1Department of Anesthesiology, the 150 Hospital of Chinese PLA, Luoyang   471031, Henan Province, China

2Department of Anesthesiology, General Hospital of Chinese PLA, Beijing   100853, China

3Department of Anesthesiology, Dongfang Hospital, Tongji University, Shanghai   200120, China

4Department of Anesthesiology, General Hospital of Jinan Military Area Command of Chinese PLA, Jinan   250031, Shandong Province, China

Qinghua Wu★, Master, Attending physician, Department of Anesthesiology, the 150 Hospital of Chinese PLA, Luoyang   471031, Henan Province, China Wu QH, Fu Q, Wang XH, Zhao JH, Liu LW, Tang SR. Brain regional changes of guanine nucleotide binding protein-inhabitant 2 in acute and chronic morphine-tolerant and -dependent rats. Neural Regen Res 2008;3(7):751-5

Abstract

BACKGROUND: Drug addiction involves two main central nervous systems, namely the dopamine and noradrenaline systems. These systems are primarily distributed in five brain regions: the ventral tegmental area, the nucleus accumbens, the prefrontal cortex, the hippocampus, and the locus coeruleus.

OBJECTIVE: To investigate regional changes of guanine nucleotide binding protein-inhabitant 2 (G_i2) in dopaminergic and noradrenergic neurons in brains of morphine-tolerant and -dependent rats.

DESIGN, TIME, AND SETTING: A randomized control study was performed at the Department of Neurobiology in the Second Military Medical University of Chinese PLA (Shanghai, China) between September 2002 and March 2004.

MATERIALS: Thirty-six, healthy, male, Sprague-Dawley (SD) rats were used to establish morphine-dependent models. Morphine hydrochloride was a product of Shenyang First Pharmaceutical Factory (China); naloxone hydrochloride was a product of Beijing Four-Ring Pharmaceutical Factory (China); and α subunit of G_i2 antibody was offered by Santa Cruz Biotechnology, Inc (USA).

METHODS: Thirty-six SD rats were randomly divided into six groups (n = 6): (1) acute morphine-dependent group, (2) acute abstinent group, (3) acute control group, (4) chronic morphine-dependent group, (5) chronic abstinent group, and (6) chronic control group. Rats in the acute morphine-dependent and the acute groups were injected with morphine (5 mg/kg), one injection every two hours, for a total of eight injections. In the acute and chronic morphine-dependent rat models, morphine withdrawal syndrome was precipitated by an injection of naloxone (5 mg/kg). Rats in the acute control group were given a peritoneal injection of physiological saline at the same administration time as the above two groups. Rats in the chronic morphine-dependent and chronic abstinent groups were injected with morphine three times per day. The administration dose on day 1 was initially 5 mg/kg at 20:00, which increased by   5 mg/kg at 8:00, 12:00, and 20:00 until day 7. On day 13, the dose continuously increased by 10 mg/kg until a chronic morphine-dependent rat model was successfully induced. Afterwards, the rats presented with withdrawal syndromes on naloxone (5 mg/kg) at 8:00 on the same day. Rats in the chronic control group were injected with physiological saline at the same time of the two chronic groups.

MAIN OUTCOME MEASURES: The concentration of G_i2 protein in the five brain regions (ventral tegmental area, nucleus accumbens, prefrontal cortex, locus coeruleus, and hippocampus) was detected by immunohistochemistry.

RESULTS: In the acute morphine-dependent and acute abstinent groups, G_i2 protein concentration was significantly decreased in the nucleus accumbens, compared to the acute control group (P < 0.01), while no obvious changes were detected in other brain regions. In the chronic morphine-dependent and chronic abstinent groups, G_i2 protein concentration was significantly decreased in the nucleus accumbens, but significantly increased in the locus coeruleus (P < 0.01) compared to the chronic control group.

CONCLUSION: Morphine dependence and tolerance may induce obvious reductions of G_i2 protein levels in the nucleus accumbens of rats. Chronic morphine dependence desensitizes the homologous neurons.

Key Words: morphine dependence/tolerance; guanine nucleotide binding protein-inhabitant 2; hippocampus; ventral tegmental area; nucleus accumbens; prefrontal cortex; locus coeruleus

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