Intracisternal nor-binaltorphimine distinguishes central and peripheral κ-opioid antinociception in rhesus monkeys

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

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43 Scopus citations


Systemic administration of nor-binaltorphimine (nor-BNI) produces a long-lasting κ-opioid receptor (κOR) antagonism and has κ1-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.

Original languageEnglish (US)
Pages (from-to)1113-1120
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number3
StatePublished - Dec 1999
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology


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