Inhibitory Effect Of Dexmedetomidine On Acid-sensing Ion Channels In Primary Sensory Neurons

Objective:Dexmedetomidine（DEX）,a selectiveα₂ adrenergic receptor（α₂-AR）agonist,has been shown to have peripheral analgesic effects in a variety of pain conditions.However,the precise molecular mechanisms have not yet been fully elucidated.Acid sensing ion channels（ASICs）,H⁺sensors,are the major player in pain associated with tissue acidosis.Given that bothα₂-ARs and ASICs exist in dorsal root ganglia（DRG）neurons,we therefore investigated the effects of DEX on the functional activity of ASICs.Here,we reported that DEX can enhance the functional activity of ASICs on DRG cells throughα₂-AR.Methods:First whole-cell patch-clamp recordings the effects of DEX on ASIC-mediated and acid-evoked currents and action potentials in dissociated rat DRG neurons.Intracellular dialysis was carried out to explore its mechanism.We also observed the effect of pretreatment DEX on acid-induced nociceptive behaviors in rats.Results:selectiveα₂-AR agonist DEX inhibited the electrophysiological activity of ASICs throughα_2A-ARs in a dose-dependent manner,DEX shifted downwards concentration-response curve to protons,with a decrease of 35.83±3.91%in the maximal current response to p H 4.5.DEX-induced inhibition of ASIC currents was blocked by theα_2A-AR antagonist BRL44408 in DRG neurons.DEX also inhibited ASIC3 currents in CHO cells co-expressing ASIC3 andα_2A-ARs,but not in ASIC3transfected CHO cells withoutα_2A-ARs expression.DEX-induced inhibition of ASIC currents was mimicked by the protein kinase A inhibitor H-89 and blocked by intracellular application of the Gi/o protein inhibitor pertussis toxin and the c AMP analog 8-Br-c AMP.In addition,peripherally administration of DEX dose-dependently relieved nociceptive responses to intraplantar injection of acetic acid in rats through localα_2A-Ars.Conclusions:DEX inhibited the functional activity of ASICs viaα_2A-ARs and intracellular Gi/o proteins and c AMP/protein kinase A signaling pathway in rat DRG neurons,which was a novel potential mechanism that probably mediated peripheral analgesia of DEX.