Inhibition of abstinence syndrome in opiate defendent mice by cyclo (His-Pro)

Intracerebral administration of cyclo (His-Pro), the postulated metabolite of thyroliberin (TRH, pGlu-His-Pro-NH₂) inhibited the naloxone induced withdrawal responses in morphine dependent mice. Mice were rendered dependent on morphine by the subcutaneous implantation of a pellet (containing 75 mg of morphine free base) for three days. Six hours after pellet removal, the naloxone ED₅₀ for the jumping response was found to be higher in mice injected with cyclo (His-Pro) compared with that of vehicle controls. Similarly, the hypothermic response observed following 50 μg/kg of naloxone given given 6 h after pellet removal or that seen with 100 μg/kg of naloxone given 24 h after pellet removal from morphine-dependent mice was inhibited by cyclo (His-Pro). Previously, we have shown similar results with TRH on the morphine abstinence syndrome. It appears, therefore, that cyclo (His-Pro) may be the active metabolite of TRH and analogs of cyclo (His-Pro) may be useful in blocking the symptoms of the opiate abstinence syndrome.