Cell Reports
(Jun 2016)
Sustained Elevated Adenosine via ADORA2B Promotes Chronic Pain through Neuro-immune Interaction
Xia Hu,
Morayo G. Adebiyi,
Jialie Luo,
Kaiqi Sun,
Thanh-Thuy T. Le,
Yujin Zhang,
Hongyu Wu,
Shushan Zhao,
Harry Karmouty-Quintana,
Hong Liu,
Aji Huang,
Yuan Edward Wen,
Oleg L. Zaika,
Mykola Mamenko,
Oleh M. Pochynyuk,
Rodney E. Kellems,
Holger K. Eltzschig,
Michael R. Blackburn,
Edgar T. Walters,
Dong Huang,
Hongzhen Hu,
Yang Xia
Affiliations
Xia Hu
Department of Biochemistry and Molecular Biology, University of Texas Medical School at Houston, Houston, TX 77030, USA
Morayo G. Adebiyi
Department of Biochemistry and Molecular Biology, University of Texas Medical School at Houston, Houston, TX 77030, USA
Jialie Luo
Department of Anesthesiology, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, USA
Kaiqi Sun
Department of Biochemistry and Molecular Biology, University of Texas Medical School at Houston, Houston, TX 77030, USA
Thanh-Thuy T. Le
Department of Biochemistry and Molecular Biology, University of Texas Medical School at Houston, Houston, TX 77030, USA
Yujin Zhang
Department of Biochemistry and Molecular Biology, University of Texas Medical School at Houston, Houston, TX 77030, USA
Hongyu Wu
Department of Biochemistry and Molecular Biology, University of Texas Medical School at Houston, Houston, TX 77030, USA
Shushan Zhao
Department of Biochemistry and Molecular Biology, University of Texas Medical School at Houston, Houston, TX 77030, USA
Harry Karmouty-Quintana
Department of Biochemistry and Molecular Biology, University of Texas Medical School at Houston, Houston, TX 77030, USA
Hong Liu
Department of Biochemistry and Molecular Biology, University of Texas Medical School at Houston, Houston, TX 77030, USA
Aji Huang
Department of Biochemistry and Molecular Biology, University of Texas Medical School at Houston, Houston, TX 77030, USA
Yuan Edward Wen
Department of Biochemistry and Molecular Biology, University of Texas Medical School at Houston, Houston, TX 77030, USA
Oleg L. Zaika
Integrative Biology and Pharmacology, University of Texas Medical School at Houston, Houston, TX 77030, USA
Mykola Mamenko
Integrative Biology and Pharmacology, University of Texas Medical School at Houston, Houston, TX 77030, USA
Oleh M. Pochynyuk
Integrative Biology and Pharmacology, University of Texas Medical School at Houston, Houston, TX 77030, USA
Rodney E. Kellems
Department of Biochemistry and Molecular Biology, University of Texas Medical School at Houston, Houston, TX 77030, USA
Holger K. Eltzschig
Department of Anesthesiology, The University of Colorado, Aurora, CO 80045, USA
Michael R. Blackburn
Department of Biochemistry and Molecular Biology, University of Texas Medical School at Houston, Houston, TX 77030, USA
Edgar T. Walters
Integrative Biology and Pharmacology, University of Texas Medical School at Houston, Houston, TX 77030, USA
Dong Huang
Department of Anesthesiology, Third XiangYa Hospital, Central South University, Hunan 440851, China
Hongzhen Hu
Department of Anesthesiology, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, USA
Yang Xia
Department of Biochemistry and Molecular Biology, University of Texas Medical School at Houston, Houston, TX 77030, USA
DOI
https://doi.org/10.1016/j.celrep.2016.05.080
Journal volume & issue
Vol. 16,
no. 1
pp.
106
– 119
Abstract
Read online
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.
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