Indomethacin facilitates acute tolerance to and dependence upon morphine as measured by changes in fixed-ratio behavior and rectal temperature in rats

The effects of indomethacin, a prostaglandin (PG) synthetase inhibitor, on acute tolerance to and dependence on morphine were investigated. Twelve mature, male Long-Evans rats were trained to lever press for food reinforcement on a fixed-ratio 30 schedule (FR 30 behavior) and have their rectal temperature taken. The experimental protocol began with taking the rat's temperature followed by a 30 minute behavioral session. Immediately after this session the animal was injected with indomethacin or its vehicle. Two-and-a-half hours later this procedure was repeated, except that morphine or saline was administered. After an additional 2.5 hours had elapsed, a 60 minute behavioral session occurred. Half-way through the session the rat was injected with morphine (tolerance), naloxone (dependence), or saline. Immediately after the session the rat's temperature was recorded. Indomethacin potentiated the acute tolerance to the behavioral suppressant and hyperthermic effects of morphine. Indomethacin pretreatment also greatly enhanced the capacity of naloxone to decrease temperature and suppress FR 30 behavior in morphine-treated rats. These effects were not due to indomethacin altering the acute effects of morphine or the amount of morphine in the brain. These data suggest that indomethacin is inhibiting synthesis of PGs which are important in morphine tolerance and dependence.