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 HuangHongzhen Hu, Yang Xia

Research output: Contribution to journalArticle

24 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)106-119
Number of pages14
JournalCell Reports
Volume16
Issue number1
DOIs
StatePublished - Jun 28 2016

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Chronic Pain
Adenosine
Adenosine A2B Receptors
Interleukin-6 Receptors
Adenosine Deaminase
Freund's Adjuvant
Nociceptors
Sickle Cell Anemia
Myeloid Cells
Animals
Chemical activation
Hypersensitivity
Therapeutics
Animal Models
Hot Temperature
Enzymes
Pain

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Hu, X., Adebiyi, M. G., Luo, J., Sun, K., Le, T. T. T., Zhang, Y., ... Xia, Y. (2016). Sustained Elevated Adenosine via ADORA2B Promotes Chronic Pain through Neuro-immune Interaction. Cell Reports, 16(1), 106-119. https://doi.org/10.1016/j.celrep.2016.05.080

Sustained Elevated Adenosine via ADORA2B Promotes Chronic Pain through Neuro-immune Interaction. / Hu, Xia; Adebiyi, Morayo G.; Luo, Jialie; Sun, Kaiqi; Le, Thanh Thuy T.; Zhang, Yujin; Wu, Hongyu; Zhao, Shushan; Karmouty-Quintana, Harry; Liu, Hong; Huang, Aji; Wen, Yuan Edward; Zaika, Oleg L.; Mamenko, Mykola; Pochynyuk, Oleh M.; Kellems, Rodney E.; Eltzschig, Holger K.; Blackburn, Michael R.; Walters, Edgar T.; Huang, Dong; Hu, Hongzhen; Xia, Yang.

In: Cell Reports, Vol. 16, No. 1, 28.06.2016, p. 106-119.

Research output: Contribution to journalArticle

Hu, X, Adebiyi, MG, Luo, J, Sun, K, Le, TTT, Zhang, Y, Wu, H, Zhao, S, Karmouty-Quintana, H, Liu, H, Huang, A, Wen, YE, Zaika, OL, Mamenko, M, Pochynyuk, OM, Kellems, RE, Eltzschig, HK, Blackburn, MR, Walters, ET, Huang, D, Hu, H & Xia, Y 2016, 'Sustained Elevated Adenosine via ADORA2B Promotes Chronic Pain through Neuro-immune Interaction', Cell Reports, vol. 16, no. 1, pp. 106-119. https://doi.org/10.1016/j.celrep.2016.05.080
Hu, Xia ; Adebiyi, Morayo G. ; Luo, Jialie ; Sun, Kaiqi ; Le, Thanh Thuy T. ; Zhang, Yujin ; Wu, Hongyu ; Zhao, Shushan ; Karmouty-Quintana, Harry ; Liu, Hong ; Huang, Aji ; Wen, Yuan Edward ; Zaika, Oleg L. ; Mamenko, Mykola ; Pochynyuk, Oleh M. ; Kellems, Rodney E. ; Eltzschig, Holger K. ; Blackburn, Michael R. ; Walters, Edgar T. ; Huang, Dong ; Hu, Hongzhen ; Xia, Yang. / Sustained Elevated Adenosine via ADORA2B Promotes Chronic Pain through Neuro-immune Interaction. In: Cell Reports. 2016 ; Vol. 16, No. 1. pp. 106-119.
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