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Vol. 285, Issue 2, 595-601, May 1998
Departments of
Pharmacology (E.R.B., M.C.K., B.V.B., G.Z.,
J.H.W.) and
Psychology (J.H.W.) and
Medicinal Chemistry, College of
Pharmacy (H.I.M., K.S.K.), University of Michigan, Ann Arbor, Michigan
The binding characteristics of the kappa opioid ligands
[3H]U69,593 and [3H]bremazocine, the
mu opioid ligand
[3H][D-ala2,N-Me-Phe4,glycol5]enkephalin
and the delta opioid ligand
[3H]p-Cl-[D-pen2,5]enkephalin
were studied in rhesus monkey brain membranes in saturation binding
experiments and were followed by competition binding experiments with a
variety of peptidic and nonpeptidic opioid ligands. The [3H]U69,593 sites appeared to be a subset of
kappa opioid receptors (kappa-1
receptors: Kd, 1.2 nM;
Bmax, 66 fmol/mg).
[3H]Bremazocine (in the presence of mu and
delta receptor-masking agents), bound to a larger
population of kappa receptors (kappa-all: Kd, 0.39 nM;
Bmax, 227 fmol/mg), which presumably
included the aforementioned kappa-1 sites. Competition
binding experiments revealed that the presently defined
kappa-1 sites were similar to previously reported sites
in other mammalian species, particularly in terms of the higher
kappa-1 selectivity observed with arylacetamide (e.g., U50,488) vs. benzomorphan
kappa agonists (e.g.,
ethylketocyclazocine). The kappa-selective antagonist
norbinaltorphimine (nor-BNI) displayed a very small (2.3-fold)
selectivity for kappa-1 vs.
kappa-all sites. This led to the prediction that in
rhesus 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-1-agonist, the arylacetamide U50,488 (0.1-3.2
mg/kg s.c.), vs. those of the benzomorphan
kappa agonist ethylketocyclazocine (0.01-056 mg/kg
s.c.). This prediction was confirmed in vivo because
nor-BNI (10 mg/kg) caused a robust and long lasting (up to 21 days)
antagonism of the antinociceptive effects of U50,488 and a small but
significant antagonism of ethylketocyclazocine. The arylacetamide
congener CI-977 (enadoline), which displayed an 11-fold
kappa-1 vs. kappa-all
binding selectivity, was not sensitive to nor-BNI pretreatment. This
indicates that the kappa subtype-binding profile 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 monkey brain.
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