trk-820 and beta-funaltrexamine

The modulation and selectivity mechanisms of seven mixed-action kappa opioid receptor (KOR)/mu opioid receptor (MOR) bitopic modulators were explored. Molecular modeling results indicated that the 'message' moiety of seven bitopic modulators shared the same binding mode with the orthosteric site of the KOR and MOR, whereas the 'address' moiety bound with different subdomains of the allosteric site of the KOR and MOR. The 'address' moiety of seven bitopic modulators bound to different subdomains of the allosteric site of the KOR and MOR may exhibit distinguishable allosteric modulations to the binding affinity and/or efficacy of the 'message' moiety. Moreover, the 3-hydroxy group on the phenolic moiety of the seven bitopic modulators induced selectivity to the KOR over the MOR.

Topics: Allosteric Regulation; Allosteric Site; Binding Sites; Humans; Ligands; Molecular Docking Simulation; Morphinans; Naltrexone; Protein Binding; Receptors, Opioid, kappa; Receptors, Opioid, mu; Spiro Compounds; Thermodynamics

The role of central mu- and kappa-opioid receptors in the regulation of itch sensation was examined using pruritogen-induced mouse scratching behavior model. Intracerebroventricular administration of beta-funaltrexamine, a selective mu-opioid receptor antagonist, inhibited the scratching behavior induced by intradermal substance P, but subcutaneous administration of beta-funaltrexamine did not. Similarly, the scratching inhibitory activity of subcutaneously administered TRK-820, (-)-17-(cyclopropylmethyl)-3, 14beta-dihydroxy-4, 5alpha-epoxy-6beta-[N-methyl-trans-3-(3-furyl) acrylamido] morphinan hydrochloride, a kappa-opioid receptor agonist, was antagonized by intracerebroventricular administration of nor-binaltorphimine (10 microg/site), a kappa-opioid receptor antagonist, but was not by subcutaneous administration of nor-binaltorphimine. In addition, the scratching induced by the direct activation of central mu-opioid receptor by intracisternal morphine was significantly and dose-dependently inhibited by subcutaneous administration of TRK-820. Taken all together, it is suggested that the central mu-opioid receptors play a role in the processing of itch sensation, and the activation of central kappa-opioid receptors antagonize the central mu-opioid receptor mediated itch processing, thereby suppressing itch sensation.

Topics: Animals; Antipruritics; Behavior, Animal; Injections, Intraventricular; Injections, Subcutaneous; Ketotifen; Male; Mice; Morphinans; Morphine; Motor Activity; Naltrexone; Narcotic Antagonists; Pruritus; Receptors, Opioid, kappa; Receptors, Opioid, mu; Spiro Compounds; Substance P