Role of lipocortin-1 in the anti-hyperalgesic actions of dexamethasone.

1. The effect of dexamethasone, lipocorton-1(2-26) and an antiserum to lipocortin-1(2-26) (LCPS1) upon the hyperalgesic activities in rats of carrageenin, bradykinin, tumour necrosis factor alpha (TNF alpha), interleukin-1(2), interleukin-6 (IL-6), interleukin-8 (IL-8), prostaglandin E beta (PGE2) and dopamine were investigated in a model of mechanical hyperalgesia. 2. Hyperalgesic responses to intraplantar (i.pl.) injections of carrageenin (100 micrograms), bradykinin (500 ng), TNF alpha (2.5 pg), IL-1 beta (0.5 pg), and IL-6 (1.0 ng), but not responses to IL-8 (0.1 ng), PGE2 (100 ng) and dopamine (10 micrograms), were inhibited by pretreatment with dexamethasone (0.5 mg kg-1, subcutaneously, s.c., or 0.04-5.0 micrograms/paw). 3. Inhibition of hyperalgesic responses to injections (i.pl.) of bradykinin (500 ng) and IL-1 beta (0.5 pg) by dexamethasone (0.5 mg kg-1, s.c.) was reversed by LCPS1 (0.5 ml kg-1, injected s.c., 24 h and 1 h before hyperalgesic substances) and hyperalgesic responses to injections (i.pl.) of bradykinin (500 ng), TNF alpha (2.5 pg) and IL-1 beta (0.5 pg), but not responses to PGE2 (100 ng), were inhibited by pretreatment with lipocortin-1(2-26) (100 micrograms/paw). Also, lipocortin-1(2-26) (30 and 100 micrograms ml-1 and dexamethasone (10 micrograms ml-1) inhibited TNF alpha release by cells of the J774 (murine macrophage-like) cell-line stimulated with LPS (3 micrograms ml-1), and LCPS1 partially reversed the inhibition by dexamethasone. These data are consistent with an important role for endogenous lipocortin-1(2-26) in mediating the anti-hyperalgesic effect of dexamethasone, with inhibiton of TNF alpha production by lipocortin-1(2-26) contributing, in part, to this role. 4. Although arachidonic acid by itself was not hyperalgesic, the hyperalgesic response to IL-1 beta (0.25 pg, i.pl.) was potentiated by arachidonic acid (50 micrograms) and the potentiated response was inhibited by dexamethasone (50 micrograms, i.pl.) and lipocortin-1(2-26) (100 micrograms, i.pl.). Also, lipocortin-1(2-26) (30 and 100 micrograms ml-1) inhibited/abolished PGE2 release by J774 cells stimulated with LPS (3 micrograms ml-1). These data suggest that, in inflammatory hyperalgesia, inhibition of the induction of cyclo-oxygenase 2 (COX-2), rather than phospholipase A2, by dexamethasone and lipocortin-1(2-26) accounts for the anti-hyperalgesic effects of these agents. 5. The above data support the notion that induction of lipocortin by dexamethasone plays a major role in the inhibition by dexamethasone of inflammatory hyperalgesia evoked by carrageenin, bradykinin and the cytokines TNF alpha, IL-1 beta and IL-6, and provides additional evidence that the biological activity of lipocortin resides within the peptide lipocortin-1(2-26). Further, the data suggest that inhibition of lipocortin-1(2-26) of eicosanoid production by COX-2 also contributes to the anti-hyperalgesic effect of lipocortin-1.