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

Abstract

BACKGROUND:

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.

METHODS:

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.

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 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.

• Authors: E Chang, X Chen, M Kim, N Gong, S Bhatia, Z D Luo
• Journal: European journal of pain (London, England) (Eur J Pain) Vol. 19 Issue 5 Pg. 639-48 (May 2015) ISSN: 1532-2149 [Electronic] England
• PMID: 25158907 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © 2014 European Pain Federation - EFIC®

Chemical References

• CACNA2D1 protein, mouse
• Calcium Channel Blockers
• Calcium Channels
• Calcium Channels, L-Type
• Calcium Channels, N-Type
• omega-Conotoxin GVIA
• Nifedipine

Topics

• Animals
• Behavior, Animal (drug effects)
• Calcium Channel Blockers (pharmacology)
• Calcium Channels (drug effects, genetics)
• Calcium Channels, L-Type (drug effects)
• Calcium Channels, N-Type (drug effects)
• Efferent Pathways (metabolism)
• Hyperalgesia (psychology)
• Injections, Spinal
• Ligation
• Male
• Mice
• Neuralgia (pathology, physiopathology)
• Nifedipine (pharmacology)
• Nociception (drug effects)
• Pain Measurement (drug effects)
• Spinal Nerves (injuries)
• omega-Conotoxin GVIA (pharmacology)