Study On The Functional Activity And Mechanism Of LPA In Enhancing P2X3 Receptors In Rat DRG Neuron

Objective:Lysophosphatidic acid（LPA）,a lipid metabolite,plays a role in bo th neuropathic and inflammatory pain through LPA₁receptors.P2X3 receptor has also been shown to participate in these pathological processes.However,it is stil l unclear whether there is a link between LPA signaling and P2X3 receptors in pa in.Herein,we show that a functional interaction between them in rat dorsal root ganglia（DRG）neurons.Methods:The whole cell patch clamp technique was used to record the electr ophysiological activity of DRG neurons in rats.The number of flinching/shrinkin g response induced by ATP injection to hind paws was observed in behaviorally.Results:Pretreatment of LPA concentration-dependently enhancedα,β-methyl ene-ATP（α,β-me ATP）-induced inward currents mediated by P2X3 receptors.LPA significantly increased the maximal current response ofα,β-me ATP,showing an upward shift of the concentration-response curve forα,β-me ATP.The LPA enhan cement was independent on the clamping-voltage.Enhancement of P2X3 receptor-mediated currents by LPA was prevented by the LPA₁receptor antagonist Ki16425,but not by the LPA₂receptor antagonist H2L5186303.The LPA-induced pote ntiation was also attenuated by intracellular dialysis of either G-protein inhibitor or protein kinase C（PKC）inhibitor,but not by Rho inhibitor.Moreover,LPA sig nificantly changed the membrane potential depolarization and action potential bu rst induced byα,β-me ATP in DRG neurons.Finally,LPA exacerbatedα,β-me ATP-induced nociceptive behaviors in rats.Conclusions:These results suggested that LPA potentiated the functional acti vity of P2X3 receptors in rat primary sensory neurons through activation of the L PA1 receptor and its downstream PKC rather than Rho signaling pathway,indicat ing a novel peripheral mechanism underlying the sensitization of pain.