ACTH: A single pretreatment enhances the analgesic efficacy of and prevents the development of tolerance to morphine

Abstract

Evidence suggests a close relationship between ACTH and opioids. They are derived from the same precursor molecule, released concomitantly in response to stress and are known to interact at receptor level. Acute exposure to endogenous opioids induces analgesia in the short-term yet shifts the morphine dose-response curve to the right for a period of several weeks. Therefore, the possiblity exists that ACTH might also exert an influence extending beyond that suggested by its biological half-life. To investigate this further. DBA/2 mice were pretreated with porcine ACTH left undisturbed for 3 days, then challenged with morphine. Dose-response studies indicated that pretreatment with 10 but not 0, 0.1 or 1.0 IU ACTH influenced responsivity to morphine, rendering a sub-analgesic dose (1.0 mg/kg) effective and significantly enhancing the degree of analgesia observed following treatment with 5 mg/kg morphine, suggesting a shift in the dose-response curve to the left. Time-course analysis revealed 5 mg/kg morphine to induce an analgesic reaction with an onset of between 15–30 and lasting between 60 and 120 min post opiate administration. ACTH pretreatment did not influence this time course, however a significantly greater degree of analgesia was observed at 60 min post morphine injection in 10 IU ACTH pretreated animals than in saline pretreated controls. ACTH pretreatment further influenced subsequent responding to chronic morphine administration. Whilst saline pretreated animals demonstrated significant analgesia in response to the first administration, tolerance to this effect had developed following four days of repeated exposure to morphine. By contrast, ACTH pretreated animals displayed analgesia on each occasion tested with the analgesic response to morphine following 12 consecutive days of chronic treatment being at least as great as that observed following the first exposure. Although the mechanisms of action of ACTH under these circumstances have yet to be elucidated, these data together do nonetheless suggest that administration of porcine ACTH to mice has profound and long-lasting consequences for subsequent responding to morphine.