2-Arylacetamido-4-phenylamino-5-substituted pyridazinones as formyl peptide receptors agonists.
In this study we investigated how the peptides derived from the glucocorticoid-inducible protein annexin 1 are able to alter the nociceptive threshold of mice. The effects of the annexin1 fragment 2-26 (Anxa1(2-26)) on nociceptive threshold were studied using both chemical (formalin test) and thermal (hot plate and tail flick test) nociceptive stimuli on mice. Subcutaneous administration of Anxa1(2-26) into the dorsal surface of the mouse's hind paw was able to selectively reduce formalin-induced nociceptive behavior in the last phase of the test. The same effect was observed after intracerebroventricular administration, however, this was not the case when performing the hot plate or tail flick tests. Of the shortest Anxa1(2-26)-derived peptides, Anxa1(2-12) reduced the nociceptive response to formalin, however, the Anxa1(2-6) did not. The possible involvement of the receptors for formylated peptide in the anti-nociceptive action of Anxa1(-26) and Anxa1(2-12) was studied, choosing the formalin test. We found that the formyl peptide receptor agonist formyl-MLF (fMLF) induced anti-nociceptive effects in the formalin test both after the peripheral and central administration. The formyl peptide receptor antagonist N-t-butoxycarbonyl-MLP did not alter the response to formalin, but it was able to block the anti-nociceptive effects of Anxa1(2-26,) Anxa1(2-12) and fMLF after peripheral or central administration. These results indicate that exogenously administered Anxa1 can peripherally and centrally inhibit the nociceptive transmission associated with inflammatory processes through a mechanism that involves formyl peptide receptors.