Direct dependence studies in rats with agents selective for different types of opioid receptor

A. Cowan, X. Z. Zhu, H. I. Mosberg, J. R. Omnaas, F. Porreca

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Abstract

The objective of this study was to describe, quantitate and compare naloxone-induced abstinence syndromes in rats infused centrally (Sylvian aqueduct) with agonists that are currently the most selective for mu ([D-Ala2, MePhe4, Gly-ol5]enkephalin), delta ([D-Pen2, D-Pen5]enkephalin) and kappa (3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl) cyclohexyl]benzeneacetamide) (U-50,488H) opioid receptors, respectively. Morphine, ethylketazocine and dynorphin A served as reference compounds. After 70 hr of infusion from s.c. implanted osmotic minipumps, three levels of abstinence were associated with the injection of naloxone (3 mg/kg s.c.): 1) negligible syndromes (scores of <21) were obtained in rats on water or the kappa-directed ligands, U-50,488H and dynorphin A; 2) a low-to-moderate abstinence score (37-38) was recorded with rats receiving [D-Pen2, D-Pen5]enkephalin and ethylketazocine; and 3) a high abstinence score (64-73) was obtained with rats on morphine and DAGO. These results reinforce the concept of developing selective, nonbenzomorphan kappa agonists as clinically useful analgesics and emphasize that, when evaluating new analgesics, high selectivity for delta receptors does not, in itself, guarantee freedom from physical dependence.

Original languageEnglish (US)
Pages (from-to)950-955
Number of pages6
JournalJournal of Pharmacology and Experimental Therapeutics
Volume246
Issue number3
StatePublished - Jan 1 1988
Externally publishedYes

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ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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