TY - JOUR AU - Muranyi, M AU - Cinar, Resat AU - Kékesi, Orsolya Sára AU - Birkás, Erika AU - Fábián, Gabriella AU - Bozó, Bea AU - Zentai, A AU - Tóth, Géza AU - Kicsi, EG AU - Macsai, M AU - Dochnal, Roberta AU - Szabó, Gyula AU - Szűcs, Mária TI - Ligand-Specific Regulation of the Endogenous Mu-Opioid Receptor by Chronic Treatment with Mu-Opioid Peptide Agonists JF - BIOMED RESEARCH INTERNATIONAL J2 - BIOMED RES INT VL - 2013 PY - 2013 PG - 9 SN - 2314-6133 DO - 10.1155/2013/501086 UR - https://m2.mtmt.hu/api/publication/2486869 ID - 2486869 AB - 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". LA - English DB - MTMT ER - TY - JOUR AU - Cinar, Resat AU - Kékesi, Orsolya Sára AU - Birkás, Erika AU - Fábián, Gabriella AU - Schmidhammer, H AU - Szűcs, Mária TI - Lack of Regulatory Changes of mu-Opioid Receptors by 14-Methoxymetopon Treatment in Rat Brain. Further Evidence for Functional Selectivity. JF - CURRENT PHARMACEUTICAL DESIGN J2 - CURR PHARM DESIGN VL - 19 PY - 2013 SP - 7348 EP - 7354 PG - 7 SN - 1381-6128 DO - 10.2174/138161281942140105161245 UR - https://m2.mtmt.hu/api/publication/2429176 ID - 2429176 AB - Here we have studied regulatory changes of mu-opioid receptors accompanying in vivo 14-methoxymetopon treatments of rats. Previously, this ligand has been shown to be an extremely potent, centrally acting mu-opioid specific analgesic with low physical dependence, tolerance, respiratory depression, constipation and other side effects. Our work shows that it is a highly potent full agonist of mu-opioid receptor coupled G-protein signaling in vitro, alike the well-known opioid agonist, etorphine. However, unlike etorphine, which desensitized and down-regulated the endogenous mu-opioid receptors, 14-methoxymetopon, given to rats intraperitoneally (i.p.) either acutely or chronically, did not change the binding or G-protein signaling of mu-opioid receptors in rat brain subcellular membranes. Thereby, these data provide further evidence that there is no direct relationship between the efficacy of the ligand in signaling and its ability to internalize or desensitize the receptor. Viewed collectively with published work, it is discussed that mu-opioid receptors display functional selectivity, also called 'biased agonism'. This concept implies that each ligand may induce unique, ligand-specific receptor conformation that can result in distinct agonist-directed trafficking and/or signal transduction pathways associated with the receptor. Ligand-specific signaling may open up new directions for designing potent analgesics that do not interact with unwanted signaling pathways, which mediate undesired side-effects, such as tolerance and dependence. LA - English DB - MTMT ER - TY - THES AU - Cinar, Resat TI - New Directions in Receptor Research: Receptor Slectivity and Promiscuity PB - Szegedi Tudományegyetem (SZTE) PY - 2010 SP - 61 UR - https://m2.mtmt.hu/api/publication/1920944 ID - 1920944 LA - English DB - MTMT ER - TY - JOUR AU - Cinar, Resat AU - Szűcs, Mária TI - Cb1 receptor-independent actions of sr141716 on g-protein signaling: coapplication with the mu-opioid agonist tyr-d-alagly-(nme)phe-gly-ol unmasks novel, pertussis toxin-insensitive opioid signaling in mu-opioid receptor-chinese hamster ovary cells JF - JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS J2 - J PHARMACOL EXP THER VL - 330 PY - 2009 IS - 2 SP - 567 EP - 574 PG - 8 SN - 0022-3565 DO - 10.1124/jpet.109.152710 UR - https://m2.mtmt.hu/api/publication/1920781 ID - 1920781 N1 - Megjegyzés-10072904 FU: National Office for Research and Technology Szeged Neurobiological : Knowledge Center [08/2004] FX: This work was supported by the National Office for Research and : Technology Szeged Neurobiological Knowledge Center [Grant 08/2004]. AB - The CB 1 cannabinoid receptor antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H -pyrazole-3-carboxamide hydrochloride (SR141716) has been shown by many investigators to inhibit basal G-protein activity, i.e., to display inverse agonism at high concentrations. However, it is not clear whether