Antagonism of morphine-induced analgesia, tolerance and dependence by alpha-melanocyte-stimulating hormone.

The effect of alpha-melanocyte-stimulating hormone (alpha-MSH) on morphine-induced analgesia, tolerance and dependence was investigated by administering alpha-MSH by intracerebroventricular (i.c.v.) injection to mice 15 min before morphine administration. alpha-MSH antagonized morphine-induced analgesia at doses lower than that necessary to demonstrate hyperalgesia. Pretreatment of mice with 100 mg/kg of morphine sulfate s.c. did not increase the ED50 of morphine in alpha-MSH-treated mice to the same degree as that of control mice. Furthermore, the increase in naloxone potency due to morphine pretreatment, which was used as an indicator of tolerance development, was inhibited by alpha-MSH. The ED50 of naloxone needed to induce withdrawal jumping in dependent mice was increased by alpha-MSH administered 15 min before morphine, but not when alpha-MSH was administered 15 min before naloxone. alpha-MSH did not alter whole-brain levels of morphine. Naloxone (1.0 mg/kg), administered i.p. 15 min before alpha-MSH, did not alter the antagonism by alpha-MSH of morphine-induced analgesia, tolerance or dependence. Furthermore, alpha-MSH did not change the affinity of opioid receptors for etorphine or the maximal number of binding sites, but alpha-MSH did exhibit a very weak affinity for opioid receptors. These results indicate that alpha-MSH antagonized the actions of morphine but this antagonism did not appear to be mediated through an interaction with opioid receptors.