Increased Density of Guanine Nucleotide-Binding Proteins in the Postmortem Brains of Heroin Addicts

OBJECTIVE: To directly evaluate the guanine nucleotide-binding (G) protein subunits alpha, beta, and gamma, which are involved in the signal transduction of opioid receptors, in the postmortem brains of heroin addicts who had died of an opiate overdose. METHODS: Specimens of the frontal cortex (Brodmann's area 9) were collected from 11 heroin addicts and 10 control subjects without a history of drug abuse. The biochemical status of human brain G protein subunits during opiate dependence was studied by means of immunoblotting techniques. Solubilized G proteins were separated by gel electrophoresis, transferred to pyroxylin membranes (western blotting) labeled with specific antiserum samples, and quantitated by image analysis after enhanced chemoluminescence. RESULTS: In the frontal cortex, relevant increases in the immunoreactivities of G alpha i 1/2 (19% +/- 4%, P < .005), G alpha o (29% +/- 7%, P < .005), and G alpha s (26% +/- 5%, P < .005) but not of G alpha i3 were found in heroin addicts compared with age- and sex-matched controls. Moreover, the amount of G protein beta-subunit immunoreactivity was also consistently increased (27% +/- 8%, P < .01) compared with controls in the same brain region. These G protein changes in the brains of human opiate addicts paralleled (with the exception of G alpha s) those obtained in the brains of morphine hydrochloride-dependent rats. The increase in G alpha s immunoreactivity that was observed in the rat brain only after the short-term morphine administration (24% +/- 3%, P < .005) suggests that the increase in G alpha s immunoreactivity in the brains of human addicts could be the cellular response to a deadly overdose of heroin. CONCLUSIONS: Alterations in the density of specific Gi and Go protein subunits that are coupled to mu-opioid and other opioid receptors may be of clinical relevance in opiate tolerance, dependence, and abstinence syndrome.