this effect is cannabinoid CB 1 receptor-mediated. Using the ligand-stimulated [S-35]guanosine 5'-3-O(thio)triphosphate(GTP gamma S) assay, we have found that 10 mu M SR141716 slightly but significantly decreases the basal [S-35] GTP gamma S binding in membranes of the wild-type and CB1 receptor knockout mouse cortex, parental Chinese hamster ovary (CHO) cells, and CHO cells stably transfected with mu-opioid receptors, MOR-CHO. Accordingly, we conclude that the inverse agonism of SR141716 is CB1 receptor-independent. Although the specific MOR agonist Tyr-D-Ala-Gly-(NMe)PheGly-ol (DAMGO) saturably and concentration-dependently stimulated [S-35]GTP gamma S binding, SR141716 (10 mu M) inhibited the basal by 25% and competitively inhibited DAMGO stimulation in the mouse cortex. In MOR-CHO membranes, DAMGO caused a 501 +/- 29% stimulation of the basal activity, which was inhibited to 456 +/- 22% by 10 mu M SR141716. The inverse agonism of SR141716 was abolished, and DAMGO alone displayed weak, naloxone-insensitive stimulation, whereas the combination of DAMGO and SR141716 (10 mu M each) resulted in a 169 +/- 22% stimulation of the basal activity (that was completely inhibited by the prototypic opioid antagonist naloxone) because of pertussis toxin (PTX) treatment to uncouple MORs from G(i)/G(o) proteins. SR141716 proved to bind directly to MORs with low affinity (IC50 = 5.7 mu M). These results suggest the emergence of novel, PTX-insensitive G-protein signaling that is blocked by naloxone when MORs are activated by the combination of DAMGO and SR141716. LA - English DB - MTMT ER - TY - JOUR AU - Cinar, Resat AU - Freund, Tamás AU - Katona, István AU - Mackie, K AU - Szűcs, Mária TI - Reciprocal inhibition of G-protein signaling is induced by CB(1) cannabinoid and GABA(B) receptor interactions in rat hippocampal membranes JF - NEUROCHEMISTRY INTERNATIONAL J2 - NEUROCHEM INT VL - 52 PY - 2008 IS - 8 SP - 1402 EP - 1409 PG - 8 SN - 0197-0186 DO - 10.1016/j.neuint.2008.02.005 UR - https://m2.mtmt.hu/api/publication/110001 ID - 110001 N1 - Institute of Biochemistry, Biological Research Center, Hungarian Academy of Sciences, Szeged, Hungary Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN 47405, United States Cited By :23 Export Date: 23 July 2019 CODEN: NEUID Correspondence Address: Szucs, M.; Institute of Biochemistry, Biological Research Center, Hungarian Academy of Sciences, Szeged, Hungary; email: szucsm@brc.hu Chemicals/CAS: 1 (2,4 dichlorophenyl) 5 (4 iodophenyl) 4 methyl n (1 piperidyl) 1h pyrazole 3 carboxamide, 183232-66-8; 2,3 dihydro 5 methyl 3 (morpholinomethyl) 6 (1 naphthoyl)pyrrolo[1,2,3 de][1,4]benzoxazine, 134959-51-6; 3 aminopropyl(methyl)phosphinic acid, 127729-35-5; baclofen, 1134-47-0; guanosine 5' o (3 thiotriphosphate), 37589-80-3; phaclofen, 108351-35-5; AM 251; Benzoxazines; GABA Agonists; GABA Antagonists; Guanosine 5'-O-(3-Thiotriphosphate), 37589-80-3; Morpholines; Naphthalenes; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Receptors, G-Protein-Coupled; Receptors, GABA-B; Win 55212-2, 134959-51-6 Funding details: F046407, ETT 561/2006 Funding details: T046820 Funding details: M.S.I. Foundation Funding details: DA11322 Funding details: TS 049817 Funding text 1: The technical assistance of Ildiko Nemeth and the contribution of Erika Birkas and Aniko Ludanyi are greatly acknowledged. This work was supported by the research grants NKTH DNT 08/2004 and OTKA TS 049817 (to M.S.), OTKA T046820 (to T.F.F.), OTKA F046407 and ETT 561/2006 (to I.K.) and NIH DA11322 (to K.M.). Institute of Biochemistry, Biological Research Center, Hungarian Academy of Sciences, Szeged, Hungary Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN 47405, United States Cited By :23 Export Date: 11 August 2019 CODEN: NEUID Correspondence Address: Szucs, M.; Institute of Biochemistry, Biological Research Center, Hungarian Academy of Sciences, Szeged, Hungary; email: szucsm@brc.hu Chemicals/CAS: 1 (2,4 dichlorophenyl) 5 (4 iodophenyl) 4 methyl n (1 piperidyl) 1h pyrazole 3 carboxamide, 183232-66-8; 2,3 dihydro 5 methyl 3 (morpholinomethyl) 6 (1 naphthoyl)pyrrolo[1,2,3 de][1,4]benzoxazine, 134959-51-6; 3 aminopropyl(methyl)phosphinic acid, 127729-35-5; baclofen, 1134-47-0; guanosine 5' o (3 thiotriphosphate), 37589-80-3; phaclofen, 108351-35-5; AM 251; Benzoxazines; GABA Agonists; GABA Antagonists; Guanosine 5'-O-(3-Thiotriphosphate), 37589-80-3; Morpholines; Naphthalenes; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Receptors, G-Protein-Coupled; Receptors, GABA-B; Win 55212-2, 134959-51-6 Funding details: F046407, ETT 561/2006 Funding details: T046820 Funding details: M.S.I. Foundation Funding details: DA11322 Funding details: TS 049817 Funding text 1: The technical assistance of Ildiko Nemeth and the contribution of Erika Birkas and Aniko Ludanyi are greatly acknowledged. This work was supported by the research grants NKTH DNT 08/2004 and OTKA TS 049817 (to M.S.), OTKA T046820 (to T.F.F.), OTKA F046407 and ETT 561/2006 (to I.K.) and NIH DA11322 (to K.M.). Institute of Biochemistry, Biological Research Center, Hungarian Academy of Sciences, Szeged, Hungary Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN 47405, United States Cited By :23 Export Date: 6 March 2020 CODEN: NEUID Correspondence Address: Szucs, M.; Institute of Biochemistry, Biological Research Center, Hungarian Academy of Sciences, Szeged, Hungary; email: szucsm@brc.hu Chemicals/CAS: 1 (2,4 dichlorophenyl) 5 (4 iodophenyl) 4 methyl n (1 piperidyl) 1h pyrazole 3 carboxamide, 183232-66-8; 2,3 dihydro 5 methyl 3 (morpholinomethyl) 6 (1 naphthoyl)pyrrolo[1,2,3 de][1,4]benzoxazine, 134959-51-6; 3 aminopropyl(methyl)phosphinic acid, 127729-35-5; baclofen, 1134-47-0; guanosine 5' o (3 thiotriphosphate), 37589-80-3; phaclofen, 108351-35-5; AM 251; Benzoxazines; GABA Agonists; GABA Antagonists; Guanosine 5'-O-(3-Thiotriphosphate), 37589-80-3; Morpholines; Naphthalenes; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Receptors, G-Protein-Coupled; Receptors, GABA-B; Win 55212-2, 134959-51-6 Funding details: Nemzeti Kutatási és Technológiai Hivatal, NKTH, DNT 08/2004, OTKA TS 049817, F046407, ETT 561/2006, T046820 Funding details: National Institutes of Health, NIH, DA11322 Funding text 1: The technical assistance of Ildiko Nemeth and the contribution of Erika Birkas and Aniko Ludanyi are greatly acknowledged. This work was supported by the research grants NKTH DNT 08/2004 and OTKA TS 049817 (to M.S.), OTKA T046820 (to T.F.F.), OTKA F046407 and ETT 561/2006 (to I.K.) and NIH DA11322 (to K.M.). Institute of Biochemistry, Biological Research Center, Hungarian Academy of Sciences, Szeged, Hungary Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN 47405, United States Cited By :23 Export Date: 12 March 2020 CODEN: NEUID Correspondence Address: Szucs, M.; Institute of Biochemistry, Biological Research Center, Hungarian Academy of Sciences, Szeged, Hungary; email: szucsm@brc.hu Chemicals/CAS: 1 (2,4 dichlorophenyl) 5 (4 iodophenyl) 4 methyl n (1 piperidyl) 1h pyrazole 3 carboxamide, 183232-66-8; 2,3 dihydro 5 methyl 3 (morpholinomethyl) 6 (1 naphthoyl)pyrrolo[1,2,3 de][1,4]benzoxazine, 134959-51-6; 3 aminopropyl(methyl)phosphinic acid, 127729-35-5; baclofen, 1134-47-0; guanosine 5' o (3 thiotriphosphate), 37589-80-3; phaclofen, 108351-35-5; AM 251; Benzoxazines; GABA Agonists; GABA Antagonists; Guanosine 5'-O-(3-Thiotriphosphate), 37589-80-3; Morpholines; Naphthalenes; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Receptors, G-Protein-Coupled; Receptors, GABA-B; Win 55212-2, 134959-51-6 Funding details: Nemzeti Kutatási és Technológiai Hivatal, NKTH, DNT 08/2004, OTKA TS 049817, F046407, ETT 561/2006, T046820 Funding details: National Institutes of Health, NIH, DA11322 Funding text 1: The technical assistance of Ildiko Nemeth and the contribution of Erika Birkas and Aniko Ludanyi are greatly acknowledged. This work was supported by the research grants NKTH DNT 08/2004 and OTKA TS 049817 (to M.S.), OTKA T046820 (to T.F.F.), OTKA F046407 and ETT 561/2006 (to I.K.) and NIH DA11322 (to K.M.). Institute of Biochemistry, Biological Research Center, Hungarian Academy of