EVIDENCE THAT NOR-BINALTORPHIMINE CAN FUNCTION AS AN ANTAGONIST AT MULTIPLE OPIOID RECEPTOR SUBTYPES

This study examined the influence of acute and repeated administration of the kappa-opioid receptor antagonist, nor-binaltorphimine, upon op ioid-induced antinociception as measured by the tail-pressure test. A single intracerebroventricular (i.c.v.) injection of nor-binaltorphimi ne (30 mu g) administered 1, 10 or 30 days prior to algesiometric test ing prevented the analgesic effect of the kappa-opioid receptor agonis t, (5 alpha,7 alpha,8 olidinyl)-1-oxaspiro(4,5)dec-8-yl)benzeneacetami de (U69593). The analgesic effect of the mu-opioid receptor agonist, [ D-Ala(2),N-methyl-Phe(4),Gly(5)-ol]enkephalin (DAMGO), and the delta-o pioid receptor agonist, [D-Pen(2),D-Pen(5)]enkephalin (DPDPE), was not modified. In contrast, when nor-binaltorphimine was administered repe atedly (twice daily i.c.v. administration of 30 mu g nor-binaltorphimi ne for 10 days), the analgesic effect of DAMGO, DPDPE as well as U6959 3 was abolished. In the case of mu- and delta-opioid receptor agonists , this abolition was apparent when testing occurred 1 or 2, but not 5 days after termination of nor-binaltorphimine treatment. This treatmen t regimen also resulted in a long-lasting antagonism (e.g. 20 days) of U69593-induced analgesia. These data show that, depending on the trea tment regimen employed, nor-binaltorphimine can function as a selectiv e kappa-opioid receptor antagonist, or as an antagonist at multiple op ioid receptor subtypes. Further, they demonstrate that nor-binaltorphi mine functions as a long-lasting kappa-opioid receptor antagonist in v ivo.