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Activation of Extracellular Signal-Regulated Kinase1/2 in the Medial Prefrontal Cortex Contributes to Stress-Induced Hyperalgesia

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Abstract

Stressful stimuli can exacerbate persistent pain disorder. However, the underlying mechanism is still unknown. Here, to reveal the underlying mechanism for stressful stimuli-induced hyperalgesia in chronic pain, we investigated the effect of extracellular signal-regulated kinase1/2 (ERK1/2) activation on pain hypersensitivity using single-prolonged stress (SPS) model, complete Freund’s adjuvant (CFA) model and SPS + CFA model. The experimental results revealed significantly reduced paw withdrawal threshold in the SPS, CFA, and SPS + CFA group compared with the control group. However, the increased phosphorylation of ERK1/2 in the medial prefrontal cortex (mPFC) was observed in the SPS- or SPS + CFA-exposed group but not the CFA group compared with control group. There was also a significant increase in mPFC ERK1/2 phosphorylation and mechanical allodynia after SPS + CFA treatment compared to SPS or CFA treatment alone. Furthermore, inhibiting ERK1/2 phosphorylation by microinjection of U0126, a MAPK kinase (MEK) inhibitor, into the mPFC attenuated SPS + CFA- and SPS- but not CFA-induced mechanical allodynia, anxiety-like behavior, and cognitive impairments. These results suggest that the activation of ERK1/2 in the mPFC may contribute to the process of stress-induced cognitive and emotional disorders, leading to an increase in pain sensitivity.

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Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (nos. 30971123, 31010103909, 81171050, 81371239).

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Authors and Affiliations

  1. Department of Anatomy, Histology and Embryology and K. K. Leung Brain Research Centre, The Fourth Military Medical University, No. 169 West Changle Road, Shaanxi, Xi’an, China

    Jian Qi, Ya-Cheng Lu, Ting Zhang, Hao Xu, Yuan-Yuan Cui, Yan-Zhou Chen, Wen Wang, Yu-Lin Dong & Yun-Qing Li

  2. Department of Pharmacy, The Second Hospital of Shandong University, Jinan, China

    Chen Chen

  3. Medical student of Grade 2011, The Fourth Military Medical University, Xi’an, China

    Yan-Zhou Chen

Authors
  1. Jian Qi
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  2. Chen Chen
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  3. Ya-Cheng Lu
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  4. Ting Zhang
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  5. Hao Xu
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  6. Yuan-Yuan Cui
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  7. Yan-Zhou Chen
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  8. Wen Wang
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  9. Yu-Lin Dong
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  10. Yun-Qing Li
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Corresponding authors

Correspondence to Wen Wang, Yu-Lin Dong or Yun-Qing Li.

Additional information

Jian Qi and Chen Chen contributed equally to this work.

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Supplementary Fig. 1

Photomicrograph of coronal brain sections from three representative rats showing bilateral microinjections in the mPFC. Diagrammatic representations based on the rat brain atlas of Paxinos and Watson indicate the location of mPFC and ACC. ACC, anterior cingulate cortex; Cg1, Cingulate cortex, area 1; IL, infralimbic cortex; PrL, prelimbic cortex; cc, corpus callosum. The microinjection sites were located in mPFC (A-D, A’-D’, A”-D”), without diffusion to other area, such as ACC (E, E’, E”). Scale Bar = 200 μm. (JPEG 869 kb)

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Qi, J., Chen, C., Lu, YC. et al. Activation of Extracellular Signal-Regulated Kinase1/2 in the Medial Prefrontal Cortex Contributes to Stress-Induced Hyperalgesia. Mol Neurobiol 50, 1013–1023 (2014). https://doi.org/10.1007/s12035-014-8707-8

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  • DOI: https://doi.org/10.1007/s12035-014-8707-8

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