Blockade of inflammatory hyperalgesia and cyclooxygenase-2

Abstract

Although the final peripheral hyperalgesic mediators in most inflammatory reactions are cyclooxygenase (COX) products a cascade of cytokines precedes their release. At the onset of the inflammatory response resident cells, particularly macrophages, act as alarm cells, signalling the presence of foreign or deleterious stimuli via the release of cytokines. Using specific antisera and COX inhibitors we have demonstrated that interleukin-lβ (IL-1β) is a key cytokine for the release of prostaglandins (PG). The release of IL-1β is preceded by the liberation of other cytokines such as tumour necrosis factor-α (TNFα) and interleukin-6 (IL-6). In inflammation increased production of PG is thought to result from the induction of phospholipase A₂ (PLA₂) and/or COX-2 by IL-1β. However, local administration into the paw of arachidonic acid in a dose that does not itself cause hyperalgesia strongly potentiates the intraplantar effect of IL-lβ or carrageenan, suggesting that induction of COX-2 is a limiting process in the development of inflammatory hyperalgesia. Induction of COX-2 is typically inhibited by corticosteroids. In our system IL-1β -induced hyperalgesia is inhibited by dexamethasone through the release of lipocortin.