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

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. British Journal of Pharmacology (2008) 154 , 1135–1142; doi: 10.1038/bjp.2008.166 ; published online 12 May 2008