Hu X, Adebiyi MG, Luo J, Sun K, Le TT, 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. Sustained Elevated Adenosine via ADORA2B Promotes Chronic Pain through Neuro-immune Interaction. Cell Rep. 2016 Jun 28;16(1):106-19. PMID: 27320922
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 prolongedelevated 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 promotedchronic pain via soluble IL-6 receptor trans-signaling, and our findings determined that prolonged accumulated circulating adenosine contributes tochronic pain by promoting immune-neuronal interaction and revealed multiple therapeutic targets.