Effects of levorphanol and several kappa-selective opioids on respiration and behavior in rhesus monkeys.
The effects of the mu-selective opioid, levorphanol (0.03-1.0 mg/kg), and the kappa-selective opioids, U-50,488 (0.03-1.0 mg/kg), tifluadom (0.01-0.3 mg/kg), bremazocine (0.0003-0.01 mg/kg) and MR 2034 (0.001-0.03 mg/kg), on ventilation and on schedule-controlled behavior were studied in rhesus monkeys. In seated, unanesthetized monkeys prepared with a head plethysmograph, ventilation during exposure to 5% CO2 mixed in air was measured after cumulative doses of each drug. In other monkeys, effects on behavior were studied by administering cumulative doses preceding sequential periods of fixed-ratio responding. Levorphanol, tifluadom, bremazocine and MR 2034 produced dose-related decreases in minute volume, tidal volume and respiratory frequency. In contrast, U-50,488 had only minimal effects on ventilation over the range of doses studied. All drugs decreased fixed-ratio rates in a dose-related manner. Comparisons between their effects in behavioral and respiratory experiments differentiated levorphanol and MR 2034 from U-50,488, bremazocine and tifluadom. Doses of levorphanol or MR 2034 that decreased minute volume markedly had little effect on behavior. In contrast, bremazocine, tifluadom and U-50,488 had less pronounced effects on minute volume at doses that suppressed behavior markedly. Naltrexone (0.03-1.0 mg/kg) antagonized decreases in minute volume produced by levorphanol, MR 2034, bremazocine and tifluadom, and apparent pA2 values were similar for each naltrexone-agonist pair. When the effects of levorphanol (0.03-0.3 mg/kg) were determined in the presence of U-50,488 (0.3 mg/kg), tifluadom (0.1 mg/kg) or bremazocine (0.003 mg/kg), the levorphanol dose-effect curve was shifted approximately 3-fold to the left, suggesting that the effects of the drugs were additive.(ABSTRACT TRUNCATED AT 250 WORDS)
Howell
L L
LL
Laboratory of Psychobiology, Harvard Medical School, Boston, Massachusetts.
Bergman
J
J
Morse
W H
WH
D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001569:Benzodiazepines / Q000494:pharmacology; D001575:Benzomorphans / Q000494:pharmacology; D002245:Carbon Dioxide / Q000494:pharmacology; D007981:Levorphanol / Q000494:pharmacology*; D008253:Macaca mulatta; D008297:Male; D011759:Pyrrolidines / Q000494:pharmacology; D011957:Receptors, Opioid / Q000378:metabolism*; D017473:Receptors, Opioid, kappa; D012119:Respiration / Q000187:drug effects*
D001575:Benzomorphans; D011759:Pyrrolidines; D011957:Receptors, Opioid; D017473:Receptors, Opioid, kappa; D001569:Benzodiazepines; D002245:Carbon Dioxide; D007981:Levorphanol; C032478:MR 2034; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; C027248:bremazocine; C035470:tifluadom