Nociceptin/orphanin FQ is a 17 amino acid peptide which acts as a potent endogenous agonist of the opioid receptor-like 1 (ORL1) receptor. ORL1 receptor is a G protein-coupled unique member of the cloned opioid receptor family. We have investigated the effects of nociceptin (1, 10 and 100 nM) on the temperature sensitivity of neurons from the preoptic area of the anterior hypothalamus (PO/AH) in rat brain slices. The body temperature of male Wistar rats was measured after intrahypothalamic application of nociceptin (1 nM) via cannulas in the PO/AH. Low dose nociceptin (1 nM) significantly increased (p < 0.05) temperature sensitivity (TC) of warm-sensitive PO/AH neurons, while the high concentration (100 nM) decreased TC in both warm-sensitive and temperature-insensitive neurons. Similar agonistic activity was obtained after addition of [Phe1 psi (CH2-NH) Gly2]-nociceptin-(1-13)-NH2 (1, 10 and 100 nM), recently proposed to be a selective antagonist of the nociceptin receptor. Neither antagonism nor additive synergism were observed when nociceptin and [Phe1 psi (CH2-NH) Gly2]-nociceptin-(1-13)-NH2 were applied simultaneously in equimolar concentrations. The selective opioid OP3 receptor antagonist CTOP, the selective opioid OP2 receptor antagonist nor-binaltorphimine and selective opioid OP1 receptor antagonist naltrindol had no influence on the effects of nociceptin on temperature sensitivity in PO/AH neurons. In vivo experiments showed that nociceptin (1 nM; 1 microliter/rat) significantly decreased body temperature (p < 0.05) between 30 and 60 min after intrahypothalamic application. These data are in agreement with the hypothesis that the specific action of endogeous substances on body temperature appears to be closely related to a specific change in the temperature sensitivity of warm-sensitive PO/AH neurons.