dihydromorphine and beta-funaltrexamine

The involvement of delta opioid receptors in supraspinal analgesia was investigated. With this aim, opioids that produced analgesia in the tail immersion test were administered i.c.v. to mice a few minutes before the irreversible antagonist, beta-funaltrexamine (beta-FNA). Protection of the respective analgesic effects from beta-FNA blockade was obtained when evaluated 24 h later. Moreover, mu ligands protected the analgesia evoked by ED50s of morphine, [D-Ala2,N-Me-Phe4,Met-(o)5-ol]enkephalin (FK 33-824), [D-Ala2,N-Me-Phe4,Gly-ol5]enkephalin (DAGO) and human beta-endorphin at doses (ED50s) lower than those required for delta ligands (approximately ED90s) to reach a similar protection. delta Preferential ligands effectively protected the analgesia induced by ED50s of [D-Ala2,D-Leu5]enkephalin (DADLE), [D-Thr2,Leu5]enkephalin-Thr6 (DTLET) and [D-Pen2,D-Pen5]enkephalin (DPDPE) from the beta-FNA-deteriorating effect. FK 33-824 and DAGO also provided good protection of the analgesia elicited by these delta ligands whereas morphine protected much less. Binding studies after i.c.v. injection of beta-FNA showed that its alkylating effect on opioid receptors was restricted to periventricular areas. In PAG, where the mu/delta receptor ratio is about 10, [3H]DADLE specific binding was still present after ED50s of DPDPE, DAGO, morphine and DADLE as protecting agents. [3H]Dihydromorphine [( 3H]DHM) binding was well protected by ED90s of morphine and DAGO, and to a lesser extent by DPDPE and DADLE. These results suggest that delta ligands, after binding to delta receptors, also need to act upon mu receptors to produce high levels of supraspinal analgesia in the tail immersion test.

Topics: Analgesics, Opioid; Animals; Brain Chemistry; Dihydromorphine; Endorphins; Enkephalin, Leucine; Enkephalin, Leucine-2-Alanine; In Vitro Techniques; Injections, Intraventricular; Male; Mice; Morphine; Naltrexone; Narcotic Antagonists; Pain Measurement; Receptors, Opioid; Receptors, Opioid, delta

beta-Funaltrexamine (beta-FNA) potently competed with the binding of a series of radiolabeled opiates and opioid peptides in standard binding assays with IC50 values under 10 nM. In addition, higher concentrations of beta-FNA produced an irreversible inhibition of binding which was relatively selective for mu receptors; delta binding was not affected much. The production of irreversible inhibition of [3H]dihydromorphine binding required concentrations of beta-FNA over 10-fold higher than beta-FNA concentrations needed in standard competition studies. Both mu 1 and mu 2 sites were irreversibly inhibited by beta-FNA, but mu 1 sites were more sensitive. The reversible and irreversible inhibition in these in vitro binding assays by beta-FNA were quite similar to naloxonazine. However, the activity of beta-FNA in the guinea-pig ileum suggests that it may not distinguish between mu 1 and mu 2 receptors as effectively as naloxonazine in bioassays and in vivo.

Topics: Animals; Binding, Competitive; Dihydromorphine; Enkephalin, Leucine; Enkephalin, Leucine-2-Alanine; In Vitro Techniques; Male; Morphine; Naloxone; Naltrexone; Narcotic Antagonists; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, Opioid, mu

A series of ester homologues 2-5 of the mu receptor nonequilibrium antagonist beta-funaltrexamine (1, beta-FNA) was synthesized. These ligands were of interest in our investigation of the relationship between the structure of the ester function and the ability to irreversibly block mu opioid receptors. While all of the ligands were potent reversible agonists in the guinea pig ileum (GPI) and mouse vas deferens (MVD) preparations, most appeared to behave as irreversible antagonists of morphine. The benzyl 5 and phenethyl 6 esters possessed irreversible mu antagonist potency that was of similar magnitude to that of beta-FNA in the GPI. In the MVD, all esters appeared to irreversibly block the agonist effect of morphine, but none of the compounds irreversibly antagonized [D-Ala2,D-Leu5]enkephalin to a significant degree. [3H]Dihydromorphine displacement studies revealed no relationship between the affinity of the esters 1-6 and the irreversible blockage of mu receptors in the GPI or MVD. Possible reasons for the observed structure-activity relationship are discussed.

Topics: Animals; Dihydromorphine; In Vitro Techniques; Morphine; Naltrexone; Narcotic Antagonists; Rats; Receptors, Opioid; Receptors, Opioid, mu; Structure-Activity Relationship