Upregulation of the voltage-gated sodium channel β2 subunit in neuropathic pain models:: Characterization of expression in injured and non-injured primary sensory neurons

The development of abnormal primary sensory neuron excitability and neuropathic pain symptoms after peripheral nerve injury is associated with altered expression of voltage-gated sodium channels ( VGSCs) and a modification of sodium currents. To investigate whether the beta 2 subunit of VGSCs participates in the generation of neuropathic pain, we used the spared nerve injury ( SNI) model in rats to examine beta 2 subunit expression in selectively injured ( tibial and common peroneal nerves) and uninjured ( sural nerve) afferents. Three days after SNI, immunohistochemistry and Western blot analysis reveal an increase in the beta 2 subunit in both the cell body and peripheral axons of injured neurons. The increase persists for > 4 weeks, although beta 2 subunit mRNA measured by real-time reverse transcription-PCR and in situ hybridization remains unchanged. Although injured neurons show the most marked upregulation, beta 2 subunit expression is also increased in neighboring non-injured neurons and a similar pattern of changes appears in the spinal nerve ligation model of neuropathic pain. That increased beta 2 subunit expression in sensory neurons after nerve injury is functionally significant, as demonstrated by our finding that the development of mechanical allodynia-like behavior in the SNI model is attenuated in beta 2 subunit null mutant mice. Through its role in regulating the density of mature VGSC complexes in the plasma membrane and modulating channel gating, the beta 2 subunit may play a key role in the development of ectopic activity in injured and non-injured sensory afferents and, thereby, neuropathic pain.