Orphanin FQ/nociceptin (OFQ/N) has been immunohistochemically localized in the rat enteric nervous system, and mRNA signals for its precursor (i.e. prepro-OFQ/-N) and cognate receptor ORL-1 are expressed in the intestinal tract. OFQ/N inhibits neurogenic contractions in a variety of stomach and small intestine preparations in vitro, but contracts rodent colon. In vivo, it acts at peripheral and central nervous system sites to stimulate or inhibit mechanical activity in the stomach and colon, respectively. Thus, OFQ/N acts as a neuromodulator of gastrointestinal motility and may have additional roles in regulation of intestinal blood flow, active ion transport, and immunity.