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, 28 (6), 670-678

The Molecular Signatures of Acute-immobilization-induced Antinociception and Chronic-immobilization-induced Antinociceptive Tolerance

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The Molecular Signatures of Acute-immobilization-induced Antinociception and Chronic-immobilization-induced Antinociceptive Tolerance

Jing-Hui Feng et al. Exp Neurobiol.

Abstract

In the present study, the productions of antinociception induced by acute and chronic immobilization stress were compared in several animal pain models. In the acute immobilization stress model (up to 1 hr immobilization), the antinociception was produced in writhing, tail-flick, and formalin- induced pain models. In chronic immobilization stress experiment, the mouse was enforced into immobilization for 1 hr/day for 3, 7, or 14 days, then analgesic tests were performed. The antinociceptive effect was gradually reduced after 3, 7 and 14 days of immobilization stress. To delineate the molecular mechanism involved in the antinociceptive tolerance development in the chronic stress model, the expressions of some signal molecules in dorsal root ganglia (DRG), spinal cord, hippocampus, and the hypothalamus were observed in acute and chronic immobilization models. The COX-2 in DRG, p-JNK, p-AMPKα1, and p-mTOR in the spinal cord, p-P38 in the hippocampus, and p-AMPKα1 in the hypothalamus were elevated in acute immobilization stress, but were reduced gradually after 3, 7 and 14 days of immobilization stress. Our results suggest that the chronic immobilization stress causes development of tolerance to the antinociception induced by acute immobilization stress. In addition, the COX-2 in DRG, p-JNK, p-AMPKα1, and p-mTOR in the spinal cord, p-P38 in the hippocampus, and p-AMPKα1 in the hypothalamus may play important roles in the regulation of antinociception induced by acute immobilization stress and the tolerance development induced by chronic immobilization stress.

Keywords: Acute stress; Antinociception; Chronic stress; Signal molecule; Tolerance.

Figures

Fig. 1
Fig. 1
Design of experimental time course.
Fig. 2
Fig. 2
Effect of acute and chronic immobilization stress on pain regulation in tail-flick, writhing, and formalin pain models. (A) Tail-flick test; (B) Writhing test; (C) Formalin-induced pain model-1st phase; (D) Formalin-induced pain model-2nd phase. The response time of tail-flick to radiant heat was measured. The number of writhing responses was counted for 30 min after acetic acid injection. In the formalin pain test, the pain behaviors such as vigorous licking and shaking paws were counted during the first (0~5 min) and the second (20~40 min) phases using a stopwatch. The vertical bars indicate the standard error of mean (*p<0.05, **p<0.01, ***p<0.001 compared to Control group). The mice number of animals used in each group was 10.
Fig. 3
Fig. 3
Effect of acute and chronic immobilization stress on proteins expression in the spinal cord. (A) JNK, (B) mTOR, (C) AMPKα1 protein phosphorylation in the spinal cord. These protein expressions were analyzed by Western blot. The number of animals in each group was 6. β-Actin (1:1000 dilution) was used as an internal loading control. Signals were quantified with the use of laser scanning densitometry and expressed as a percentage of the control. Values are mean±SEM (*p<0.05, **p<0.01, ***p<0.001; compared to Control group).
Fig. 4
Fig. 4
Effect of acute and chronic immobilization stress on COX-2 protein expression in DRG. The protein expression was analyzed by Western blot. The number of animals in each group was 6. β-Actin (1:1000 dilution) was used as an internal loading control. Signals were quantified with the use of laser scanning densitometry and expressed as a percentage of the control. Values are mean±SEM (*p<0.05, **p<0.01; compared to Control group).
Fig. 5
Fig. 5
Effect of acute and chronic immobilization stress on p-P38 protein expression in the hippocampus. The protein expression was analyzed by Western blot. The number of animals in each group was 6. β-Actin (1:1000 dilution) was used as an internal loading control. Signals were quantified with the use of laser scanning densitometry and expressed as a percentage of the control. Values are mean±SEM (*p<0.05, **p<0.01, ***p<0.001; compared to Control group).
Fig. 6
Fig. 6
Effect of acute and chronic immobilization stress on AMPKα1 protein phosphorylation expression in the hypothalamus. The protein expression was analyzed by Western blot. The number of animals in each group was 6. β-Actin (1:1000 dilution) was used as an internal loading control. Signals were quantified with the use of laser scanning densitometry and expressed as a percentage of the control. Values are mean±SEM (*p<0.05, **p<0.01, ***p<0.001; compared to Control group).

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