INCREASED SENSITIVITY OF THE CENTRAL NERVOUS-SYSTEM TO MORPHINE ANALGESIA BY AMITRIPTYLINE IN NAIVE AND MORPHINE-TOLERANT RATS

The effects of amitriptyline (AT) (20 mg/kg, i.p.), given 1 h before [14C]morphine administration, on the analgesic response and tissue distribution of [14C]morphine and [14C]morphine glucuronide (MG) were studied in naive and morphine-tolerant rats. Rats were rendered tolerant to morphine analgesia by s.c. implantation for 3 days of a pellet containing 75 mg of morphine base. In naive rats, AT treatment increased the intensity and prolonged the duration of morphine analgesia. Amitriptyline treatment did not cause any significant change in the concentrations of [14C]morphine in the brain or of total 14C in the plasma 30, 60 and 90 min after administration of [14C]morphine. With the exception of a slight increase in total 14C in the liver at 30-min, AT treatment did not affect the concentrations of total 14C in the liver and urine. The fact that the percentages of total 14C in the liver or urine as [14C]MG were not changed by AT treatment suggests that AT did not affect biotransformation of morphine. This suggestion was supported by a previous report that a metabolic drug interaction with morphine would be reflected by a change in the percentage of total 14C as [14C]MG in the liver and urine. Potentiation of morphine analgesia, similar to that seen in naive rats, was found in morphine-tolerant rats. The brain concentration of [14C]morphine in AT-treated morphine-tolerant rats at 60 min was lower than that in controlled morphine-tolerant rats. The concentrations of total 14C in liver and urine and the percentage of total 14C in liver or urine as [14C]MG were not changed significantly by AT treatment in morphine-tolerant rats. AT treatment apparently prolonged morphine analgesia by increasing the sensitivity of the CNS to morphine rather than by changing morphine pharmacokinetics.