Differential effects of voltage‐gated calcium channel blockers on calcium channel alpha‐2‐delta‐1 subunit protein‐mediated nociception

Background Overexpression of the voltage‐gated calcium channel ( VGCC ) alpha‐2‐delta1 subunit protein ( C a v α 2 δ 1 ) has been shown to cause pain states. However, whether VGCC are involved in pain states driven by abnormal C a v α 2 δ 1 expression is not known. Methods Intrathecal injection of N ‐, P / Q ‐ and L ‐type VGCC blockers were tested in two models: a transgenic neuronal C a v α 2 δ 1 overexpression ( TG ) model with behavioural hypersensitivity and a spinal nerve ligation ( SNL ) model with C a v α 2 δ 1 overexpression in sensory pathways and neuropathy pain states. Results The nociceptive response to mechanical stimuli was significantly attenuated in both models with ω‐conotoxin GVIA (an N ‐type VGCC blocker) and nifedipine (an L ‐type VGCC blocker), in which ω‐conotoxin GVIA appeared more potent than nifedipine. Treatments with ω‐agatoxin IVA ( P ‐ VGCC blocker), but not ω‐conotoxin MVIIC ( Q ‐ VGCC blocker) had similar potency in the TG model as the N ‐type VGCC blocker, while both ω‐agatoxin IVA and ω‐conotoxin MVIIC had minimal effects in the SNL model compared with controls. Conclusion These findings suggest that, at the spinal level, N ‐ and L ‐type VGCC are likely involved in behavioural hypersensitivity states driven by C a v α 2 δ 1 overexpression. Q ‐type VGCC has minimal effects in both models. The anti‐nociceptive effects of P ‐type VGCC blocker in the C a v α 2 δ 1 TG mice, but minimally at the SNL model with presynaptic C a v α 2 δ 1 up‐regulation, suggest that its potential action site(s) is at the post‐synaptic and/or supraspinal level. These findings support that N ‐, L ‐ and P / Q ‐type VGCC have differential contributions to behavioural hypersensitivity modulated by C a v α 2 δ 1 dysregulation at the spinal cord level.