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Research ArticleArticle

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 and James H. Woods
Journal of Pharmacology and Experimental Therapeutics December 1999, 291 (3) 1113-1120;
M. C. Holden Ko
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Mark D. Johnson
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Eduardo R. Butelman
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Kurt J. Willmont
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Henry I. Mosberg
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James H. Woods
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Abstract

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.

Footnotes

  • Send reprint requests to: Dr. M. C. Holden Ko, Department of Pharmacology, University of Michigan Medical School, 1301 Medical Science Research Building III, Ann Arbor, MI 48109-0632. E-mail: mko{at}umich.edu

  • ↵1 This study was supported by U.S. Public Health Service Grant DA00254. Preliminary results were presented at the 61th annual meeting of the College on Problems of Drug Dependence, Acapulco, Mexico, June 12–17, 1999.

  • Abbreviations:
    κOR
    κ-opioid receptors
    nor-BNI
    nor-binaltorphimine
    CNS
    central nervous system
    U50,488
    (trans)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]benzeneacetamide
    i.c.
    intracisternal
    MPE
    maximum possible effect
    • Received April 7, 1999.
    • Accepted August 11, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 291 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 291, Issue 3
1 Dec 1999
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Research ArticleArticle

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 and James H. Woods
Journal of Pharmacology and Experimental Therapeutics December 1, 1999, 291 (3) 1113-1120;

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Research ArticleArticle

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 and James H. Woods
Journal of Pharmacology and Experimental Therapeutics December 1, 1999, 291 (3) 1113-1120;
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