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.

Automated summary

The involvement of S1PR1 in neuropathic pain suggests the need for further exploration of signaling pathways downstream of S1PR1 for the development of antagonists. Experimental results indicate that IL-1 beta and ADK play significant roles in the actions of S1PR1.