Lack of cross-tolerance between U69,593 and bremazocine suggests kappa-opioid receptor multiplicity in mice.
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.
Horan
P J
PJ
Department of Pharmacology, University of Arizona Health Sciences Center, Tucson 85724.
Porreca
F
F
D000700:Analgesics / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D044482:Benzeneacetamides; D001575:Benzomorphans / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D007276:Injections, Intraventricular; D008297:Male; D051379:Mice; D011759:Pyrrolidines / Q000008:administration & dosage / Q000494:pharmacology*; D017473:Receptors, Opioid, kappa / Q000187:drug effects* / Q000502:physiology
D000700:Analgesics; D044482:Benzeneacetamides; D001575:Benzomorphans; D011759:Pyrrolidines; D017473:Receptors, Opioid, kappa; C027248:bremazocine; C045444:U 69593