The effect of ABT-702, a novel adenosine kinase inhibitor, on the responses of spinal neurones following carrageenan inflammation and peripheral nerve injury

1 Adenosine (ADO) receptor activation modulates sensory transmission in the dorsal horn. Little is known about the circumstances underlying release of the purine. The present study was conducted to investigate the effect of a novel and potent non-nucleoside adenosine kinase (AK) inhibitor, ABT-702, on the responses of dorsal horn neurones to selected peripheral stimuli. AB T-702 is orally effective to reduce behavioural signs of nociception in mod els of acute, inflammatory, and neuropathic pain. 2 Electrophysiological recordings were made from wide dynamic range (WDR) n eurones in halothane-anaesthetized rats. ABT-702 was given subcutaneously f ollowing either carrageenan inflammation or peripheral nerve injury (L5/L6 spinal nerve ligation). Comparisons were made between carrageenan and uninj ected control animals, and similarly between spinal nerve ligated (SNL) and sham operated animals. 3 ABT-702 produced inhibition of the postdischarge, wind-up and C-fibre evo ked responses in both carrageenan and nerve-injured animals. Furthermore, t he mechanical and thermal evoked responses were similarly reduced in SNL ra ts. Overall, ABT-702 produced a significantly greater inhibition of these r esponses in SNL rats as compared to sham controls. Similarly ABT-702 tended to produce greater effects after carrageenan inflammation, however this di d not reach significance. 4 Protection of endogenous adenosine by ABT-702 therefore produces a marked inhibition of the noxious evoked neuronal activity in inflamed and neuropa thic rats. Our results demonstrate a plasticity in the endogenous adenosine -mediated inhibitory system following SNL and provide a possible basis for the use of this compound for the treatment of neuropathic and other persist ent pain states.