The purpose of these investigations was to determine 1) whether peripherally located mu, delta and kappa opioid receptors can inhibit the rate of gastrointestinal transit and, if so, 2) do peripheral opioid receptors mediate the constipation caused by systemic morphine? and 3) whether constipation can be separated from analgesia on the basis of different sites of action. We studied the effects of peripherally administered (s.c.) mu, delta and kappa opioid receptor selective agonists on the rate of gastrointestinal transit in mice. We used peptidergic agonists with high peripheral selectivity (limited ability to cross the blood-brain barrier) including [MePhe3,D-Pro4]morphiceptin (PL017) (mu), [D-Pen2,D-Pen5]enkephalin (DPDPE) (delta) and Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Ile-Arg (dynorphin 1-9) (kappa). As peripheral selectivity is dose-related, we included the hot-plate test as an index of that dose at which each compound lost its peripheral selectivity and entered the central nervous system. When given s.c., [MePhe3,D-Pro4]morphiceptin inhibited transit (IC50 = 0.37 mg/kg s.c.) at doses much lower than those needed to produce analgesia (A50 = 30 mg/kg s.c.), indicating that peripheral mu receptors can inhibit transit independently of central mu receptors. The independence of peripheral mu antitransit receptors from central receptors was demonstrated further as the lack of antagonism of s.c. [MePhe3,D-Pro4]morphiceptin antitransit effects by simultaneous i.c.v. administration of the mu receptor antagonist D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Pen-Thr-NH2 (CTP) (1 microgram i.c.v.).(ABSTRACT TRUNCATED AT 250 WORDS)