Sciences, Szeged, Hungary Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN 47405, United States Cited By :23 Export Date: 19 April 2020 CODEN: NEUID Correspondence Address: Szucs, M.; Institute of Biochemistry, Biological Research Center, Hungarian Academy of Sciences, Szeged, Hungary; email: szucsm@brc.hu Chemicals/CAS: 1 (2,4 dichlorophenyl) 5 (4 iodophenyl) 4 methyl n (1 piperidyl) 1h pyrazole 3 carboxamide, 183232-66-8; 2,3 dihydro 5 methyl 3 (morpholinomethyl) 6 (1 naphthoyl)pyrrolo[1,2,3 de][1,4]benzoxazine, 134959-51-6; 3 aminopropyl(methyl)phosphinic acid, 127729-35-5; baclofen, 1134-47-0; guanosine 5' o (3 thiotriphosphate), 37589-80-3; phaclofen, 108351-35-5; AM 251; Benzoxazines; GABA Agonists; GABA Antagonists; Guanosine 5'-O-(3-Thiotriphosphate), 37589-80-3; Morpholines; Naphthalenes; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Receptors, G-Protein-Coupled; Receptors, GABA-B; Win 55212-2, 134959-51-6 Funding details: Nemzeti Kutatási és Technológiai Hivatal, NKTH, DNT 08/2004, OTKA TS 049817, F046407, ETT 561/2006, T046820 Funding details: National Institutes of Health, NIH, DA11322 Funding text 1: The technical assistance of Ildiko Nemeth and the contribution of Erika Birkas and Aniko Ludanyi are greatly acknowledged. This work was supported by the research grants NKTH DNT 08/2004 and OTKA TS 049817 (to M.S.), OTKA T046820 (to T.F.F.), OTKA F046407 and ETT 561/2006 (to I.K.) and NIH DA11322 (to K.M.). Institute of Biochemistry, Biological Research Center, Hungarian Academy of Sciences, Szeged, Hungary Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN 47405, United States Cited By :23 Export Date: 24 April 2020 CODEN: NEUID Correspondence Address: Szucs, M.; Institute of Biochemistry, Biological Research Center, Hungarian Academy of Sciences, Szeged, Hungary; email: szucsm@brc.hu Chemicals/CAS: 1 (2,4 dichlorophenyl) 5 (4 iodophenyl) 4 methyl n (1 piperidyl) 1h pyrazole 3 carboxamide, 183232-66-8; 2,3 dihydro 5 methyl 3 (morpholinomethyl) 6 (1 naphthoyl)pyrrolo[1,2,3 de][1,4]benzoxazine, 134959-51-6; 3 aminopropyl(methyl)phosphinic acid, 127729-35-5; baclofen, 1134-47-0; guanosine 5' o (3 thiotriphosphate), 37589-80-3; phaclofen, 108351-35-5; AM 251; Benzoxazines; GABA Agonists; GABA Antagonists; Guanosine 5'-O-(3-Thiotriphosphate), 37589-80-3; Morpholines; Naphthalenes; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Receptors, G-Protein-Coupled; Receptors, GABA-B; Win 55212-2, 134959-51-6 Funding details: Nemzeti Kutatási és Technológiai Hivatal, NKTH, DNT 08/2004, OTKA TS 049817, F046407, ETT 561/2006, T046820 Funding details: National Institutes of Health, NIH, DA11322 Funding text 1: The technical assistance of Ildiko Nemeth and the contribution of Erika Birkas and Aniko Ludanyi are greatly acknowledged. This work was supported by the research grants NKTH DNT 08/2004 and OTKA TS 049817 (to M.S.), OTKA T046820 (to T.F.F.), OTKA F046407 and ETT 561/2006 (to I.K.) and NIH DA11322 (to K.M.). Institute of Biochemistry, Biological Research Center, Hungarian Academy of Sciences, Szeged, Hungary Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN 47405, United States Cited By :23 Export Date: 18 May 2020 CODEN: NEUID Correspondence Address: Szucs, M.; Institute of Biochemistry, Biological Research Center, Hungarian Academy of Sciences, Szeged, Hungary; email: szucsm@brc.hu Chemicals/CAS: 1 (2,4 dichlorophenyl) 5 (4 iodophenyl) 4 methyl n (1 piperidyl) 1h pyrazole 3 carboxamide, 183232-66-8; 2,3 dihydro 5 methyl 3 (morpholinomethyl) 6 (1 naphthoyl)pyrrolo[1,2,3 de][1,4]benzoxazine, 134959-51-6; 3 aminopropyl(methyl)phosphinic acid, 127729-35-5; baclofen, 1134-47-0; guanosine 5' o (3 thiotriphosphate), 37589-80-3; phaclofen, 108351-35-5; AM 251; Benzoxazines; GABA Agonists; GABA Antagonists; Guanosine 5'-O-(3-Thiotriphosphate), 37589-80-3; Morpholines; Naphthalenes; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Receptors, G-Protein-Coupled; Receptors, GABA-B; Win 55212-2, 134959-51-6 Funding details: Nemzeti Kutatási és Technológiai Hivatal, NKTH, DNT 08/2004, OTKA TS 049817, F046407, ETT 