Suppression of P2X3 receptor-mediated currents by the activation of α2A -adrenergic receptors in rat dorsal root ganglion neurons.

AIMS The α2 -adrenergic receptor (α2 -AR) agonists have been shown to be effective in the treatment of various pain. For example, dexmedetomidine (DEX), a selective α2A -AR agonist, can be used for peripheral analgesia. However, it is not yet fully elucidated for the precise molecular mechanisms. P2X3 receptor is a major receptor processing nociceptive information in primary sensory neurons. Herein, we show that a functional interaction of α2A -ARs and P2X3 receptors in dorsal root ganglia (DRG) neurons could contribute to peripheral analgesia of DEX. METHODS Electrophysiological recordings were carried out on rat DRG neurons, and nociceptive behavior was quantified in rats. RESULTS The activation of α2A -ARs by DEX suppressed P2X3 receptor-mediated and α,β-methylene-ATP (α,β-meATP)-evoked inward currents in a concentration-dependent and voltage-independent manner. Pre-application of DEX shifted the α,β-meATP concentration-response curve downwards, with a decrease of 50.43 ± 4.75% in the maximal current response of P2X3 receptors to α,β-meATP in the presence of DEX. Suppression of α,β-meATP-evoked currents by DEX was blocked by the α2A -AR antagonist BRL44408 and prevented by intracellular application of the Gi/o protein inhibitor pertussis toxin, the adenylate cyclase activator forskolin, and the cAMP analog 8-Br-cAMP. DEX also suppressed α,β-meATP-evoked action potentials through α2A -ARs in rat DRG neurons. Finally, the activation of peripheral α2A -ARs by DEX had an analgesic effect on the α,β-meATP-induced nociception. CONCLUSIONS These results suggested that activation of α2A -ARs by DEX suppressed P2X3 receptor-mediated electrophysiological and behavioral activity via a Gi/o proteins and cAMP signaling pathway, which was a novel potential mechanism underlying analgesia of peripheral α2A -AR agonists.