EFFECTS OF THE STRUCTURALLY NOVEL OPIOID O-2,1-ETHANEDIYL)IMINO]]BIS(7,8-DIHYDROMORPHINONE) SCHEDULE-CONTROLLED BEHAVIOR AND THERMAL NOCICEPTION IN RHESUS-MONKEYS

The in vivo pharmacology of the structurally novel opioid 14 o-2,1-eth anediyl)imino]]bis(7,8-dihydromorphinone) (TAMO) was examined in rhesu s monkeys with assays of schedule-controlled behavior and thermal noci ception. TAMO (0.032-1.8 mg/kg) produced dose-dependent decreases in r esponse rates maintained under a fixed-ratio 30 schedule of food deliv ery (n = 3) and increases in tail-withdrawal latencies in a warm-water tail-withdrawal procedure (n = 3). Both the rate-decreasing and antin ociceptive effects of TAMO (1.0 mg/kg) were maximal after 40 to 80 min and lasted at least 160 min. Pretreatment with the mu-selective opioi d antagonist quadazocine (0.001-0.1 mg/kg) antagonized the effects of TAMO and shifted the TAMO dose-effect curves to the right. Schild anal ysis yielded in vivo apparent pA(2) values (mean +/- S.E.M.) of 8.8 +/ - 0.072 and 8.7 +/- 0.40 for quadazocine antagonism of the rate-decrea sing and antinociceptive effects, respectively, of TAMO, which suggest s that the effects of TAMO were mediated by mu-opioid receptors. in ad dition, quadazocine (0.1-1.0 mg/kg) reversed the behavioral effects of TAMO (1.0 mg/kg) when quadazocine was administered immediately after TAMO had attained its maximal effect. Twenty-four-hour pretreatment wi th 1.0 mg/kg TAMO did not significantly alter the rate-decreasing or a ntinociceptive effects of fentanyl or the rate-decreasing effects of m orphine. The dose-effect curve for morphine antinociception was shifte d 4-fold to the right 24 hr after pretreatment with 1.0 mg/kg TAMO. Ho wever, 24-hr pretreatment with an equiactive dose of morphine (10.0 mg /kg) also produced a small (2-fold) but significant rightward shift in the dose-effect curve for morphine antinociception. Twenty-four-hour pretreatment with 1.8 mg/kg TAMO had no effect on the antinociceptive effects of U69,593 (0.0032-0.1 mg/kg). These results suggest that TAMO acts as a reversible mu agonist with a relatively slow onset and a du ration of action and relative efficacy similar to those of morphine in rhesus monkeys. Twenty-four hours after TAMO administration, the high est doses of TAMO that could be safely administered produced little or no mu agonist effects and no kappa antagonist effects.