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 (Cavα2δ1) has been shown to cause pain states. However, whether VGCC are involved in pain states driven by abnormal Cavα2δ1 expression is not known. Methods Intrathecal injection of N-, P/Q- and L-type VGCC blockers were tested in two models: a transgenic neuronal Cavα2δ1 overexpression (TG) model with behavioural hypersensitivity and a spinal nerve ligation (SNL) model with Cavα2δ1 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 Cavα2δ1 overexpression. Q-type VGCC has minimal effects in both models. The anti-nociceptive effects of P-type VGCC blocker in the Cavα2δ1 TG mice, but minimally at the SNL model with presynaptic Cavα2δ1 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 Cavα2δ1 dysregulation at the spinal cord level.