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

Abstract

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.