Lack of cross-tolerance between U69,593 and bremazocine suggests kappa-opioid receptor multiplicity in mice

Eur J Pharmacol. 1993 Aug 3;239(1-3):93-8. doi: 10.1016/0014-2999(93)90980-v.


The development of tolerance, and the possibility of cross-tolerance, to the kappa-opioid receptor-mediated antinociceptive effects of U69,593 and bremazocine was studied in mice. U69,593 and bremazocine elicited dose-related and kappa-receptor-mediated antinociception following i.c.v. administration to mice. After a 3 day treatment regimen (twice daily injections) with an approximate antinociceptive A90 dose (90 nmol, i.c.v.) of U69,593, tolerance developed as demonstrated by a 5.6-fold rightward shift of the U69,593 dose-response line. The i.c.v. dose-response line for bremazocine was unaltered in U69,593-tolerant mice. Pretreatment with an approximate antinociceptive A90 dose of bremazocine (30 nmol, i.c.v.) for 3 days also produced tolerance as shown by a greater than 15-fold rightward shift in the bremazocine antinociceptive dose-response line. The i.c.v. dose-response line for U69,593 was unaltered in bremazocine-tolerant mice. These data demonstrate that while tolerance develops to the antinociceptive effects of both U69,593 and bremazocine, a two-way lack of cross-tolerance can be demonstrated between these kappa-agonists in this endpoint. These data suggest mechanistic differences in the antinociceptive effects of these kappa-agonists. Such suggestions are consistent with antinociceptive action of these agonists at subtypes of kappa-receptors.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Analgesics / administration & dosage
  • Analgesics / pharmacology*
  • Animals
  • Benzeneacetamides*
  • Benzomorphans / administration & dosage
  • Benzomorphans / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Tolerance
  • Injections, Intraventricular
  • Male
  • Mice
  • Pyrrolidines / administration & dosage
  • Pyrrolidines / pharmacology*
  • Receptors, Opioid, kappa / drug effects*
  • Receptors, Opioid, kappa / physiology


  • Analgesics
  • Benzeneacetamides
  • Benzomorphans
  • Pyrrolidines
  • Receptors, Opioid, kappa
  • bremazocine
  • U 69593