Comparative effects of thyrotropin releasing hormone, MK-771 and DN-1417 on morphine abstinence syndrome

The effects of thyrotropin releasing hormone (TRH) were compared with two of its analogs, L-N-(2-oxopiperidine-6-yl-carbonyl)-L-histidyl-L-thiazolidine-4-carbo xam ide (MK-771) and gamma-butyrolactone-4-carboxyl-histidyl-prolineamide (DN-1417) on the abrupt and naloxone-precipitated abstinence symptoms in morphine-dependent male Swiss-Wester mice. Mice were made physically dependent on morphine by subcutaneous implantation for 3 days of a pellet containing 75 mg morphine free base. Control mice were implanted with placebo pellets. Intracerebral administration of TRH (10 ng-10 micrograms per mouse) immediately after removal of placebo pellets had no effect on the basal temperature of mice. Mice implanted with morphine pellets exhibited a characteristic hypothermic response following the removal of the pellets. TRH at all doses employed prevented the hypothermia observed during abrupt withdrawal of morphine (pellet removal). DN-1417 and MK-771 (10 ng-10 micrograms per mouse) on the other hand produced a short lived hyperthermic response in mice from which placebo pellets had been removed. However, both TRH analogs produced long-lasting antagonism of withdrawal hypothermia in mice from which morphine pellets had been removed. TRH and its analogs had no effect on the body weight loss observed during abrupt withdrawal of morphine. Intracerebral administration of 10 micrograms TRH and its analogs inhibited the naloxone-induced jumping response as evidenced by increases in naloxone ED50 values to elicit this response. It is concluded that TRH and its analogs may be useful in combating some of the withdrawal symptoms in opiate-dependent subjects.