561/2006, T046820 Funding details: National Institutes of Health, NIH, DA11322 Funding text 1: The technical assistance of Ildiko Nemeth and the contribution of Erika Birkas and Aniko Ludanyi are greatly acknowledged. This work was supported by the research grants NKTH DNT 08/2004 and OTKA TS 049817 (to M.S.), OTKA T046820 (to T.F.F.), OTKA F046407 and ETT 561/2006 (to I.K.) and NIH DA11322 (to K.M.). Institute of Biochemistry, Biological Research Center, Hungarian Academy of Sciences, Szeged, Hungary Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN 47405, United States Cited By :23 Export Date: 20 May 2020 CODEN: NEUID Correspondence Address: Szucs, M.; Institute of Biochemistry, Biological Research Center, Hungarian Academy of Sciences, Szeged, Hungary; email: szucsm@brc.hu Chemicals/CAS: 1 (2,4 dichlorophenyl) 5 (4 iodophenyl) 4 methyl n (1 piperidyl) 1h pyrazole 3 carboxamide, 183232-66-8; 2,3 dihydro 5 methyl 3 (morpholinomethyl) 6 (1 naphthoyl)pyrrolo[1,2,3 de][1,4]benzoxazine, 134959-51-6; 3 aminopropyl(methyl)phosphinic acid, 127729-35-5; baclofen, 1134-47-0; guanosine 5' o (3 thiotriphosphate), 37589-80-3; phaclofen, 108351-35-5; AM 251; Benzoxazines; GABA Agonists; GABA Antagonists; Guanosine 5'-O-(3-Thiotriphosphate), 37589-80-3; Morpholines; Naphthalenes; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Receptors, G-Protein-Coupled; Receptors, GABA-B; Win 55212-2, 134959-51-6 Funding details: Nemzeti Kutatási és Technológiai Hivatal, NKTH, DNT 08/2004, OTKA TS 049817, F046407, ETT 561/2006, T046820 Funding details: National Institutes of Health, NIH, DA11322 Funding text 1: The technical assistance of Ildiko Nemeth and the contribution of Erika Birkas and Aniko Ludanyi are greatly acknowledged. This work was supported by the research grants NKTH DNT 08/2004 and OTKA TS 049817 (to M.S.), OTKA T046820 (to T.F.F.), OTKA F046407 and ETT 561/2006 (to I.K.) and NIH DA11322 (to K.M.). Institute of Biochemistry, Biological Research Center, Hungarian Academy of Sciences, Szeged, Hungary Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN 47405, United States Cited By :23 Export Date: 24 May 2020 CODEN: NEUID Correspondence Address: Szucs, M.; Institute of Biochemistry, Biological Research Center, Hungarian Academy of Sciences, Szeged, Hungary; email: szucsm@brc.hu Chemicals/CAS: 1 (2,4 dichlorophenyl) 5 (4 iodophenyl) 4 methyl n (1 piperidyl) 1h pyrazole 3 carboxamide, 183232-66-8; 2,3 dihydro 5 methyl 3 (morpholinomethyl) 6 (1 naphthoyl)pyrrolo[1,2,3 de][1,4]benzoxazine, 134959-51-6; 3 aminopropyl(methyl)phosphinic acid, 127729-35-5; baclofen, 1134-47-0; guanosine 5' o (3 thiotriphosphate), 37589-80-3; phaclofen, 108351-35-5; AM 251; Benzoxazines; GABA Agonists; GABA Antagonists; Guanosine 5'-O-(3-Thiotriphosphate), 37589-80-3; Morpholines; Naphthalenes; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Receptors, G-Protein-Coupled; Receptors, GABA-B; Win 55212-2, 134959-51-6 Funding details: Nemzeti Kutatási és Technológiai Hivatal, NKTH, DNT 08/2004, OTKA TS 049817, F046407, ETT 561/2006, T046820 Funding details: National Institutes of Health, NIH, DA11322 Funding text 1: The technical assistance of Ildiko Nemeth and the contribution of Erika Birkas and Aniko Ludanyi are greatly acknowledged. This work was supported by the research grants NKTH DNT 08/2004 and OTKA TS 049817 (to M.S.), OTKA T046820 (to T.F.F.), OTKA F046407 and ETT 561/2006 (to I.K.) and NIH DA11322 (to K.M.). Institute of Biochemistry, Biological Research Center, Hungarian Academy of Sciences, Szeged, Hungary Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN 47405, United States Cited By :23 Export Date: 28 May 2020 CODEN: NEUID Correspondence Address: Szucs, M.; Institute of Biochemistry, Biological Research Center, Hungarian Academy of Sciences, Szeged, Hungary; email: szucsm@brc.hu Chemicals/CAS: 1 (2,4 dichlorophenyl) 5 (4 iodophenyl) 4 methyl n (1 piperidyl) 1h pyrazole 3 carboxamide, 183232-66-8; 2,3 dihydro 5 methyl 3 (morpholinomethyl) 6 (1 naphthoyl)pyrrolo[1,2,3 de][1,4]benzoxazine, 134959-51-6; 3 aminopropyl(methyl)phosphinic