Our principal object is the continuation of the investigation of the physiological role of the endogenous opioid peptides by correlating the results obtained from the binding at the three major mu, delta-, and kappa-sites with those obtained in pharmacological experiments. One of the important problems is the coupling mechanism between binding of an opioid ligand and the response of the effector system. In this respect, the investigation of the differences found in the binding of selective ligands at mu-, delta-, and kappa-sites and their modulation by monovalent and divalent cations and by guanyl nucleotides will be continued. The selective agonists are the mu-ligand (3H)-(D-Ala2,MePhe4,Gly-ol5)enkephalin, the delta-ligand (3H)-(D-Pen2,D-Pen5)enkephalin and the kappa- ligands (3H)-dynorphin A (1-9) and (3H)-U-69,593. It is of particular importance to extend this investigation to use the selective mu-antagonist D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP; V.J. Hruby), the selective delta-antagonist naltrindole and the selective kappa-antagonist norbinaltorphimine, both developed in the laboratory of Portoghese. The other important problem is the mechanism involved in the release of fragments of pro-enkephalin and Pro-dynorphin. The basis for the investigation of the release is published in J. Neurochemistry (in press). The principle of the method is the use of two successive HPLC systems which separate the endogenous opioid peptides for subsequent assay in the mouse vas deferens. It is now possible to determine the evoked release of (Met)enkephalin, (Leu)enkephalin, (Met)enkephalyl-Arg-Gly-Leu, and (Met)enkephalyl- Arg, Phe. BAM 8 amide, (Met)enkephalyl-Arg-Arg-Val-NH;, is also released but there is no detectable release of BAM 18 although it is present in the non-stimulated tissue. The amount of released opioid varies between 18 to 30% of the tissue content.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
2R01DA000662-14
Application #
3206807
Study Section
Pharmacology I Research Subcommittee (DABR)
Project Start
1973-06-01
Project End
1992-03-31
Budget Start
1989-05-01
Budget End
1990-03-31
Support Year
14
Fiscal Year
1989
Total Cost
Indirect Cost
Name
University of Aberdeen
Department
Type
DUNS #
212381045
City
Aberdeen
State
Country
United Kingdom
Zip Code
AB24 3FX
Hughes, J; Kosterlitz, H W; Smith, T W (1997) The distribution of methionine-enkephalin and leucine-enkephalin in the brain and peripheral tissues. 1977. Br J Pharmacol 120:428-36; discussion 426-7
Sagan, S; Corbett, A D; Amiche, M et al. (1991) Opioid activity of dermenkephalin analogues in the guinea-pig myenteric plexus and the hamster vas deferens. Br J Pharmacol 104:428-32
Corbett, A D; Gillan, M G; Kosterlitz, H W (1991) Electrically-induced release of opioid peptides from the guinea-pig myenteric plexus preparation. J Recept Res 11:665-73
Paterson, S J; Robson, L E; Kosterlitz, H W et al. (1990) Effect of Tris, HEPES, and TES buffers on binding at mu-, delta-, and kappa-opioid sites in guinea pig brain. J Pharmacol Methods 23:275-83
Kosterlitz, H W; Corbett, A D; Paterson, S J (1989) Opioid receptors and ligands. NIDA Res Monogr 95:159-66
Petrillo, P; La Regina, A; Sbacchi, M et al. (1989) Regional variations in binding capacities at mu-, delta- and kappa-opioid sites in membrane suspensions from rabbit brain. Eur J Pharmacol 166:213-7
Kosterlitz, H W; Paterson, S J; Robson, L E (1988) Modulation of binding at opioid receptors by mono- and divalent cations and by cholinergic compounds. J Recept Res 8:363-73
Corbett, A D; McKnight, A T; Kosterlitz, H W (1988) Tissue content of opioid peptides in the myenteric plexus-longitudinal muscle of guinea-pig small intestine. J Neurochem 51:32-7
Kosterlitz, H W; Paterson, S J; Robson, L E et al. (1987) Effects of cations on binding, in membrane suspensions, of various opioids at mu-sites of rabbit cerebellum and kappa-sites of guinea-pig cerebellum. Br J Pharmacol 91:431-7
Traynor, J R; Corbett, A D; Kosterlitz, H W (1987) Diprenorphine has agonist activity at opioid kappa-receptors in the myenteric plexus of the guinea-pig ileum. Eur J Pharmacol 137:85-9

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