Biochemical correlates of morphine withdrawal. 2. Effects of clonidine

Naloxone-precipitated morphine withdrawal in the rat has been shown to deplete adrenal epinephrine and to increase adrenal and locus ceruleus tyrosine hydroxylase activities. Administration of clonidine (0.1 - 1.0 mg/kg) through the first 6 hr of withdrawal blocked adrenal epinephrine depletion in a dose-dependent fashion. Clonidine also blocked the increases in tyrosine hydroxylase activity seen in the adrenal and locus ceruleus during withdrawal. Clonidine attenuated the weight loss and inhibited the diarrhea during withdrawal. The alpha-2 adrenergic antagonist yohimbine reversed the effects of clonidine in blocking withdrawal. Morphine withdrawal caused only a slight depletion of epinephrine in the denervated adrenal; however, clonidine (0.3 mg/kg) prevented this decrease. These results suggest that clonidine suppresses adrenal and central adrenergic function during morphine withdrawal. This effect occurs through an alpha-2 adrenergic mechanism, possibly at the level of the locus ceruleus although clonidine appears to also have a direct effect on the adrenal medulla. The results are discussed in terms of adrenergic mechanisms of opiate withdrawal and the actions of clonidine on this syndrome.