acid, 127729-35-5; baclofen, 1134-47-0; guanosine 5' o (3 thiotriphosphate), 37589-80-3; phaclofen, 108351-35-5; AM 251; Benzoxazines; GABA Agonists; GABA Antagonists; Guanosine 5'-O-(3-Thiotriphosphate), 37589-80-3; Morpholines; Naphthalenes; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Receptors, G-Protein-Coupled; Receptors, GABA-B; Win 55212-2, 134959-51-6 Funding details: Nemzeti Kutatási és Technológiai Hivatal, NKTH, DNT 08/2004, OTKA TS 049817, F046407, ETT 561/2006, T046820 Funding details: National Institutes of Health, NIH, DA11322 Funding text 1: The technical assistance of Ildiko Nemeth and the contribution of Erika Birkas and Aniko Ludanyi are greatly acknowledged. This work was supported by the research grants NKTH DNT 08/2004 and OTKA TS 049817 (to M.S.), OTKA T046820 (to T.F.F.), OTKA F046407 and ETT 561/2006 (to I.K.) and NIH DA11322 (to K.M.). Institute of Biochemistry, Biological Research Center, Hungarian Academy of Sciences, Szeged, Hungary Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN 47405, United States Cited By :24 Export Date: 4 August 2020 CODEN: NEUID Correspondence Address: Szucs, M.; Institute of Biochemistry, Biological Research Center, Hungarian Academy of Sciences, Szeged, Hungary; email: szucsm@brc.hu Chemicals/CAS: 1 (2,4 dichlorophenyl) 5 (4 iodophenyl) 4 methyl n (1 piperidyl) 1h pyrazole 3 carboxamide, 183232-66-8; 2,3 dihydro 5 methyl 3 (morpholinomethyl) 6 (1 naphthoyl)pyrrolo[1,2,3 de][1,4]benzoxazine, 134959-51-6; 3 aminopropyl(methyl)phosphinic acid, 127729-35-5; baclofen, 1134-47-0; guanosine 5' o (3 thiotriphosphate), 37589-80-3; phaclofen, 108351-35-5; AM 251; Benzoxazines; GABA Agonists; GABA Antagonists; Guanosine 5'-O-(3-Thiotriphosphate), 37589-80-3; Morpholines; Naphthalenes; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Receptors, G-Protein-Coupled; Receptors, GABA-B; Win 55212-2, 134959-51-6 Funding details: Nemzeti Kutatási és Technológiai Hivatal, NKTH, DNT 08/2004, OTKA TS 049817, F046407, ETT 561/2006, T046820 Funding details: National Institutes of Health, NIH, DA11322 Funding text 1: The technical assistance of Ildiko Nemeth and the contribution of Erika Birkas and Aniko Ludanyi are greatly acknowledged. This work was supported by the research grants NKTH DNT 08/2004 and OTKA TS 049817 (to M.S.), OTKA T046820 (to T.F.F.), OTKA F046407 and ETT 561/2006 (to I.K.) and NIH DA11322 (to K.M.). Institute of Biochemistry, Biological Research Center, Hungarian Academy of Sciences, Szeged, Hungary Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN 47405, United States Cited By :26 Export Date: 9 March 2021 CODEN: NEUID Correspondence Address: Szucs, M.; Institute of Biochemistry, , Szeged, Hungary; email: szucsm@brc.hu Chemicals/CAS: 1 (2,4 dichlorophenyl) 5 (4 iodophenyl) 4 methyl n (1 piperidyl) 1h pyrazole 3 carboxamide, 183232-66-8; 2,3 dihydro 5 methyl 3 (morpholinomethyl) 6 (1 naphthoyl)pyrrolo[1,2,3 de][1,4]benzoxazine, 134959-51-6; 3 aminopropyl(methyl)phosphinic acid, 127729-35-5; baclofen, 1134-47-0; guanosine 5' o (3 thiotriphosphate), 37589-80-3; phaclofen, 108351-35-5; AM 251; Benzoxazines; GABA Agonists; GABA Antagonists; Guanosine 5'-O-(3-Thiotriphosphate), 37589-80-3; Morpholines; Naphthalenes; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Receptors, G-Protein-Coupled; Receptors, GABA-B; Win 55212-2, 134959-51-6 Funding details: National Institutes of Health, NIH Funding details: National Institute on Drug Abuse, NIDA, K05DA021696, R01DA011322 Funding details: Nemzeti Kutatási és Technológiai Hivatal, NKTH, DNT 08/2004, ETT 561/2006, F046407, OTKA TS 049817, T046820 Funding text 1: The technical assistance of Ildiko Nemeth and the contribution of Erika Birkas and Aniko Ludanyi are greatly acknowledged. This work was supported by the research grants NKTH DNT 08/2004 and OTKA TS 049817 (to M.S.), OTKA T046820 (to T.F.F.), OTKA F046407 and ETT 561/2006 (to I.K.) and NIH DA11322 (to K.M.). Institute of Biochemistry, Biological Research Center, Hungarian Academy of Sciences, Szeged, Hungary Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN 