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Signaling Mechanism of Cannabinoid Receptor-2 Activation-Induced β-Endorphin Release

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Abstract

Activation of cannabinoid receptor-2 (CB2) results in β-endorphin release from keratinocytes, which then acts on primary afferent neurons to inhibit nociception. However, the underlying mechanism is still unknown. The CB2 receptor is generally thought to couple to Gi/o to inhibit cAMP production, which cannot explain the peripheral stimulatory effects of CB2 receptor activation. In this study, we found that in a keratinocyte cell line, the Gβγ subunits from Gi/o, but not Gαs, were involved in CB2 receptor activation-induced β-endorphin release. Inhibition of MAPK kinase, but not PLC, abolished CB2 receptor activation-induced β-endorphin release. Also, CB2 receptor activation significantly increased intracellular Ca2+. Treatment with BAPTA-AM or thapsigargin blocked CB2 receptor activation-induced β-endorphin release. Using a rat model of inflammatory pain, we showed that the MAPK kinase inhibitor PD98059 abolished the peripheral effect of the CB2 receptor agonist on nociception. We thus present a novel mechanism of CB2 receptor activation-induced β-endorphin release through Gi/o-Gβγ-MAPK-Ca2+ signaling pathway. Our data also suggest that stimulation of MAPK contributes to the peripheral analgesic effect of CB2 receptor agonists.

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Acknowledgments

This work was supported by a grant from the National Natural Science Foundation of China (#81173328, #31300598), funds for the Doctoral Program of Higher Education of China (20120142110021), and the Fundamental Research Funds for the Central Universities, HUST:2010JC065.

Conflict of Interest

The authors declare no competing interests.

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Authors and Affiliations

  1. Department of Neurobiology and Key Laboratory of Neurological Diseases of Ministry of Education, The Institute of Brain Research, School of Basic Medicine, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, 430030, People’s Republic of China

    Fang Gao, Ling-Hong Zhang, Tang-Feng Su, Miao Peng, Cai-Hua Wu, Xiao-Cui Yuan, Ning Sun, Xian-Fang Meng, Bo Tian, Jing Shi & Man Li

  2. Department of Anesthesiology and Perioperative Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA

    Hui-Lin Pan

  3. Biomolecular Physics and Modeling Group, Department of Physics, Huazhong University of Science and Technology, Wuhan, 430074, People’s Republic of China

    Lin Li & Rui Zhou

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  1. Fang Gao
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Correspondence to Man Li.

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Gao, F., Zhang, LH., Su, TF. et al. Signaling Mechanism of Cannabinoid Receptor-2 Activation-Induced β-Endorphin Release. Mol Neurobiol 53, 3616–3625 (2016). https://doi.org/10.1007/s12035-015-9291-2

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  • DOI: https://doi.org/10.1007/s12035-015-9291-2

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