediated via the induced release of IL-1 beta, (c) hyperalgesia is mediated via activation of subdiaphragmatic vagal afferents, and (d) the effects of subdiaphragmatic vagotomy cannot be explained by a generalized depression of neural excitability.
Department of Psychology, University of Colorado at Boulder 80309, USA.
L R
LR
Watkins
L E
LE
Goehler
J
J
Relton
M T
MT
Brewer
S F
SF
Maier
D000818:Animals; D004305:Dose-Response Relationship, Drug; D005557:Formaldehyde; D006801:Humans; D006930:Hyperalgesia / Q000139:chemically induced* / Q000503:physiopathology; D007274:Injections, Intraperitoneal; D007375:Interleukin-1 / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D017288:Pain Threshold / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors; D011994:Recombinant Proteins / Q000633:toxicity; D014409:Tumor Necrosis Factor-alpha / Q000633:toxicity*; D014628:Vagotomy; D014630:Vagus Nerve / Q000503:physiopathology
D007375:Interleukin-1; D017472:Receptors, Interleukin-1; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D005557:Formaldehyde