Modulation Of Ion Channels By Oxytocin And Arginine Vasopression In The Primary Sensory Neurons

A growing number of studies have demonstrated that oxytocin(OT)plays an analgesic role in modulation of nociception and pain.Most work to date has focused on the central mechanisms of OT analgesia,but little is known whether the peripheral mechanisms are also involved.Acid-sensing ion channels(ASICs)are distributed in peripheral sensory neurons and participate in nociception.The first part,we investigated the effects of OT on the activity of ASICs in dorsal root ganglion(DRG)neurons.Electrophysiological experiments were performed on neurons from rat DRG.Nociceptive behavior was induced by acetic acid in rats and mice lacking vasopressin-1a receptor(V1aR).OT can exert an inhibitory effect on the functional activity of native ASICs.First,OT dose-dependently decreased the amplitude of ASIC currents in DRG neurons.Second,the OT inhibition of ASIC currents was mimicked by arginine vasopressin(AVP)and completely blocked by V1aR antagonist SR 49059,but not by oxytocin receptor(OTR)antagonist L-368,899.Third,OT altered acidosis-evoked membrane excitability of DRG neurons and caused a significant decrease in the amplitude of the depolarization and the number of action potentials induced by acid stimuli.Finally,peripherally administered OT or AVP inhibited nociceptive responses to intraplantar injection of acetic acid in rat.OT or AVP-induced analgesic effect on acidosis-evoked pain was completely absent in V1aR knockout mice,but present in wild-type littermates.These results reveal a novel peripheral mechanism of OT analgesic action by modulating native ASICs in primary sensory neurons.The second part,the aim of the present study was to explore the modulatory effect of arginine vasopressin on GABA-activated currents in dorsal root ganglion(DRG)neurons in rats.GABA-evoked inward currents were potentiated by pre-treatment with AVP in a concentration depentent manner(10-5-10-10 mol/L)and shifted the GABA concentration-response curve upwards,with an increase of 49.1±4.0%in the maximal current response but with no significant change in the EC50(agonist concentration producing a half-maximal response)value(52.5±5.4 ?mol/L vs 55.3?6.8 ?mol/L;t-test,P>0.05;n=8).The effects of AVP on IGAB Awere voltage independent.This potentiation of IGABA induced by AVP was almost completely blocked by SR49059(3×10-6 mol/L),an AVP receptor antagonist V1a.The AVP-induced potentiation of IGABA was removed by intracellular dialysis of either GDP-?-S(5×10-4 mol/L),a non-hydrolyzable GAP analog or GF109203X(2×10-6 mol/L),a selective protein kinase C(PKC)inhibitor,with the re-patch clamp.These results suggest that AVP up-regulates the function of the GABAA receptor via G protein-coupled receptors and protein kinase C dependent signal pathways in rat dorsal root ganglion(DRG)neurons and this potentiation might underlie the analgesia induced by AVP.