Increased susceptibility of annexin-A1 null mice to nociceptive pain is indicative of a spinal antinociceptive action of annexin-A1

Abstract

Background and purpose: Annexin-A1 (ANXA1), a glucocorticoid-regulated protein, mediates several of the anti-inflammatory actions of the glucocorticoids. Previous studies demonstrated that ANXA1 is involved in pain modulation. The current study, using ANXA1 knockout mice (ANXA1 -/-), is aimed at addressing the site and mechanism of the modulatory action of ANXA1 as well as possible involvement of ANXA1 in mediating the analgesic action of glucocorticoids. Experimental approach: The acetic acid-induced writhing response was performed in ANXA1 -/- and wild-type (ANXA1 +/+) mice with spinal and brain levels of prostaglandin E 2 (PGE 2) examined in both genotypes. The effect of the ANXA1 peptomimetic Ac2-26 as well as methylprednisolone on the writhing response and on spinal cord PGE 2 of ANXA1 +/+ and ANXA1 -/- was compared. The expression of proteins involved in PGE 2 synthesis, cytosolic phospholipase A 2 (cPLA 2) and cyclooxygenases (COXs), in the spinal cord of ANXA1 +/+ and ANXA1 -/- was also compared. Key results: ANXA1 -/- mice exhibited a significantly greater writhing response and increased spinal cord levels of PGE 2 compared with ANXA1 +/+ mice. Ac2-26 produced analgesia and reduced spinal PGE 2 levels in ANXA1 +/+ and ANXA1 -/- mice, whereas methylprednisolone reduced the writhing response and spinal PGE 2 levels in ANXA1 +/+, but not in ANXA1 -/- mice. The expression of cPLA 2, COX-1, COX-2 and COX-3 in spinal cord tissues was upregulated in ANXA1 -/-compared with ANXA1 +/+. Conclusions and implications: We conclude that ANXA1 protein modulates nociceptive processing at the spinal level, by reducing synthesis of PGE 2 by modulating cPLA 2 and/or COX activity. The analgesic activity of methylprednisolone is mediated by spinal ANXA1. © 2008 Nature Publishing Group All rights reserved.