Role of Adenosine Kinase in Sphingosine-1-Phosphate Receptor 1-Induced Mechano-Hypersensitivities

Emerging evidence implicates the sphingosine-1-phosphate receptor subtype 1 (S1PR1) in the development of neuropathic pain. Continued investigation of the signaling pathways downstream of S1PR1 are needed to support development of S1PR1 antagonists. In rodents, intrathecal (i.th.) injection of SEW2871, a selective S1PR1 agonist, activates the nod-like receptor family, pyrin domain containing 3 inflammasome, increases interleukin-1 beta (IL-1 beta) and causes behavioral hypersensitivity. I.th. injection of a IL-1 beta receptor antagonist blocks SEW2871-induced hypersensitivity, suggesting that IL-1 beta contributes to S1PR1's actions. Interestingly, previous studies have suggested that IL-1 beta increases the expression/activity of adenosine kinase (ADK), a key regulator of adenosine signaling at its receptors (ARs). Increased ADK expression reduces adenosine signaling whereas inhibiting ADK restores the action of adenosine. Here, we show that SEW287-induced behavioral hypersensitivity is associated with increased expression of ADK in astrocytes of the dorsal horn of the spinal cord. Moreover, the ADK inhibitor, ABT702, blocks SEW2871-induced hypersensitivity. These findings link ADK activation to S1PR1. If SEW2871-induced pain is mediated by IL-1 beta, which in turn activates ADK and leads to mechano-allodynia, then blocking ADK should attenuate IL-1 beta effects. In support of this idea, recombinant rat (rrIL-1 beta)-induced allodynia was blocked by at least 90% with ABT702, functionally linking ADK to IL-1 beta. Moreover, the selective A(3)AR antagonist, MRS1523, prevents the ability of ABT702 to block SEW2871 and IL-1 beta-induced allodynia, implicating A(3)AR signaling in the beneficial effects exerted by ABT702. Our findings provide novel mechanistic insight into how S1PR1 signaling in the spinal cord produces hypersensitivity through IL1-beta and ADK activation.