47405, United States Cited By :26 Export Date: 29 March 2021 CODEN: NEUID Correspondence Address: Szucs, M.; Institute of Biochemistry, , Szeged, Hungary; email: szucsm@brc.hu Chemicals/CAS: 1 (2,4 dichlorophenyl) 5 (4 iodophenyl) 4 methyl n (1 piperidyl) 1h pyrazole 3 carboxamide, 183232-66-8; 2,3 dihydro 5 methyl 3 (morpholinomethyl) 6 (1 naphthoyl)pyrrolo[1,2,3 de][1,4]benzoxazine, 134959-51-6; 3 aminopropyl(methyl)phosphinic acid, 127729-35-5; baclofen, 1134-47-0; guanosine 5' o (3 thiotriphosphate), 37589-80-3; phaclofen, 108351-35-5; AM 251; Benzoxazines; GABA Agonists; GABA Antagonists; Guanosine 5'-O-(3-Thiotriphosphate), 37589-80-3; Morpholines; Naphthalenes; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Receptors, G-Protein-Coupled; Receptors, GABA-B; Win 55212-2, 134959-51-6 Funding details: National Institutes of Health, NIH Funding details: National Institute on Drug Abuse, NIDA, K05DA021696, R01DA011322 Funding details: Nemzeti Kutatási és Technológiai Hivatal, NKTH, DNT 08/2004, ETT 561/2006, F046407, OTKA TS 049817, T046820 Funding text 1: The technical assistance of Ildiko Nemeth and the contribution of Erika Birkas and Aniko Ludanyi are greatly acknowledged. This work was supported by the research grants NKTH DNT 08/2004 and OTKA TS 049817 (to M.S.), OTKA T046820 (to T.F.F.), OTKA F046407 and ETT 561/2006 (to I.K.) and NIH DA11322 (to K.M.). Institute of Biochemistry, Biological Research Center, Hungarian Academy of Sciences, Szeged, Hungary Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN 47405, United States Cited By :26 Export Date: 31 March 2021 CODEN: NEUID Correspondence Address: Szucs, M.; Institute of Biochemistry, , Szeged, Hungary; email: szucsm@brc.hu Chemicals/CAS: 1 (2,4 dichlorophenyl) 5 (4 iodophenyl) 4 methyl n (1 piperidyl) 1h pyrazole 3 carboxamide, 183232-66-8; 2,3 dihydro 5 methyl 3 (morpholinomethyl) 6 (1 naphthoyl)pyrrolo[1,2,3 de][1,4]benzoxazine, 134959-51-6; 3 aminopropyl(methyl)phosphinic acid, 127729-35-5; baclofen, 1134-47-0; guanosine 5' o (3 thiotriphosphate), 37589-80-3; phaclofen, 108351-35-5; AM 251; Benzoxazines; GABA Agonists; GABA Antagonists; Guanosine 5'-O-(3-Thiotriphosphate), 37589-80-3; Morpholines; Naphthalenes; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Receptors, G-Protein-Coupled; Receptors, GABA-B; Win 55212-2, 134959-51-6 Funding details: National Institutes of Health, NIH Funding details: National Institute on Drug Abuse, NIDA, K05DA021696, R01DA011322 Funding details: Nemzeti Kutatási és Technológiai Hivatal, NKTH, DNT 08/2004, ETT 561/2006, F046407, OTKA TS 049817, T046820 Funding text 1: The technical assistance of Ildiko Nemeth and the contribution of Erika Birkas and Aniko Ludanyi are greatly acknowledged. This work was supported by the research grants NKTH DNT 08/2004 and OTKA TS 049817 (to M.S.), OTKA T046820 (to T.F.F.), OTKA F046407 and ETT 561/2006 (to I.K.) and NIH DA11322 (to K.M.). Institute of Biochemistry, Biological Research Center, Hungarian Academy of Sciences, Szeged, Hungary Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN 47405, United States Cited By :26 Export Date: 20 April 2021 CODEN: NEUID Correspondence Address: Szucs, M.; Institute of Biochemistry, , Szeged, Hungary; email: szucsm@brc.hu Chemicals/CAS: 1 (2,4 dichlorophenyl) 5 (4 iodophenyl) 4 methyl n (1 piperidyl) 1h pyrazole 3 carboxamide, 183232-66-8; 2,3 dihydro 5 methyl 3 (morpholinomethyl) 6 (1 naphthoyl)pyrrolo[1,2,3 de][1,4]benzoxazine, 134959-51-6; 3 aminopropyl(methyl)phosphinic acid, 127729-35-5; baclofen, 1134-47-0; guanosine 5' o (3 thiotriphosphate), 37589-80-3; phaclofen, 108351-35-5; AM 251; Benzoxazines; GABA Agonists; GABA Antagonists; Guanosine 5'-O-(3-Thiotriphosphate), 37589-80-3; Morpholines; Naphthalenes; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Receptors, G-Protein-Coupled; Receptors, GABA-B; Win 55212-2, 134959-51-6 Funding details: National Institutes of Health, NIH Funding details: National Institute on Drug Abuse, NIDA, K05DA021696, R01DA011322 Funding details: Nemzeti Kutatási és Technológiai