Morphine withdrawal syndrome and G protein expression: a study of the time course in the rat central nervous system

We followed the changes in G protein alpha subunit expression and levels throughout the brain during the naltrexone-precipitated withdrawal syndrome in morphine-dependent rats. Intraperitoneally injected naltrexone (10 mg/kg) in rats made tolerant to morphine resulted in sustained withdrawal. Additional naltrexone doses 6, 24 and 72 h later still induced a significant abstinence syndrome. At the fifth naltrexone injection (8 days later) counted signs were completely resolved but checked ones were not. Besides the behavioural modifications, opiate withdrawal affected G protein expression in the central nervous system. In situ hybridization showed that G alpha s and G alpha o mRNA, whose levels are increased in tolerance, changed further during opiate withdrawal. Specifically, as alpha s mRNA in the hypothalamus was reduced after the first naltrexone injection and reached the control level with subsequent doses. However, alpha a mRNA expression in the olfactory system remained elevated after repeated naltrexone injections, declining to the control value of only after the fifth dose. The amounts of G alpha s and G alpha o protein closely followed the time course of mRNA. The relationship between behavioural and biochemical parameters is discussed, together with the regional selectivity of the modifications.