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

Abstract

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. 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). 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. 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. 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.