BRAIN PASSAGE OF BUBU, A HIGHLY SELECTIVE AND POTENT AGONIST FOR DELTA-OPIOID RECEPTORS - INVIVO BINDING AND MU-RECEPTORS VERSUS DELTA-RECEPTORS OCCUPANCY

The peptidase-resistance and bioavailability of BUBU [H-Tyr-D.Ser(OtBu)-Gly-Phe-Leu-Thr(OtBu)-OH], a highly selective and potent agonist of the delta-opioid receptor, have been investigated in vitro and in vivo. In vitro at 37-degrees-C, the peptide was fully resistant to degradation by rat serum and strongly resistant to degradation by rat brain membranes. In vivo 0.065% of the dose of [H-3]BUBU injected intravenously to the mouse was present 15 min later in the brain. The percentage determined for [H-3]DAGO [H-Tyr-D.Ala-Gly-(NMe)Phe-Gly-ol], a selective ligand for mu-sites, was 0.038%. Specific binding to mouse brain membranes, determined after intracerebroventricular injection of [H-3]BUBU, was saturable and a high affinity (K(Dapp) = 25 pmol) was evaluated for the delta-agonist. Competition experiments showed that BUBU is a selective ligand for delta-receptors in vivo. Comparisons of the analgesic potency (hot plate test) of ICV of IV administered increasing doses of BUBU and DAGO with their in vivo binding properties supports the preferential involvement of mu-receptors in supraspinal analgesia. BUBU also induced an increase in spontaneous locomotion after IV administration at a dose lower than that which produced analgesia. The quantitative results obtained in the present study demonstrate that BUBU and DAGO could be used to characterize the pharmacological responses induced by selective stimulation of delta and mu-receptors after systemic administration.