Effects of neuropathy on high-voltage-activated Ca 2+ current in sensory neurones

Abstract

Voltage-dependent Ca 2+ channels (VDCCs) have emerged as targets to treat neuropathic pain; however, amongst VDCCs, the precise role of the Ca V2.3 subtype in nociception remains unproven. Here, we investigate the effects of partial sciatic nerve ligation (PSNL) on Ca 2+ currents in small/medium diameter dorsal root ganglia (DRG) neurones isolated from Ca V2.3(−/−) knock-out and wild-type (WT) mice. DRG neurones from Ca V2.3(−/−) mice had significantly reduced sensitivity to SNX-482 versus WT mice. DRGs from Ca V2.3(−/−) mice also had increased sensitivity to the Ca V2.2 VDCC blocker ω-conotoxin. In WT mice, PSNL caused a significant increase in ω-conotoxin-sensitivity and a reduction in SNX-482-sensitivity. In Ca V2.3(−/−) mice, PSNL caused a significant reduction in ω-conotoxin-sensitivity and an increase in nifedipine sensitivity. PSNL-induced changes in Ca 2+ current were not accompanied by effects on voltage-dependence of activation in either Ca V2.3(−/−) or WT mice. These data suggest that Ca V2.3 subunits contribute, but do not fully underlie, drug-resistant (R-type) Ca 2+ current in these cells. In WT mice, PSNL caused adaptive changes in Ca V2.2- and Ca V2.3-mediated Ca 2+ currents, supporting roles for these VDCCs in nociception during neuropathy. In Ca V2.3(−/−) mice, PSNL-induced changes in Ca V1 and Ca V2.2 Ca 2+ current, consistent with alternative adaptive mechanisms occurring in the absence of Ca V2.3 subunits.