The N-formyl peptide receptors (FPRs) are a family of G-protein coupled receptors that respond to pro-inflammatory N-formylated bacterial peptides (e.g. formyl-Met-Leu-Phe, fMLP) and, thus, contribute to the host response to bacterial infection. A growing body of evidence suggests that some members of this receptor family may also be targets for certain anti-inflammatory molecules, e.g. lipoxins and annexin 1 (ANXA1), a mediator of glucocorticoid (GC) action in the host defence system. To explore further the potential role of FPRs in mediating ANXA1 actions, we have focused on the pituitary gland, where ANXA1 has a well-defined role as a cell-cell mediator of the inhibitory effects of GCs on the secretion of corticotrophin (ACTH), and used well-established in vitro rodent preparations as experimental models together with molecular, pharmacological and transgenic approaches. RT-PCR analysis identified mRNAs for four FPR family members in the mouse anterior pituitary gland, Fpr-rs1, Fpr-rs2, Fpr-rs6 and Fpr-rs7. Functional studies confirmed that like GCs, ANXA1 and two ANXA1-derived peptides (ANXA11-188 and ANXA1Ac2-26) inhibit the evoked release of ACTH from rodent anterior pituitary tissue in vitro. The actions of ANXA1 were mimicked by lipoxin A4 (LXA4, 0.02-2µM, a lipid mediator with high affinity for Fpr-rs1) and by high (1-100µM) but not lower (10-100nM) concentrations of fMLP. Boc1 (100µM), a non-selective FPR antagonist, effectively antagonised inhibitory effects of dexamethasone, ANXA11-188, ANXA1Ac2-26, fMLP and LXA4 on ACTH release, although at a lower concentration (50μM) it was without effect. The suppressive effects of dexamethasone or ANXA1Ac2-26 on ACTH release were not affected by Fpr1 gene deletion. Similarly, at low concentrations sufficient for selective activation of Fpr1 (10-100nM), fMLP failed to modify ACTH release. Together the results suggest that the actions of ANXA1 in the pituitary gland are independent of Fpr1 but may involve other FPR family members, in particular, Fpr-rs1. They thus provide the first evidence for a role of this receptor family in the regulation of neuroendocrine function.