Intracellular Sodium Regulates Opioid Signalling in Peripheral Sensory Neurons

Abstract

Opioid receptors signal more effectively in sensory neurons from pain-free mice lacking the voltagegated sodium channel Nav1.7. Type-A GPCRs are known to be regulated through a specific sodium binding site, the occupancy of which diminishes agonist binding. We have used an electrophysiological assay of Protein Kinase A activity to examine the role of intracellular sodium on opioid signalling. Phosphorylation of sodium channel Nav1.8 by activation of Protein Kinase A with db-cAMP is unaffected by altered intracellular sodium. By contrast, there is a dose-dependent inhibition of fentanyl action on Nav1.8 currents when intracellular sodium is increased from 0 mM to 20 mM. Fentanyl shows a 50% loss of activity and 80-fold increase in EC50 with 20 mM intracellular sodium. These data demonstrate that altered intracellular sodium levels modulate opioid receptor signalling.