CYTOKINES, NERVE GROWTH-FACTOR AND INFLAMMATORY HYPERALGESIA - THE CONTRIBUTION OF TUMOR-NECROSIS-FACTOR-ALPHA

1 Peripheral inflammation is characterized by heightened pain sensitiv ity. This hyperalgesia is the consequence of the release of inflammato ry mediators, cytokines and growth factors. A key participant is the i nduction of the neurotrophin nerve growth factor (NGF) by interleukin- 1 beta (IL-1 beta). 2 Tumour necrosis factor alpha (TNF alpha) has bee n shown both to produce hyperalgesia and to upregulate IL-1 beta. We h ave now examined whether the induction of TNF alpha in inflammatory le sions 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 pla te test and in the mechanical threshold for eliciting the flexion with drawal reflex. 4 The CFA-induced inflammation resulted in significant elevation in the levels of TNF beta, 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 hi ndpaw. No increase in serum TNF alpha was detected at 24 h post CFA in jection. 5 Intraplantar recombinant murine TNF alpha injections produc e a short-lived (3-6 h) dose-dependent (50-500 ng) increase in thermal and mechanical sensitivity which was significantly attenuated by prio r 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 NG F in the hindpaw. 7 A single injection of anti-TNF beta antiserum, 1 h before the CFA, at a dose sufficient to reduce the effects of a 100 n g 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 infla mmation, by virtue of its capacity to induce IL-1 beta and NGF, may co ntribute to the initiation of inflammatory hyperalgesia.