Loss of protein kinase C-alpha beta in brain of heroin addicts and morphine-dependent rats.

The biochemical status of human brain protein kinase C (PKC)-alpha beta during opiate dependence was studied by means of immunoblotting techniques in postmortem brain of heroin addicts who had died by opiate overdose. In the frontal cortex, a marked decrease (53%, p < 0.05) in the immunoreactivity of PKC-alpha beta was found in heroin addicts compared with matched controls. The loss of PKC-alpha beta in the brain of human addicts paralleled that observed in the frontal cortex of rats after chronic treatment with morphine (10-100 mg/kg i.p. for 5 days) (PKC-alpha beta decreased by 34%, p < 0.05). Chronic treatment with naloxone (1 mg/kg i.p. every 12 h for 5 days) did not alter PKC-alpha beta immunoreactivity in the rat brain. However, in morphine-dependent rats, naloxone-precipitated withdrawal induced a rapid and strong behavioral reaction with a concomitant up-regulation of PKC-alpha beta immunoreactivity to control values. These results indicated that the decrease of brain PKC-alpha beta induced by heroin/morphine is a mu-opioid receptor-mediated effect. The chronic administration of opiates has been associated with a marked sensitization of the adenylyl cyclase/cyclic AMP system, although this phenomenon is not exclusive of the opioid system but the general cellular adaptation to chronic inhibition of adenylyl cyclase. In this context, chronic treatment of rats with other inhibitory agonists (e.g., clonidine, 1 mg/kg i.p. every 12 h for 14 days) acting through receptors (e.g., alpha 2-adrenoceptors) also coupled to adenylyl cyclase did not alter brain PKC-alpha beta immunoreactivity.(ABSTRACT TRUNCATED AT 250 WORDS)