Nor-binaltorphimine: an ultra-long acting kappa-opioid antagonist in pigeons.
This study assessed the ability of naltrexone and nor-binaltorphimine (NBNI) to antagonize the rate-decreasing effects of opioid agonists. Food-restricted pigeons were trained to peck a lit key under a fixed-ratio (FR) 20 schedule of food reinforcement. Bremazocine, a kappa-opioid agonist, decreased food-reinforced responding (ED(50) = 0.02mg/kg), and naltrexone (5.6mg/kg) reduced the potency of bremazocine six-fold. The effect of naltrexone lasted less than 24h. A single injection of NBNI (1mg/kg) was given to four pigeons, and the time course of antagonism of the rate-decreasing effects of bremazocine was measured. One hour after NBNI was given, it was ineffective. Eight days later, NBNI produced a five-fold reduction in the potency of bremazocine. Between 12 and 20 days after NBNI, it reduced the potency of bremazocine 14-fold. NBNI continued to antagonize bremazocine for 11 weeks. Smaller doses of NBNI (0.001-0.1mg/kg) were ineffective. The effect of NBNI was not due to tolerance to bremazocine, since tolerance failed to develop to bremazocine administered repeatedly. NBNI (1mg/kg) did not antagonize the response rate-decreasing effects of morphine, a mu-opioid agonist, or BW373U86, a delta-opioid agonist. NBNI was an effective and extremely long-lasting kappa-opioid antagonist in the pigeon. The duration of action of NBNI is among the longest yet described in any species.
Department of Pharmacology, University of Michigan Medical School, 1301 Medical Sciences Research Building III, Ann Arbor, MI 48109-0632, USA.
D.C.
DC
Jewett
J.H.
JH
Woods