We showed that somatostatin (SST) exerts anti-inflammatory and anti-nociceptive effects through somatostatin receptor subtypes 4 and 1 (sst(4)/sst(1)). Since cortistatin (CST) is a structurally similar peptide, we aimed at comparing the sst(1)- and sst(4)-binding and activating abilities, as well as the effects of SST-14 and CST-14 on inflammatory and nociceptive processes. CST-14 concentration-dependently displaced radiolabeled SST-14 binding, induced similar sst(1) and sst(4)-activation with a less potency, and exerted significantly greater inhibitory effect on endotoxin-stimulated interleukin (IL)-1β production of murine peritoneal macrophages. Capsaicin-induced calcitonin gene-related peptide release from peripheral sensory nerve terminals of isolated rat tracheae was significantly decreased by 2 μM CST and 100 nM SST, but concentration-response correlation was not found. Mustard oil-evoked acute neurogenic plasma protein extravasation in the rat hindpaw skin, carrageenan-induced mouse paw edema, mechanical hyperalgesia, and IL-1β, tumor necrosis factor-α production, as well as mild heat injury-evoked thermal hyperalgesia were similarly attenuated by both peptides. In the latter case, i.pl. and i.p. injections exerted equal inhibitory actions. CST-14 and SST-14 similarly diminish both acute neurogenic and cellular inflammatory processes, as well as mechanical and heat hyperalgesia, in which their inhibitory effect on sensory nerve endings is likely to be involved. However, CST-14 exerts remarkably greater inhibition on cytokine production.