title: Cytokines, nerve growth factor and inflammatory hyperalgesia: the contribution of tumour necrosis factor alpha.
abstract: 1. Peripheral inflammation is characterized by heightened pain sensitivity. This hyperalgesia is the consequence of the release of inflammatory mediators, cytokines and growth factors. A key participant is the induction of the neurotrophin nerve growth factor (NGF) by interleukin-1 beta (IL-1 beta). 2. Tumour necrosis factor alpha (TNF alpha) has been shown both to produce hyperalgesia and to upregulate IL-1 beta. We have now examined whether the induction of TNF alpha in inflammatory lesions contributes to inflammatory sensory hypersensitivity by inducing IL-1 beta and NGF. 3. The intraplantar injection of complete Freund's adjuvant (CFA) in adult rats produced a localized inflammation of the hindpaw with a rapid (3 h) reduction in withdrawal time in the hot plate test and in the mechanical threshold for eliciting the flexion withdrawal reflex. 4. The CFA-induced inflammation resulted in significant elevation in the levels of TNF alpha, IL-1 beta and NGF in the inflamed paw. In the case of TNF alpha, an elevation was detected at 3 h, rose substantially at 6 h, peaked at 24 h and remained elevated at 5 days, with similar but smaller changes in the contralateral non-inflamed hindpaw. No increase in serum TNF alpha was detected at 24 h post CFA injection. 5. Intraplantar recombinant murine TNF alpha injections produce a short-lived (3-6 h) dose-dependent (50-500 ng) increase in thermal and mechanical sensitivity which was significantly attenuated by prior administration of anti-NGF antiserum. 6. Intraplantar TNF alpha (100-500 ng) also elevated at 6 but not 48 h the levels of IL-1 beta and NGF in the hindpaw. 7. A single injection of anti-TNF alpha antiserum, 1 h before the CFA, at a dose sufficient to reduce the effects of a 100 ng intraplantar injection of TNF alpha, significantly delayed the onset of the resultant inflammatory hyperalgesia and reduced IL-1 beta but not NGF levels measured at 24 h. 8. The elevation of TNF alpha in inflammation, by virtue of its capacity to induce IL-1 beta and NGF, may contribute to the initiation of inflammatory hyperalgesia.
authors.affiliation: Department of Anatomy and Developmental Biology, University College London.
authors.forename: C J
authors.initials: CJ
authors.lastname: Woolf
authors.forename: A
authors.initials: A
authors.lastname: Allchorne
authors.forename: B
authors.initials: B
authors.lastname: Safieh-Garabedian
authors.forename: S
authors.initials: S
authors.lastname: Poole
mesh_terms: D000818:Animals; D006930:Hyperalgesia / Q000209:etiology*; D007249:Inflammation / Q000503:physiopathology*; D007375:Interleukin-1 / Q000494:pharmacology; D008297:Male; D009414:Nerve Growth Factors / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
chemical_list: D007375:Interleukin-1; D009414:Nerve Growth Factors; D014409:Tumor Necrosis Factor-alpha