A1 adenosine receptor activation inhibits P2X3 receptor-mediated ATP currents in rat dorsal root ganglion neurons

Abstract Purinergic signaling is involved in multiple pain processes. P2X3 receptor is a key target in pain therapeutics, while A1 adenosine receptor signaling plays a role in analgesia. However, it remains unclear whether there is a link between them in pain. The present results showed that the A1 adenosine receptor agonist N6-cyclopentyladenosine (CPA) concentration-dependently suppressed P2X3 receptor-mediated and α,β-methylene-ATP (α,β-meATP)-evoked inward currents in rat dorsal root ganglion (DRG) neurons. CPA significantly decreased the maximal current response of α,β-meATP, as shown a downward shift of its concentration-response curve. The CPA-induced suppression was independent on the clamping-voltageof the membrane. Inhibition of ATP currents by CPA was completely prevented by the A1 adenosine receptor antagonist KW-3902, and disappeared after the intracellular dialysis of either the Gi/o-protein inhibitor pertussis toxin, the adenylate cyclase activator forskolin, or the cAMP analog 8-Br-cAMP. Morover, CPA suppressed the membrane potential depolarization and action potential burst induced by α,β-meATP in DRG neurons. Finally, CPA relieved α,β-meATP-induced nociceptive behaviors in rats by activating peripheral A1 adenosine receptors in dose-dependent manner. These results indicated that CPA inhibited P2X3 receptor activity in rat primary sensory neurons by activating A1 adenosine receptors, Gi/o-proteins and intracellular cAMP signaling, revealing a novel peripheral mechanism underlying its analgesic effect.