KAPPA-OPIOID RECEPTOR-BINDING POPULATIONS IN RHESUS-MONKEY BRAIN - RELATIONSHIP TO AN ASSAY OF THERMAL ANTINOCICEPTION

The binding characteristics of the kappa opioid ligands [H-3]U69,593 a nd [H-3]bremazocine, the mu opioid ligand [H-3][D-ala(2),N-Me-Phe(4),g lycol(5)]enkephalin and the delta opioid ligand [H-3]p-Cl-[D-pen(2,5)] enkephalin were studied in rhesus monkey brain membranes in saturation binding experiments and were followed by competition binding experime nts with a variety of peptidic and nonpeptidic opioid ligands. The [H- 3]U69,593 sites appeared to be a subset of kappa opioid receptors (kap pa-l receptors: K-d, 1.2 nM; B-max, 66 fmol/mg). [H-3]Bremazocine (in the presence of mu and delta receptor-masking agents), bound to a larg er population of kappa receptors (kappa-all: K-d, 0.39 nM; B-max, 227 fmol/mg), which presumably included the aforementioned kappa-l sites. Competition binding experiments revealed that the presently defined ka ppa-l sites were similar to previously reported sites in other mammali an species, particularly in terms of the higher kappa-l selectivity ob served with arylacetamide (e.g., U50,488) vs, benzomorphan kappa agoni sts (e.g., ethylketocyclazocine). The kappa-selective antagonist norbi naltorphimine (nor-BNI) displayed a very small (2.3-fold) selectivity for kappa-l vs, kappa-all sites. This led to the prediction that in rh esus monkeys (n = 3), systemically administered nor-BNI (10 mg/kg s.c. ) should have a very moderate degree of antagonist selectivity for the antinociceptive effects of a putative kappa-l-agonist, the arylacetam ide U50,488 (0.1-3.2 mg/kg s.c.), vs, those of the bentomorphan kappa agonist ethylketocyclazocine (0.01-056 mg/kg s.c.). This prediction wa s confirmed in vivo because nor-BNI (10 mg/kg) caused a robust and lon g lasting (up to 21 days) antagonism of the antinociceptive effects of U50,488 and a small but significant antagonism of ethylketocyclazocin e. The arylacetamide congener CI-977 (enadoline), which displayed an I i-fold kappa-l vs. kappa-all binding selectivity, was not sensitive to nor-BNI pretreatment. This indicates that the kappa subtype-binding p rofile of an agonist is not necessarily predictive of its sensitivity to nor-BNI in vivo. Overall, the present results suggest that at least two functional kappa receptor populations may be present in rhesus mo nkey brain.