Chang E, Chen X, Kim M, Gong N, Bhatia S, Luo Z D
Department of Anesthesiology and Perioperative Care, University of California Irvine, Irvine, USA; Department of Physical Medicine and Rehabilitation, University of California Irvine, Irvine, USA; Reeve-Irvine Research Center for Spinal Cord Injury, University of California Irvine, Irvine, USA.
Eur J Pain. 2015 May;19(5):639-48. doi: 10.1002/ejp.585. Epub 2014 Aug 27.
Overexpression of the voltage-gated calcium channel (VGCC) alpha-2-delta1 subunit protein (Cav α2 δ1 ) has been shown to cause pain states. However, whether VGCC are involved in pain states driven by abnormal Cav α2 δ1 expression is not known.
Intrathecal injection of N-, P/Q- and L-type VGCC blockers were tested in two models: a transgenic neuronal Cav α2 δ1 overexpression (TG) model with behavioural hypersensitivity and a spinal nerve ligation (SNL) model with Cav α2 δ1 overexpression in sensory pathways and neuropathy pain states.
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.
These findings suggest that, at the spinal level, N- and L-type VGCC are likely involved in behavioural hypersensitivity states driven by Cav α2 δ1 overexpression. Q-type VGCC has minimal effects in both models. The anti-nociceptive effects of P-type VGCC blocker in the Cav α2 δ1 TG mice, but minimally at the SNL model with presynaptic Cav α2 δ1 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 Cav α2 δ1 dysregulation at the spinal cord level.
电压门控钙通道（VGCC）α2δ1亚基蛋白（Cavα2δ1）的过表达已被证明会导致疼痛状态。然而，VGCC是否参与由异常Cavα2δ1表达驱动的疼痛状态尚不清楚。
在两种模型中测试鞘内注射N型、P/Q型和L型VGCC阻滞剂：一种是具有行为超敏反应的转基因神经元Cavα2δ1过表达（TG）模型，另一种是感觉通路中Cavα2δ1过表达且存在神经病理性疼痛状态的脊髓神经结扎（SNL）模型。
在两种模型中，使用ω-芋螺毒素GVIA（一种N型VGCC阻滞剂）和硝苯地平（一种L型VGCC阻滞剂）后，对机械刺激的伤害性反应均显著减弱，其中ω-芋螺毒素GVIA似乎比硝苯地平更有效。在TG模型中，使用ω-阿加毒素IVA（P型VGCC阻滞剂）治疗，但不使用ω-芋螺毒素MVIIC（Q型VGCC阻滞剂），其效力与N型VGCC阻滞剂相似，而与对照组相比，在SNL模型中，ω-阿加毒素IVA和ω-芋螺毒素MVIIC的作用均最小。
这些发现表明，在脊髓水平，N型和L型VGCC可能参与由Cavα2δ1过表达驱动的行为超敏反应状态。Q型VGCC在两种模型中的作用均最小。P型VGCC阻滞剂在Cavα2δ1转基因小鼠中具有抗伤害感受作用，但在突触前Cavα2δ1上调的SNL模型中的作用最小，这表明其潜在作用位点位于突触后和/或脊髓上水平。这些发现支持N型、L型和P/Q型VGCC在脊髓水平对由Cavα2δ1失调调节的行为超敏反应有不同的贡献。
