Morphine withdrawal produces circadian rhythm alterations of clock genes in mesolimbic brain areas and peripheral blood mononuclear cells in rats

Apr 23, 2009Journal of neurochemistry

Morphine withdrawal changes daily patterns of biological clock genes in brain reward areas and blood cells in rats

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Abstract

Chronic morphine withdrawal led to desynchronization of clock gene expression in the central nervous system and peripheral blood mononuclear cells.

Rats exhibited clear withdrawal signs, including teeth chattering and weight loss, 14 hours after the last morphine dose.
Expression of rPER1 and rPER2 showed robust circadian rhythms in most brain regions of morphine-treated rats, similar to control rats.
In the ventral tegmental area, rPER1 expression was completely phase-reversed in morphine-treated rats.
Blunting of circadian oscillations for rPER1 occurred in the central amygdala, hippocampus, nucleus accumbens core, and PBMCs of morphine-treated rats.
rPER2 expression was also blunted in the central amygdala, prefrontal cortex, nucleus accumbens core, and PBMCs following morphine treatment.
rCLOCK expression did not show rhythmic changes in morphine-treated rats, remaining similar to controls.

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Previous studies have shown that clock genes are expressed in the suprachiasmatic nucleus (SCN) of the hypothalamus, other brain regions, and peripheral tissues. Various peripheral oscillators can run independently of the SCN. However, no published studies have reported changes in the expression of clock genes in the rat central nervous system and peripheral blood mononuclear cells (PBMCs) after withdrawal from chronic morphine treatment. Rats were administered with morphine twice daily at progressively increasing doses for 7 days; spontaneous withdrawal signs were recorded 14 h after the last morphine administration. Then, brain and blood samples were collected at each of eight time points (every 3 h: ZT 9; ZT 12; ZT 15; ZT 18; ZT 21; ZT 0; ZT 3; ZT 6) to examine expression of rPER1 and rPER2 and rCLOCK. Rats presented obvious morphine withdrawal signs, such as teeth chattering, shaking, exploring, ptosis, and weight loss. In morphine-treated rats, rPER1 and rPER2 expression in the SCN, basolateral amygdala, and nucleus accumbens shell showed robust circadian rhythms that were essentially identical to those in control rats. However, robust circadian rhythm in rPER1 expression in the ventral tegmental area was completely phase-reversed in morphine-treated rats. A blunting of circadian oscillations of rPER1 expression occurred in the central amygdala, hippocampus, nucleus accumbens core, and PBMCs and rPER2 expression occurred in the central amygdala, prefrontal cortex, nucleus accumbens core, and PBMCs in morphine-treated rats compared with controls. rCLOCK expression in morphine-treated rats showed no rhythmic change, identical to control rats. These findings indicate that withdrawal from chronic morphine treatment resulted in desynchronization from the SCN rhythm, with blunting of rPER1 and rPER2 expression in reward-related neurocircuits and PBMCs.

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Morphine withdrawal produces circadian rhythm alterations of clock genes in mesolimbic brain areas and peripheral blood mononuclear cells in rats

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