Extremely long-lasting antagonistic actions of nor-binaltorphimine (nor- BNI) in the mouse tail-flick test

The duration of antagonistic action of nor-binaltorphimine (nor-BNI), a kappa antagonist, of antinociception resulting from selective opioid agonists, was examined using the mouse tail-flick assay as the endpoint. Nor- BNI (1 nmol, i.c.v. at -20 min) antagonized equiantinociceptive doses of the opioid kappa agonists (5α,7α,8β)-(-)-N-methyl-N-(7-(1-pyrrolidinyl)-1- oxaspiro(4,5)dec-8-yl) benzeneacetamide (U69,593) (70 nmol i.c.v.) or bremazocine (25 nmol i.c.v.), but did not antagonize antinociception produced by the mu opioid-selective [D-Ala², NMePhe⁴, Gly-ol]enkephalin or the delta opioid-selective [D-Pen², D-Pen⁵]enkephalin. Pretreatment with nor-BNI (1 nmol i.c.v.) antagonized the antinociceptive effects of U69,593 and bremazocine for up to 28 days. At all pretreatment times, the antinociceptive dose-response lines for these kappa agonists were displaced to the right to various degrees in a parallel fashion; an increasing rightward displacement of the U69,593 and bremazocine antinociceptive dose-response lines was observed at 1 and 3 days after a single nor-BNI pretreatment, with a gradual return toward the control level at later times after pretreatment. Increasing the dose of nor-BNI to 10 nmol produced only a transient blockade of equiantinociceptive doses of the mu selective agonist [D-Ala², NMePhe⁴, Gly-ol]enkephalin and the delta selective agonist [D-Pen², D- Pen⁵]enkephalin (at 20-30 min post-nor-BNI pretreatment). Radioligand binding studies in vitro demonstrated a 23-and 30-fold decrease in the affinity of [³H]U69,593 at 1 and 3 days after nor-BNI, respectively, followed by a return toward control affinity levels; no change in the number of binding sites was detected. These results indicate that nor-BNI produces a remarkably long-lasting blockade of opioid kappa receptors, and may indicate that nor-BNI remains in the brain for up to 56 days after a single i.c.v. dose.