Sustained Elevation of Adenosine-ADORA2B Signaling Promotes Chronic Pain through Neuro-Immune Interaction in Sickle Cell Disease

Sickle cell disease (SCD) is a common inherited hemolytic disorder that can cause severe health complications. One of the main complications of SCD is chronic pain. The molecular mechanism behind SCD chronic pain is poorly understood and effective mechanism-based treatments for SCD chronic pain are extremely limited. Recent studies show that an accumulated adenosine level induces sickling and disease progression by activation of adenosine A2B receptor (ADORA2B) (Zhang et.al 2011, Nature Medicine).  However, the functional role of persistently elevated adenosine signaling in SCD chronic pain is undetermined.  Here we report that SCD mice have persistent mechanical and thermal hypersensitivity due to sustained elevated circulating adenosine by activation of ADORA2B.  Extending from SCD mice, we further demonstrated that elevated circulating adenosine contributes to chronic pain behavior in two additional animal models independent of sickling, mice lacking adenosine deaminase (ADA), an enzyme necessary for the breakdown of adenosine, and mice with Complete Freund’s Adjuvant pawn injection, a well-accepted inflammatory chronic pain model, by activation of ADORA2B. Mechanistically, we revealed that adenosine does not directly activates neuronal cells. Instead, elevated adenosine activating ADORA2B on myeloid-derived immune cells causes nociceptor hyperexcitability and promotes chronic pain via IL-6-soluble IL-6 receptor trans-signaling cascade. Overall, our findings have identified that prolonged elevated adenosine promotes the cross talk between immune and neural cells and contributes to chronic pain in three independent animal models.  These findings add significant new insight to molecular basis for chronic pain and immediately suggest novel therapeutic possibilities for anti-chronic pain.