Contribution of Phosphoinositide Signaling Pathway to Opioid-Mediated Control of P2X3 Receptors in the Primary Sensory Neurons

Homomeric P2X3 receptors expressed by primary nociceptive neurons are crucial elements in pain signaling. In turn, opioid system regulates the intensity of this signaling in both central and peripheral nervous system. Here we describe the role of PLC signaling in modulation of P2X3 receptors by opioids examined by standard patch clamp technique. An activation of G-protein coupled opioid receptors by endogenous opioid Leu-enkephalin resulted in two opposite effects on P2X3 currents expressed in DRG neurons of rat. In particular, an application of 1 µM Leu-enkephalin lead to complete inhibition of P2X3 currents. However, after pretreatment of the neuron with a Gi/o-protein inhibitor pertussis toxin, the same concentration of Leu caused facilitation of P2X3 currents. Both facilitating and inhibitory effects of Leu on P2X3 currents were completely supressed by pretreatment of the neuron with 1 µM U-73122, an inhibitor of PLC activity. Thus, opioid receptor agonists cause two oppositely directed effects on P2X3 receptors in DRG neurons of rat, and both of them are mediated through PLC signaling pathway. These data point out to a feasible molecular mechanism for the well-known alteration of the inhibitory action of opioids (analgesia) to facilitating one (hyperalgesia).