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

Aims: The alpha(2)-adrenergic receptor (alpha(2)-AR) agonists have been shown to be effective in the treatment of various pain. For example, dexmedetomidine (DEX), a selective alpha(2A)-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 alpha(2A)-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 alpha(2A)-ARs by DEX suppressed P2X3 receptor-mediated and alpha,beta-methylene-ATP (alpha,beta-meATP)-evoked inward currents in a concentration-dependent and voltage-independent manner. Pre-application of DEX shifted the alpha,beta-meATP concentration-response curve downwards, with a decrease of 50.43 +/- 4.75% in the maximal current response of P2X3 receptors to alpha,beta-meATP in the presence of DEX. Suppression of alpha,beta-meATP-evoked currents by DEX was blocked by the alpha(2A)-AR antagonist BRL44408 and prevented by intracellular application of the G(i/o) protein inhibitor pertussis toxin, the adenylate cyclase activator forskolin, and the cAMP analog 8-Br-cAMP. DEX also suppressed alpha,beta-meATP-evoked action potentials through alpha(2A)-ARs in rat DRG neurons. Finally, the activation of peripheral alpha(2A)-ARs by DEX had an analgesic effect on the alpha,beta-meATP-induced nociception. Conclusions: These results suggested that activation of alpha(2A)-ARs by DEX suppressed P2X3 receptor-mediated electrophysiological and behavioral activity via a G(i/o) proteins and cAMP signaling pathway, which was a novel potential mechanism underlying analgesia of peripheral alpha(2A)-AR agonists.

Automated summary

In this study, it was found that the α2A-AR agonist DEX has an analgesic effect by activating peripheral α2A-AR and suppressing P2X3 receptor activity. This effect is mediated through intracellular G(i/o) proteins and cAMP signaling pathways in neurons.