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 U69,5 93 and bremazocine was studied in mice. U69,593 and bremazocine elicit ed 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 nmo l, i.c.v.) of U69,593, tolerance developed as demonstrated by a 5.6-fo ld 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 bremazoci ne (30 nmol, i.c.v.) for 3 days also produced tolerance as shown by a greater than 15-fold rightward shift in the bremazocine antinociceptiv e dose-response line. The i.c.v. dose-response line for U69,593 was un altered in bremazocine-tolerant mice. These data demonstrate that whil e tolerance develops to the antinociceptive effects of both U69,593 an d bremazocine, a two-way lack of cross-tolerance can be demonstrated b etween these kappa-agonists in this endpoint. These data suggest mecha nistic differences in the antinociceptive effects of these kappa-agoni sts. Such suggestions are consistent with antinociceptive action of th ese agonists at subtypes of kappa-receptors.