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

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 291; no. 3; p. 1113
• Main Authors: M. C. Holden Ko, Mark D. Johnson, Eduardo R. Butelman, Kurt J. Willmont, Henry I. Mosberg, James H. Woods
• Format: Journal Article
• Language: English
• Published: American Society for Pharmacology and Experimental Therapeutics 01.12.1999
• ISSN: 0022-3565; 1521-0103

Systemic administration of nor-binaltorphimine (nor-BNI) produces a long-lasting κ-opioid receptor (κOR) antagonism and has κ 1 -selectivity in nonhuman primates. The aim of this study was to establish the pharmacological basis of central κOR 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 κOR 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 κOR antagonism and support the notion of two functional κOR subtypes in the central nervous system. Moreover, it provides a valuable pharmacological basis for further characterizing different sources of κOR-mediated effects, namely, from central or peripheral nervous system receptors.