Abstract Interleukin-1β (IL-1β) stimulates corticotropin-releasing hormone (CRH) secretion in hypothalamus, which involves the release of prostaglandins (PGE2) and nitric oxide (NO). We have demonstrated that melanocortins can inhibit the early effects of IL-1β on the HPA axis by acting on the central nervous system (CNS). Our study investigated whether α-melanocyte stimulating hormone (α-MSH) and γ-MSH could inhibit IL-1β-induced PGE2 and NO release in hypothalamus in the rapid activation of the HPA axis. An i.c.v. injection of 12.5 ng/μl of IL-1β significantly increased the release of PGE2 and NOS activity in the hypothalamus. Treatment with α-MSH (0.1 μg/μl) inhibited the effect of IL-1β on PGE2 release. Also, γ-MSH (1 μg/μl) eliminated the increase in NOS activity induced by IL-1β. Our data indicate the modulatory role of melanocortins in the early hypothalamic response to IL-1β, with different regulation of PGE2 and NO release.