Mu antagonist properties of kappa agonists in a model of rat urinary bladder motility in vivo

R. J. Sheldon, L. Nunan, F. Porreca

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39 Scopus citations


The possibility that the kappa agonists, U50,488H, ethylketazocine and tifluadom, might act as opioid antagonists was studied using the inhibition of the anesthetized rat micturition reflex in vivo as a pharmacological endpoint. Intracerebroventricular administration of equieffective doses of the mu agonists [D-Ala2, NMePhe4, Gly-ol]enkephalin (0.01 nmol), [N-MePhe3, D-Pro4]enkephalin (0.03 nmol), morphine (0.08 nmol), normorphine (0.3 nmol), sufentanil (0.002 nmol), etorphine (0.004 nmol), phenazocine (17 nmol) and meperidine (176 nmol) inhibited spontaneous bladder contractions for a duration of approximately 20 to 30 min. Similarly, i.c.v. administration of the delta-selective agonist (D-Pen2, D-Pen5]enkephalin (15 nmol) inhibited the micturition reflex for approximately the same duration. The kappa agonists U50,488H (22 nmol), ethylketazocine (3 nmol) and tifluadom (3 nmol) did not alter bladder activity after i.c.v. administration. Higher doses of ethylketazocine (10 nmol) or tifluadom (20 nmol), but not U50,488H, produced consistent suppression of bladder contractions. Pretreatment of rats (-15 min, i.c.v.) with doses of U50,488H, ethylketazocine or tifluadom which did not produce an agonist effect consistently blocked the inhibitory actions of the mu agonists morphine and normorphine on bladder motility, but failed to antagonize the similar actions of the mu agonists [D-Ala2, NMePhe4, Gly-ol]enkephalin, [N-MePhe3, D-Pro4]enkephalin, phenazocine, meperidine or those of the delta agonist (D-Pen2, D-Pen5]enkephalin. Centrally initiated bladder effects of the mu agonists etorphine and sufentanil were antagonized by U50,488H but unaffected by ethylketazocine or tifluadom. In addition, administration of U50,488H (i.c.v.) during a morphine-induced bladder shotdown resulted in either an immediate recovery of bladder activity or a shortened duration of action. Furthermore, pretreatment with U50,488H produced a parallel, rightward shift of the morphine dose-response curve without change in efficacy, suggestive of a competitive interaction. These findings may reflect either 1) the presence of mu receptor subtypes (isoreceptors) within the central nervous system that are differentially antagonized by kappa agonists or 2) differences in the intrinsic activity of mu agonists at a common receptor, such that less efficacious compounds are more susceptible to antagonism by kappa agonists.

Original languageEnglish (US)
Pages (from-to)234-240
Number of pages7
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number1
StatePublished - 1987

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology


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