Clonidine suppression of noradrenergic hyperactivity during morphine withdrawal by clonidine: biochemical studies in rodents and primates.

In rodents, naloxone-precipitated withdrawal of morphine-dependent animals causes an increase in NE turnover and MHPG accumulation in certain regions of the brain. This increase in NE turnover and MHPG accumulation is suppressed by clonidine to a dose-dependent degree via a naloxone-insensitive mechanism. In general, drugs which have been shown by electrophysiological studies to cause changes in the activity of NE neurons in the locus coeruleus also alter the brain levels of MHPG. These studies suggest that the brain levels of MHPG may be used as a biochemical measure of alterations of impulse flow in NE neurons of the locus coeruleus. In morphine-dependent vervet monkeys, administration of naloxone or naltrexone causes an increase in the brain levels of MHPG. The increase in MHPG observed during withdrawal is suppressed by clonidine. Brain levels of MHPG measured in both drug-treated and control monkeys correlate significantly with plasma and CSF measures of MHPG. These observations suggest that under controlled conditions plasma MHPG can provide a reasonable measure of brain NE metabolism in primates. Pilot data from clinical studies taken together with the more direct observations made in non-human primates are consistent with the hypothesis that in humans brain NE systems become hyperactive during opiate withdrawal and that this hyperactivity of NE systems is suppressed by clonidine.