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

• Adenosine (Ado) deaminase deficient mice displayed chronic pain
• Excess Ado signaling via ADORA2B promotes chronic pain in three distinct models
• ADORA2B activation induces immunoneuronal interaction and promotes chronic pain
• IL-6 trans-signaling underlies ADORA2B-induced prolonged hypersensitive nociception

SummaryThe 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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