There is a strong pharmacological rationale for the development of mixed opioid µ agonist/δ antagonists as analgesics with no or low propensity to produce tolerance and dependence. Bifunctional compounds with this profile would interact with distinct non-interacting µ and δ opioid receptors and the lack of tolerance/dependence development would be due to interactions at the systems level. Alternatively, a bivalent ligand containing a µ agonist and a δ antagonist component connected via a linker of the correct length could simultaneously interact with µ and δ binding sites in a putative µ/δ receptor heterodimer. However, on the basis of simple thermodynamic considerations, the modest binding affinity increases seen with such “bivalent” µ/δ ligands as well as with “bivalent” ligands proposed to interact with other G-protein-coupled receptor heterodimers do not support a bivalent binding mode. Bifunctional compounds may contain integrated, overlapping or distinct pharmacophores. As expected, a µ agonist/δ antagonist tetrapeptide of the integrated pharmacophore type, DIPP-NH2[Ψ], given i.c.v. produced potent antinociception in the rat tail-flick assay, little tolerance and no physical dependence. In an effort to develop a µ agonist/δ antagonist capable of crossing the blood-brain barrier (BBB), a series of chimeric peptides containing the µ agonist [Dmt1]DALDA linked to a δ antagonist of the TIPP family were synthesized. In these bifunctional compounds [Dmt1]DALDA plays a dual role as potent analgesic in both acute and neuropathic pain models1,2 and as vector for carrying the entire peptide construct across the BBB. Several of these compounds showed the expected µ agonist/δ antagonist profile in vitro. One of them given s.c. was a potent centrally acting analgesic and, in comparison with morphine, was longer acting and produced less tolerance. These results indicate that systemically active, bifunctional opioid peptides of this type look promising as drug candidates for chronic pain treatment.