BUTORPHANOL - CHARACTERIZATION OF AGONIST AND ANTAGONIST EFFECTS IN RHESUS-MONKEYS

The effects of butorphanol were studied in assays of antinociception, respiratory depression, sedation, diuresis and reinforcing effects in rhesus monkeys, and opioid binding in monkey brain. Butorphanol (0.003 -0.1 mg/kg s.c.) was effective in the warm-water tail withdrawal assay in 50 degrees C water but not in 55 degrees C. Over a similar dose ra nge, butorphanol caused substantial respiratory depression, without an obvious plateau. Constrained quadazocine apparent pA(2) analysis on t he respiratory depressant and antinociceptive effects of butorphanol y ielded different values between the two assays (respiratory depression pA(2) = 6.61; antinociception pA(2) = 8.26). Butorphanol (0.1 mg/kg) antagonized the antinociceptive effects of etonitazene in 55 degrees C water, but caused a nonparallel leftward shift in the U50,488 dose-ef fect curve; both effects were probably due to butorphanol's intermedia te efficacy at mu receptors. Butorphanol (0.0001-0.003 mg/kg per injec tion i.v.) was self-administered; unlike other mu opioid agonists, its maximum effect was depressed after pretreatment with quadazocine (0.0 1-1.0 mg/kg). Butorphanol (0.003-0.32 mg/kg) was devoid of substantial sedative or muscle relaxant effects, as measured by observational rat ing scales. Butorphanol (0.01-0.1 mg/kg s.c.), unlike U50,488 (0.01-0. 32 mg/kg) did not cause diuresis. Kappa agonist or antagonist effects of butorphanol were not detected in the present studies. This profile is consistent with butorphanol's binding characteristics in rhesus mon key brain which indicated 12-fold murkappa selectivity and 34-fold mur delta selectivity.