The 17-amino acid peptide nociceptin/orphanin FQ (N/OFQ) plays a role in the regulation of stress responses and of emotional disorders. The objective of this study is to evaluate whether long-term peripheral N/OFQ could dose- and time-dependently influence the responses to repeated cold-restraint stress on the rat gastric and colonic mucosa. Rats were exposed to cold-restraint stress for 3h per day for 1, 2 and 3 consecutive days. N/OFQ was administered at doses of 0.1, 1 and 10 microg/kg/h via Alzet osmotic minipumps. In the gastric fundus, N/OFQ exerted dose-dependent beneficial effects against acute and repeated stress but, after prolonged treatment, became damaging in non-stressed rats. In the distal colon, N/OFQ exerted a protective effect against damage by acute and repeated stress with no influence on epithelial integrity in non-stressed rats. In both regions, the peptide itself dose- and time-dependently reduced intraepithelial mucins. The reduction in mucin content caused by stress was effectively counteracted by N/OFQ, 0.1 microg/kg/h, in the distal colon only. N/OFQ did not modify basal mucosal cell proliferation. The peptide at 0.1 and 1 microg/kg/h had no influence while at 10 microg/kg/h abolished stress-induced increase in cell proliferation. The present results provide evidence that N/OFQ is implicated in the regulation of resting and stress-challenged mucosal integrity and activity of mucin-producing cells.