Effects of levorphanol and several kappa-selective opioids on respiration and behavior in rhesus monkeys

Abstract

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)