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

Abstract

1 The e ect 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 a (TNFa), interleukin-1 2 , interleukin-6 (IL-6), interleukin-8 (IL-8), prostaglandin Eb (PGE 2 ) and dopamine were investigated in a model of mechanical hyperalgesia. 2 Hyperalgesic responses to intraplantar (i.pl.) injections of carrageenin (100 mg), bradykinin (500 ng), TNFa (2.5 pg), IL-1b (0.5 pg), and IL-6 (1.0 ng), but not responses to IL-8 (0.1 ng), PGE 2 (100 ng) and dopamine (10 mg), were inhibited by pretreatment with dexamethasone (0.5 mg kg 71 , subcutaneously, s.c., or 0.04 ± 5.0 mg/paw). 3 Inhibition of hyperalgesic responses to injections (i.pl.) of bradykinin (500 ng) and IL-1b (0.5 pg) by dexamethasone (0.5 mg kg 71 , s.c.) was reversed by LCPS1 (0.5 ml kg 71 , injected s.c., 24 h and 1 h before hyperalgesic substances) and hyperalgesic responses to injections (i.pl.) of bradykinin (500 ng), TNFa (2.5 pg) and IL-1b (0.5 pg), but not responses to PGE 2 (100 ng), were inhibited by pretreatment with lipocortin-1 2 ± 26 (100 mg/paw). Also, lipocortin-1 2 ± 26 (30 and 100 mg ml 71 and dexamethasone (10 mg ml 71 ) inhibited TNFa release by cells of the J774 (murine macrophage-like) cell-line stimulated with LPS (3 mg ml 71 ), 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 e ect of dexamethasone, with inhibiton of TNFa 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-1b (0.25 pg, i.pl.) was potentiated by arachidonic acid (50 mg) and the potentiated response was inhibited by dexamethasone (50 mg, i.pl.) and lipocortin-1 2 ± 26 (100 mg, i.pl.). Also, lipocortin-1 2 ± 26 (30 and 100 mg ml 71 ) inhibited/abolished PGE 2 release by J774 cells stimulated with LPS (3 mg ml 71 ). These data suggest that, in in¯ammatory hyperalgesia, inhibition of the induction of cyclo-oxygenase 2 (COX-2), rather than phospholipase A 2 , by dexamethasone and lipocortin-1 2 ± 26 accounts for the antihyperalgesic e ects 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 in¯ammatory hyperalgesia evoked by carrageenin, bradykinin and the cytokines TNFa, IL-1b 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 e ect of lipocortin-1.

A Novel Effect for Annexin 1-Derived Peptide Ac2-26: Reduction of Allergic Inflammation in the Rat

“…A number of studies have provided evidence for the involvement of this protein in the regulation by glucocorticoids of neutrophil migration , inflammatory edema (Cirino et al, 1989), ischemic damage (Cuzzocrea et al, 1997), pain (Ferreira et al, 1997), and fever (Davidson et al, 1991). Nevertheless, it is clear that annexin 1 modulation is not the only mechanism of glucocorticoid action that can involve a variety of mechanisms, including direct and indirect genomic routes and other annexin 1-independent signaling effects (Hannon et al, 2003).…”

“…This peptide of 25 amino acids inhibits tissue recruitment of neutrophils caused by different stimuli in vivo . Peptide Ac2-26 can also reproduce the anti-inflammatory effect of annexin 1 in other processes, including hyperalgesia (Ferreira et al, 1997) and tissue injury caused by artery occlusion and reperfusion shock (Cuzzocrea et al, 1997). The hypothesis that the annexin 1 fragment might be able to affect allergen-induced eosinophil recruitment was previously investigated in a mouse skin model (Teixeira et al, 1998).…”

Cytokine inhibitors and pain control

“…Furthermore, there is evidence that the antinociceptive effects of dexamethasone are, at least in part, mediated by annexin-1 (previously designated lipocortin-1). The lipocortin-1-mediated glucocorticoids antinociceptive effect was demonstrated by Ferreira et al (95) , using the rat paw constant pressure test. The inhibition of hypernociceptive responses to injections of bradykinin and IL-1β by dexamethasone was reversed by antiserum anti-lipocortin-1, injected subcutaneously, 24h and 1h before hypernociceptive substances.…”

Untitled

“…IL-1β has been identified as one of many algogenic agents that may play a role in neuropathic pain. In the periphery, IL-1β itself results in prolonged hyperalgesia and allodynia after intraplantar 88 , intraperitoneal 89 and intrathecal 90 administration.…”