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Cell Rep. 2016 Jun 28;16(1):106-119. doi: 10.1016/j.celrep.2016.05.080. Epub 2016 Jun 16.

Sustained Elevated Adenosine via ADORA2B Promotes Chronic Pain through Neuro-immune Interaction.

Author information

1
Department of Biochemistry and Molecular Biology, University of Texas Medical School at Houston, Houston, TX 77030, USA; Department of Anesthesiology, Third XiangYa Hospital, Central South University, Hunan 440851, China.
2
Department of Biochemistry and Molecular Biology, University of Texas Medical School at Houston, Houston, TX 77030, USA; Graduate School of Biomedical Sciences, The University of Texas, Houston, TX 77030, USA.
3
Department of Anesthesiology, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, USA.
4
Department of Biochemistry and Molecular Biology, University of Texas Medical School at Houston, Houston, TX 77030, USA.
5
Integrative Biology and Pharmacology, University of Texas Medical School at Houston, Houston, TX 77030, USA.
6
Department of Anesthesiology, The University of Colorado, Aurora, CO 80045, USA.
7
Department of Anesthesiology, Third XiangYa Hospital, Central South University, Hunan 440851, China.
8
Department of Biochemistry and Molecular Biology, University of Texas Medical School at Houston, Houston, TX 77030, USA; Graduate School of Biomedical Sciences, The University of Texas, Houston, TX 77030, USA. Electronic address: yang.xia@uth.tmc.edu.

Abstract

The molecular mechanisms of chronic pain are poorly understood and effective mechanism-based treatments are lacking. Here, we report that mice lacking adenosine deaminase (ADA), an enzyme necessary for the breakdown of adenosine, displayed unexpected chronic mechanical and thermal hypersensitivity due to sustained elevated circulating adenosine. Extending from Ada(-/-) mice, we further discovered that prolonged elevated adenosine contributed to chronic pain behaviors in two additional independent animal models: sickle cell disease mice, a model of severe pain with limited treatment, and complete Freund's adjuvant paw-injected mice, a well-accepted inflammatory model of chronic pain. Mechanistically, we revealed that activation of adenosine A2B receptors on myeloid cells caused nociceptor hyperexcitability and promoted chronic pain via soluble IL-6 receptor trans-signaling, and our findings determined that prolonged accumulated circulating adenosine contributes to chronic pain by promoting immune-neuronal interaction and revealed multiple therapeutic targets.

PMID:
27320922
PMCID:
PMC5662192
DOI:
10.1016/j.celrep.2016.05.080
[Indexed for MEDLINE]
Free PMC Article

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