Effects of the structurally novel opioid 14 alpha, 14' beta-[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 14 alpha, 14' beta-[dithiobis[(2-oxo-2,1-ethanediyl)imino]]bis(7,8-dihydromorphinon e) (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 mu-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 mu-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 after 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 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 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 mu antagonist effects and no kappa antagonist effects.
Gatch
M B
MB
Alcohol and Drug Abuse Research Center, McLean Hospital, Harvard Medical School, Belmont, Massachusetts, USA.
Negus
S S
SS
Mello
N K
NK
Archer
S
S
Bidlack
J M
JM
D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D001392:Azocines / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects*; D044482:Benzeneacetamides; D005260:Female; D005283:Fentanyl / Q000494:pharmacology; D006358:Hot Temperature; D004091:Hydromorphone / Q000031:analogs & derivatives* / Q000494:pharmacology; D008253:Macaca mulatta; D008297:Male; D009020:Morphine / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D010146:Pain / Q000517:prevention & control*; D011759:Pyrrolidines / Q000494:pharmacology; D017473:Receptors, Opioid, kappa / Q000819:agonists*; D017450:Receptors, Opioid, mu / Q000819:agonists* / Q000037:antagonists & inhibitors*
D000700:Analgesics; D001392:Azocines; D044482:Benzeneacetamides; D009292:Narcotic Antagonists; D011759:Pyrrolidines; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; C076027:14-thioglycolamido-7,8-dihydromorphinone; D009020:Morphine; C045444:U 69593; D004091:Hydromorphone; D005283:Fentanyl; C035969:quadazocine