Sodium Channels in Pain Transmission

Sodium Channels in Pain Transmission

• Sodium channels (Nav channels) are involved in all stages of pain transmission
• They play a role in inflammatory and chronic/neuropathic pain

Nav Channel Types and Expression

• Nav1.1: Found in the central nervous system (CNS) and peripheral nervous system (PNS)

  • Expressed in cerebellum, striatum, hippocampus, and thalamus, as well as DRG large cells, Aδ-fibres and Aaβ-fibres and outer plexiform layer

• Nav1.2: Expressed in CNS (cerebellum and hippocampus), and PNS (DRG large cells, Aδ-fibres, and Aaβ-fibres and outer plexiform layer)

  • Found in neuronal somas and proximal dendrites

• Nav1.3: Found in CNS (neocortex, hippocampus, and dentate gyrus), but absent in PNS

  • Located in neuronal somas and proximal dendrites

• Nav1.6: Found in CNS (cerebellum and hippocampus), and PNS

• Nav1.7: CNS and PNS

  • Extensive expression in DRG large and medium cells, Aδ-fibres, Aaβ-fibres, myenteric neurons, cochlear ganglion, outer plexiform layer

• Nav1.8: Primarily CNS, expressed across DRG and trigeminal and nodosal ganglia neurons

• Nav1.9: Found in CNS and PNS

  • Expressed in DRG small and medium cells and fibres, enteric neurons and trigeminal ganglia

Nav1.7 and Pain

• Nav1.7 is a genetically validated target for pain

• Loss-of-function (LoF) mutations are associated with Congenital Insensitivity to Pain (CIP)

• Gain-of-function (GoF) mutations are associated with inherited erythromelalgia (IEM) and Paroxysmal extreme pain disorder (PEPD)

• There are polymorphisms in ~30% of Caucasians associated with IEM and SFN

• Nav1.7 amplifies generator potentials close to resting membrane potential (r.m.p.)

• It regulates action potential (AP) firing and excitability

• Characterized by rapid activation and inactivation

Nav1.8 and Pain

• Sensory neurons specifically contribute to pain transmission through AP upstroke

• It promotes sustained, repetitive firing

• Inflammation mediators (PGE2 and others) modulate Nav1.8 activity lowering triggering threshold

• Gain-of-function mutations of Nav1.8 cause painful neuropathy

Nav1.9 and Pain

• Nav1.9 is expressed in sensory neurons
• It has a hyperpolarized activation threshold (approximately -60/-70mV)
• Characterized by very slow inactivation
• Thus, Nav1.9 is a "threshold channel" that is important in inflammatory and diabetic neuropathy pain
• Mutations in this channel are linked to painful peripheral neuropathy

This quiz explores the role of sodium channels, specifically Nav channels, in pain transmission. It covers their expression in different regions of the central and peripheral nervous systems, as well as their involvement in inflammatory and neuropathic pain. Test your understanding of the various types of Nav channels and their significance in pain pathways.