DIFFERENTIAL-EFFECTS OF SYSTEMICALLY ADMINISTERED NOR-BINALTORPHIMINE(NOR-BNI) ON KAPPA-OPIOID AGONISTS IN THE MOUSE WRITHING ASSAY

The opioid antagonist effects of systemically administered nor-binalto rphimine (nor-BNI) were evaluated against the kappa agonists CI-977, U 69,593, U50,488, ethylketocyclazocine (EKC), Mr2034 and bremazocine, t he mu agonist morphine and the alkaloid delta agonist BW-373U86 in the acetic acid-induced writhing assay in mice. All eight agonists comple tely and dose-dependently inhibited writhing. Antagonism of CI-977 was apparent 1 h after administration of 32 mg/kg nor-BNI, peaking after 4 h and was maintained for at least 4 weeks; no antagonist effects of nor-BNI were apparent after 8 weeks. Nor-BNI (32 mg/kg) caused little or no antagonism of morphine or BW-373U86 at 1 h and none at 24 h afte r nor-BNI administration. Subsequently, dose-effect curves for CI-977, U50,488, U69,593, EKC, Mr2034 and bremazocine were determined 24 h af ter pretreatment with 3.2, 10 and 32 mg/kg nor-BNI. Pretreatment with 3.2 mg/kg nor-BNI produced significant antagonism of all six kappa ago nists, suggesting that their antinociceptive effects were mediated at least in part by nor-BNI-sensitive kappa receptors. At higher doses, n or-BNI dose-dependently shifted the agonist dose-effect curves of CI-9 77, U50,488, U69,593 and bremazocine, but not those of EKC and Mr2034, suggesting that the latter compounds may be producing effects via nor -BNI-insensitive receptors. Mu receptor involvement was demonstrated f ollowing a 24 h pretreatment with 32 mg/kg beta-FNA in combination wit h nor-BNI, which significantly increased the degree of antagonism of M r2034 and EKC from that seen with nor-BNI alone. Hence, SC administere d nor-BNI selectively antagonized agonist activity mediated through ka ppa-opioid receptors without differentiating between kappa subtypes. N or-BNI also enabled the mu agonist activity of proposed kappa agonists to be measured.