title: Ligand-specific regulation of the endogenous mu-opioid receptor by chronic treatment with mu-opioid peptide agonists.
abstract: Since the discovery of the endomorphins (EM), the postulated endogenous peptide agonists of the mu-opioid receptors, several analogues have been synthesized to improve their binding and pharmacological profiles. We have shown previously that a new analogue, cis-1S,2R-aminocyclohexanecarboxylic acid(2)-endomorphin-2 (ACHC-EM2), had elevated mu-receptor affinity, selectivity, and proteolytic stability over the parent compound. In the present work, we have studied its antinociceptive effects and receptor regulatory processes. ACHC-EM2 displayed a somewhat higher (60%) acute antinociceptive response than the parent peptide, EM2 (45%), which peaked at 10 min after intracerebroventricular (icv) administration in the rat tail-flick test. Analgesic tolerance developed to the antinociceptive effect of ACHC-EM2 upon its repeated icv injection that was complete by a 10-day treatment. This was accompanied by attenuated coupling of mu-sites to G-proteins in subcellular fractions of rat brain. Also, the density of mu-receptors was upregulated by about 40% in the light membrane fraction, with no detectable changes in surface binding. Distinct receptor regulatory processes were noted in subcellular fractions of rat brains made tolerant by the prototypic full mu-agonist peptide, DAMGO, and its chloromethyl ketone derivative, DAMCK. These results are discussed in light of the recently discovered phenomenon, that is, the "so-called biased agonism" or "functional selectivity".
authors.affiliation: Institute of Biochemistry, Biological Research Center, Hungarian Academy of Sciences, P.O. Box 521, Szeged 6701, Hungary.
authors.forename: Marianna
authors.initials: M
authors.lastname: Murányi
authors.affiliation: Institute of Biochemistry, Biological Research Center, Hungarian Academy of Sciences, P.O. Box 521, Szeged 6701, Hungary.
authors.forename: Resat
authors.initials: R
authors.lastname: Cinar
authors.affiliation: Institute of Biochemistry, Biological Research Center, Hungarian Academy of Sciences, P.O. Box 521, Szeged 6701, Hungary.
authors.forename: Orsolya
authors.initials: O
authors.lastname: Kékesi
authors.affiliation: Institute of Biochemistry, Biological Research Center, Hungarian Academy of Sciences, P.O. Box 521, Szeged 6701, Hungary.
authors.forename: Erika
authors.initials: E
authors.lastname: Birkás
authors.affiliation: Institute of Biochemistry, Biological Research Center, Hungarian Academy of Sciences, P.O. Box 521, Szeged 6701, Hungary.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Fábián
authors.affiliation: Institute of Biochemistry, Biological Research Center, Hungarian Academy of Sciences, P.O. Box 521, Szeged 6701, Hungary.
authors.forename: Beáta
authors.initials: B
authors.lastname: Bozó
authors.affiliation: Institute of Biochemistry, Biological Research Center, Hungarian Academy of Sciences, P.O. Box 521, Szeged 6701, Hungary ; Department of Pathophysiology, Faculty of Medicine, University of Szeged, Szeged, Hungary.
authors.forename: András
authors.initials: A
authors.lastname: Zentai
authors.affiliation: Institute of Biochemistry, Biological Research Center, Hungarian Academy of Sciences, P.O. Box 521, Szeged 6701, Hungary.
authors.forename: Géza
authors.initials: G
authors.lastname: Tóth
authors.affiliation: Institute of Biochemistry, Biological Research Center, Hungarian Academy of Sciences, P.O. Box 521, Szeged 6701, Hungary.
authors.forename: Emese Gabriella
authors.initials: EG
authors.lastname: Kicsi
authors.affiliation: Department of Pathophysiology, Faculty of Medicine, University of Szeged, Szeged, Hungary.
authors.forename: Mónika
authors.initials: M
authors.lastname: Mácsai
authors.affiliation: Department of Pathophysiology, Faculty of Medicine, University of Szeged, Szeged, Hungary.
authors.forename: Roberta
authors.initials: R
authors.lastname: Dochnal
authors.affiliation: Department of Pathophysiology, Faculty of Medicine, University of Szeged, Szeged, Hungary.
authors.forename: Gyula
authors.initials: G
authors.lastname: Szabó
authors.affiliation: Institute of Biochemistry, Biological Research Center, Hungarian Academy of Sciences, P.O. Box 521, Szeged 6701, Hungary.
authors.forename: Mária
authors.initials: M
authors.lastname: Szücs
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000378:metabolism; D008024:Ligands; D018847:Opioid Peptides / Q000378:metabolism*; D010147:Pain Measurement / Q000379:methods; D051381:Rats; D017208:Rats, Wistar; D017450:Receptors, Opioid, mu / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D000700:Analgesics; D008024:Ligands; D018847:Opioid Peptides; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; C052900:tyrosyl-alanyl-glycyl-N(alpha)-methylphenylalanine chloromethyl ketone; D019204:GTP-Binding Proteins