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

Abstract

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 α (TNFα), interleukin-12, interleukin-6 (IL-6), interleukin-8 (IL-8), prostaglandin Eβ (PGE₂) and dopamine were investigated in a model of mechanical hyperalgesia.

2. Hyperalgesic responses to intraplantar (i.pl.) injections of carrageenin (100 μg), bradykinin (500 ng), TNFα (2.5 pg), IL-1β (0.5 pg), and IL-6 (1.0 ng), but not responses to IL-8 (0.1 ng), PGE₂ (100 ng) and dopamine (10 μg), were inhibited by pretreatment with dexamethasone (0.5 mg kg⁻¹, subcutaneously, s.c., or 0.04–5.0 μg/paw).

3. Inhibition of hyperalgesic responses to injections (i.pl.) of bradykinin (500 ng) and IL-1β (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), TNFα (2.5 pg) and IL-1β (0.5 pg), but not responses to PGE₂ (100 ng), were inhibited by pretreatment with lipocortin-1_2–26 (100 μg/paw). Also, lipocortin-1_2–26 (30 and 100 μg ml⁻¹) and dexamethasone (10 μg ml⁻¹) inhibited TNFα release by cells of the J774 (murine macrophage-like) cell-line stimulated with LPS (3 μg 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 TNFα 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-1β (0.25 pg, i.pl.) was potentiated by arachidonic acid (50 μg) and the potentiated response was inhibited by dexamethasone (50 μg, i.pl.) and lipocortin-1_2–26 (100 μg, i.pl.). Also, lipocortin-1_2–26 (30 and 100 μg ml⁻¹) inhibited/abolished PGE₂ release by J774 cells stimulated with LPS (3 μg 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 TNFα, IL-1β 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.

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