Effects of the structurally novel opioid 14α,14′β-[dithiobis [(2-oxo-2,1-ethanediyl)imino]]bis(7,8-dihydromorphinone) on schedule-controlled behavior and thermal nociception in rhesus monkeys

The in vivo pharmacology of the structurally novel opioid 14α,14′β-[dithiobis[(2-oxo-2,1-ethanediyl)imino]]bis(7,8- dihydromorphinone) (TAMO) was examined in rhesus monkeys with assays of schedule-controlled behavior and thermal nociception. TAMO (0.032-1.8 mg/kg) produced dose-dependent decreases in response rates maintained under a fixed-ratio 30 schedule of food delivery (n = 3) and increases in tail-withdrawal latencies in a warm-water tail-withdrawal procedure (n = 3). Both the rate-decreasing and antinociceptive effects of TAMO (1.0 mg/kg) were maximal after 40 to 80 min and lasted at least 160 min. Pretreatment with the μ-selective opioid antagonist quadazocine (0.001-0.1 mg/kg) antagonized the effects of TAMO and shifted the TAMO dose-effect curves to the right. Schild analysis yielded in vivo apparent pA₂ values (mean ± S.E.M.) of 8.8 ± 0.072 and 8.7 ± 0.40 for quadazocine antagonism of the rate-decreasing and antinociceptive effects, respectively, of TAMO, which suggests that the effects of TAMO were mediated by μ-opioid receptors. In addition, 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 with 1.0 mg/kg TAMO did not significantly alter the rate-decreasing or antinociceptive effects of fentanyl or the rate-decreasing effects of morphine. The dose-effect curve for morphine antinociception was shifted 4-fold to the right 24 hr after pretreatment with 1.0 mg/kg TAMO. However, 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 1/69,593 (0.0032-0.1 mg/kg). These results suggest that TAMO acts as a reversible μ agonist with a relatively slow onset and a duration of action and relative efficacy similar to those of morphine in rhesus monkeys. Twenty-four hours after TAMO administration, the highest doses of TAMO that could be safely administered produced little or no μ antagonist effects and no κ antagonist effects.