Hivatal, NKTH, DNT 08/2004, ETT 561/2006, F046407, OTKA TS 049817, T046820 Funding text 1: The technical assistance of Ildiko Nemeth and the contribution of Erika Birkas and Aniko Ludanyi are greatly acknowledged. This work was supported by the research grants NKTH DNT 08/2004 and OTKA TS 049817 (to M.S.), OTKA T046820 (to T.F.F.), OTKA F046407 and ETT 561/2006 (to I.K.) and NIH DA11322 (to K.M.). Institute of Biochemistry, Biological Research Center, Hungarian Academy of Sciences, Szeged, Hungary Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN 47405, United States Cited By :27 Export Date: 7 September 2021 CODEN: NEUID Correspondence Address: Szucs, M.; Institute of Biochemistry, , Szeged, Hungary; email: szucsm@brc.hu Chemicals/CAS: 1 (2,4 dichlorophenyl) 5 (4 iodophenyl) 4 methyl n (1 piperidyl) 1h pyrazole 3 carboxamide, 183232-66-8; 2,3 dihydro 5 methyl 3 (morpholinomethyl) 6 (1 naphthoyl)pyrrolo[1,2,3 de][1,4]benzoxazine, 134959-51-6; 3 aminopropyl(methyl)phosphinic acid, 127729-35-5; baclofen, 1134-47-0; guanosine 5' o (3 thiotriphosphate), 37589-80-3; phaclofen, 108351-35-5; AM 251; Benzoxazines; GABA Agonists; GABA Antagonists; Guanosine 5'-O-(3-Thiotriphosphate), 37589-80-3; Morpholines; Naphthalenes; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Receptors, G-Protein-Coupled; Receptors, GABA-B; Win 55212-2, 134959-51-6 Funding details: National Institutes of Health, NIH Funding details: National Institute on Drug Abuse, NIDA, K05DA021696, R01DA011322 Funding details: Nemzeti Kutatási és Technológiai Hivatal, NKTH, DNT 08/2004, ETT 561/2006, F046407, OTKA TS 049817, T046820 Funding text 1: The technical assistance of Ildiko Nemeth and the contribution of Erika Birkas and Aniko Ludanyi are greatly acknowledged. This work was supported by the research grants NKTH DNT 08/2004 and OTKA TS 049817 (to M.S.), OTKA T046820 (to T.F.F.), OTKA F046407 and ETT 561/2006 (to I.K.) and NIH DA11322 (to K.M.). AB - Cannabinoid CB(1) and the metabotropic GABA(B) receptors have been shown to display similar pharmacological effects and co-localization in certain brain regions. Previous studies have reported a functional link between the two systems. As a first step to investigate the underlying molecular mechanism, here we show cross-inhibition of G-protein signaling between GABA(B) and CB(1) receptors in rat hippocampal membranes. The CB(1) agonist R-Win55,212-2 displayed high potency and efficacy in stimulating guanosine-5'-O-(3-[(35)S]thio)triphosphate, [(35)S]GTPgammaS binding. Its effect was completely blocked by the specific CB(1) antagonist AM251 suggesting that the signaling was via CB(1) receptors. The GABA(B) agonists baclofen and SKF97541 also elevated [(35)S]GTPgammaS binding by about 60%, with potency values in the micromolar range. Phaclofen behaved as a low potency antagonist with an ED(50) approximately 1mM. However, phaclofen at low doses (1 and 10nM) slightly but significantly attenuated maximal stimulation of [(35)S]GTPgammaS binding by the CB(1) agonist R-Win55,212-2. The observation that higher concentrations of phaclofen had no such effect rule out the possibility of its direct action on CB(1) receptors. The pharmacologically inactive stereoisomer S-Win55,212-3 had no effect either alone or in combination with phaclofen establishing that the interaction is stereospecific in hippocampus. The specific CB(1) antagonist AM251 at a low dose (1nM) also inhibited the efficacy of G-protein signaling of the GABA(B) receptor agonist SKF97541. Cross-talk of the two receptor systems was not detected in either spinal cord or cerebral cortex membranes. It is speculated that the interaction might occur via an allosteric interaction between a subset of GABA(B) and CB(1) receptors in rat hippocampal membranes. Although the exact molecular mechanism of the reciprocal inhibition between CB(1) and GABA(B) receptors will have to be explored by future studies it is intriguing that the cross-talk might be involved in balance tuning the endocannabinoid and GABAergic signaling in hippocampus. LA - English DB - MTMT ER -