Nocistatin is a peptide derived from the pronociceptin precursor, the source of nociceptin, the endogenous ligand for the nociceptin (NOP or ORL1). Despite nocistatin showing activity in a wide range of assays for nociception and other CNS activities, there is a dearth of information regarding the cellular actions of this peptide in the brain, and no receptor for nocistatin has been identified. In a study published in this issue of the British Journal of Pharmacology, Fantin and colleagues demonstrate that nocistatin inhibits 5-HT release from cortical synaptosomes in a concentration-dependent and Pertussis toxin-sensitive manner. The actions of nocistatin are independent of activity at NOP receptors. This study represents the first unambiguous demonstration of nocistatin agonist actions in brain and, taken together with previous work in the spinal cord, provides strong evidence that there is an as yet unidentified G protein-coupled receptor for nocistatin.