Effects of neuropathy on high-voltage-activated Ca(2+) current in sensory neurones.
Voltage-dependent Ca(2+) channels (VDCCs) have emerged as targets to treat neuropathic pain; however, amongst VDCCs, the precise role of the Ca(V)2.3 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(V)2.3(-/-) knock-out and wild-type (WT) mice. DRG neurones from Ca(V)2.3(-/-) mice had significantly reduced sensitivity to SNX-482 versus WT mice. DRGs from Ca(V)2.3(-/-) mice also had increased sensitivity to the Ca(V)2.2 VDCC blocker omega-conotoxin. In WT mice, PSNL caused a significant increase in omega-conotoxin-sensitivity and a reduction in SNX-482-sensitivity. In Ca(V)2.3(-/-) mice, PSNL caused a significant reduction in omega-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(V)2.3(-/-) or WT mice. These data suggest that Ca(V)2.3 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(V)2.2- and Ca(V)2.3-mediated Ca(2+) currents, supporting roles for these VDCCs in nociception during neuropathy. In Ca(V)2.3(-/-) mice, PSNL-induced changes in Ca(V)1 and Ca(V)2.2 Ca(2+) current, consistent with alternative adaptive mechanisms occurring in the absence of Ca(V)2.3 subunits.
Yang
Li
L
School of Pharmacy, University of Reading, Whiteknights, Reading RG6 6AJ, United Kingdom.
Stephens
Gary J
GJ
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020864:Calcium Channels, N-Type / Q000235:genetics / Q000378:metabolism*; D020908:Calcium Channels, R-Type / Q000235:genetics / Q000378:metabolism; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism; D005727:Ganglia, Spinal / Q000378:metabolism; D066298:In Vitro Techniques; D015640:Ion Channel Gating; D051379:Mice; D018345:Mice, Knockout / Q000378:metabolism; D009619:Nociceptors / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D020426:Sciatic Neuropathy / Q000503:physiopathology*
C500963:Cacna1b protein, mouse; C498916:Cacna1e protein, mouse; D020864:Calcium Channels, N-Type; D020908:Calcium Channels, R-Type; D027682:Cation Transport Proteins; D002118:Calcium