Vol. 291, Issue 3, 1113-1120, December 1999

Intracisternal Nor-Binaltorphimine Distinguishes Central and Peripheral -Opioid Antinociception in Rhesus Monkeys¹

M. C. Holden Ko, Mark D. Johnson, Eduardo R. Butelman, Kurt J. Willmont, Henry I. Mosberg and James H. Woods

Department of Pharmacology, Medical School (M.C.H.K., M.D.J., J.H.W.); Department of Psychology, Biopsychology Program (K.J.W., J.H.W.); Division of Medicinal Chemistry, College of Pharmacy (H.I.M.), The University of Michigan, Ann Arbor, Michigan; and Laboratory of the Biology of Addictive Diseases (E.R.B.), Rockefeller University, New York, New York

Systemic administration of nor-binaltorphimine (nor-BNI) produces a long-lasting -opioid receptor (OR) antagonism and has ₁-selectivity in nonhuman primates. The aim of this study was to establish the pharmacological basis of central OR antagonism in rhesus monkeys (Macaca mulatta). After intracisternal (i.c.) administration of small doses of nor-BNI, the duration and selectivity of nor-BNI antagonism were evaluated against two OR agonists, (trans)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]benzeneacetamide (U50,488) and bremazocine. Thermal antinociception was measured in the warm water (50°C) tail-withdrawal assay and sedation was evaluated by observers blind to treatment conditions. Following i.c. pretreatment with 0.32 mg nor-BNI, a 5- to 10-fold rightward shift of the U50,488 baseline dose-effect curve was observed in antinociception. In contrast, this dose of nor-BNI only produced an insignificant 2-fold shift against bremazocine. Pretreatment with a smaller dose (0.032 mg) of nor-BNI produced a 3-fold shift of U50,488, which lasted for 7 days, but failed to alter the potency of bremazocine. This differential antagonism profile of i.c. nor-BNI also was observed in sedation ratings. In addition, the centrally effective dose of nor-BNI (0.32 mg), when administered s.c. in the back, did not antagonize either U50,488- or bremazocine-induced antinociception and sedation. After i.c. pretreatment with the same dose, nor-BNI also did not antagonize the peripherally mediated effect of U50,488 against capsaicin-induced thermal nociception in the tail. These results indicate that i.c. nor-BNI produces central OR antagonism and support the notion of two functional OR subtypes in the central nervous system. Moreover, it provides a valuable pharmacological basis for further characterizing different sources of OR-mediated effects, namely, from central or peripheral nervous system receptors.