Kappa-opioid receptors are differentially labeled by arylacetamides and benzomorphans.
Using Chinese Hamster Ovary cell membranes that stably expressed the human kappa-opioid receptor, we investigated the hypothesis that kappa(1)- and kappa(2)-opioid receptors, historically defined by their pharmacological selectivity for either arylacetamides or benzomorphans are, in fact, different affinity states or binding sites on the same kappa-opioid receptors. Receptor binding studies showed that GTP gamma S potently inhibited [3H](5 alpha,7 alpha,8 beta)-(+)-N-methyl-N-(7-[1-pyrrolidinyl]-1-oxaspiro [4.5]dec-8-yl)-benzeneacetamide (U69,593) binding, compared to virtually no inhibition of [3H]bremazocine binding. Saturation binding experiments showed a three-fold decrease in [3H]U69,593 affinity in the presence of GTP gamma S, but GTP gamma S had no effect on [3H]bremazocine affinity. The kappa-opioid receptor antagonist nor-binaltorphimine had a four-fold higher affinity for [3H]U69,593-labeled receptors than for [3H]bremazocine-labeled receptors. Functional selectivity studies, measuring the stimulation of [35S]GTP gamma S agonist-induced binding, showed a significantly higher U69,593-induced G protein-receptor activation in comparison to the stimulation observed with bremazocine. These results suggest that pharmacologically defined 1 kappa-opioid receptor subtypes may be different affinity states of the same receptor.
Rusovici
Daniela E
DE
Department of Pharmacology and Physiology, School of Medicine and Dentistry, University of Rochester, P.O. Box 711, 601 Elmwood Avenue, Rochester, NY 14642-8711, USA.
Negus
S Stevens
SS
Mello
Nancy K
NK
Bidlack
Jean M
JM
D000081:Acetamides / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D044482:Benzeneacetamides / Q000378:metabolism / Q000494:pharmacology; D001575:Benzomorphans / Q000378:metabolism* / Q000494:pharmacology; D016466:CHO Cells; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D006801:Humans; D011485:Protein Binding / Q000502:physiology; D011759:Pyrrolidines / Q000378:metabolism / Q000494:pharmacology; D017473:Receptors, Opioid, kappa / Q000819:agonists / Q000378:metabolism*
D000081:Acetamides; D044482:Benzeneacetamides; D001575:Benzomorphans; D011759:Pyrrolidines; D017473:Receptors, Opioid, kappa; C027248:bremazocine; C045444:U 69593