A recently developed series of highly selective and systemically active delta-agonists such as Tyr-X-Gly-Phe-Leu-Thr(OtBu), with X = D.Ser (OtBu) in BUBU and X = D.Cys(StBu) in BUBUC, and complete inhibitors of enkephalin metabolism (Kelatorphan, RB 38 A, PC 12) have enabled the major role played by mu-opioid receptors in supraspinal analgesia to be demonstrated. This is in agreement with the results of in vivo mu-receptor occupancy measured by taking into account the cross-reactivity of the delta-ligands for mu-sites. In contrast, mu and delta binding sites seem to act independently to control pain at the spinal level. Strong analgesic effects, especially in arthritic rats, can also be obtained by complete protection of tonically or phasically released endogenous enkephalins with mixed inhibitors such as RB38A. Chronic icv administration of the mu agonist DAGO, led to a severe naloxone precipitated withdrawal syndrome whilst a weak dependence was seen with the delta agonist, DSTBULET or with RB 38 A. Moreover, mixed inhibitors did not induce any significant respiratory depression. All these data emphasize the interest in developing delta-agonists and mixed inhibitors with appropriate bioavailability for clinical evaluation.