Excess extracellular adenosine signaling via ADORA2B receptor contributes to priapism, penile fibrosis, and pain in SCD mice. (A) Excess extracellular adenosine activates ADORA2B receptor in corpus cavernosum and smooth muscle relaxation, contributing to penile fibrosis and priapism, respectively, in SCD. (B) Excess extracellular adenosine activates ADORA2B receptor to induce secretion of IL-6 and sIL-6R from myeloid cells. IL-6 and sIL-6R form a complex that can transactivate gp130 in DRG neurons. gp130 activation leads to activation of phosphorylated STAT3 (pSTAT3), which, in turn, increases TRPV1 gene expression in DRG neurons and overall nociception in SCD mice. ADORA2B–IL-6–sIL-6–gp130 signaling networks are innovative therapeutic targets for priapism and chronic pain. cGMP, guanosine 3′,5′-cyclic monophosphate; PDE, phosphodiesterase.