It is known that intracerebroventricular (ICV) administration of a low dose of interleukin-1β (IL-1β) induces hyperalgesia and that this effect can be inhibited by α-melanophore-stimulating hormone (α-MSH). To identify the part of the brain that is affected by hyperalgesia-induced IL-1β and the possible site of α-MSH inhibition, we have examined Fos expression in the rat brain in response to ICV microinjection of α-MSH and/or IL-1β. Following injection of 10 pg IL-1β, hyperalgesia was induced and Fos became expressed in the paraventricular nucleus (PVN) of the hypothalamus and in the arcuate nucleus (ARC), which contains α-MSH-producing neurons. IL-1β injection did not induce Fos expression in the pars intermedia of the pituitary gland, which contains endocrine melanotrope cells that release α-MSH into the systemic circulation. ICV co-injection of IL-1β with 30 ng α-MSH fully inhibited both hyperalgesia and Fos expression in the PVN and the ARC. We conclude that PVN neurons are activated by hyperalgesic IL-1β and propose that this effect is abolished by α-MSH possibly released from the ARC but not from the pituitary gland.