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


METHODS
The acetic acid-induced writhing response was performed in ANXA1-/- and wild-type (ANXA1+/+) mice with spinal and brain levels of prostaglandin E2 (PGE2) examined in both genotypes. The effect of the ANXA1 peptomimetic Ac2-26 as well as methylprednisolone on the writhing response and on spinal cord PGE2 of ANXA1+/+ and ANXA1-/- was compared. The expression of proteins involved in PGE2 synthesis, cytosolic phospholipase A2 (cPLA2) and cyclooxygenases (COXs), in the spinal cord of ANXA1+/+ and ANXA1-/- was also compared.


RESULTS
ANXA1-/- mice exhibited a significantly greater writhing response and increased spinal cord levels of PGE2 compared with ANXA1+/+ mice. Ac2-26 produced analgesia and reduced spinal PGE2 levels in ANXA1+/+ and ANXA1-/- mice, whereas methylprednisolone reduced the writhing response and spinal PGE2 levels in ANXA1+/+, but not in ANXA1-/- mice. The expression of cPLA2, COX-1, COX-2 and COX-3 in spinal cord tissues was upregulated in ANXA1-/-compared with ANXA1+/+.


CONCLUSIONS
We conclude that ANXA1 protein modulates nociceptive processing at the spinal level, by reducing synthesis of PGE2 by modulating cPLA2 and/or COX activity. The analgesic activity of methylprednisolone is mediated by spinal ANXA1.
Ayoub
S S
SS
Centre for Biochemical Pharmacology, William Harvey Research Institute, St Bart's and the London School of Medicine and Dentistry, Queen Mary, University of London, Charterhouse Square, London, UK. s.s.ayoub@qmul.ac.uk
Yazid
S
S
Flower
R J
RJ
D019342:Acetic Acid; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D017305:Annexin A1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D015232:Dinoprostone / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005938:Glucocorticoids / Q000494:pharmacology; D008297:Male; D008775:Methylprednisolone / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010146:Pain / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D010147:Pain Measurement; D010455:Peptides / Q000494:pharmacology; D054510:Phospholipases A2, Cytosolic / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013116:Spinal Cord / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism
D000700:Analgesics; D017305:Annexin A1; D005938:Glucocorticoids; D010455:Peptides; C096153:annexin A1 peptide (2-26); D011451:Prostaglandin-Endoperoxide Synthases; D054510:Phospholipases A2, Cytosolic; D015232:Dinoprostone; D019342:Acetic Acid; D008775:Methylprednisolone