title: 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.
  
  
  CONCLUSIONS
  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.affiliation: 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.
authors.forename: E
authors.initials: E
authors.lastname: Chang
authors.forename: X
authors.initials: X
authors.lastname: Chen
authors.forename: M
authors.initials: M
authors.lastname: Kim
authors.forename: N
authors.initials: N
authors.lastname: Gong
authors.forename: S
authors.initials: S
authors.lastname: Bhatia
authors.forename: Z D
authors.initials: ZD
authors.lastname: Luo
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000187:drug effects* / Q000235:genetics; D020746:Calcium Channels, L-Type / Q000187:drug effects; D020864:Calcium Channels, N-Type / Q000187:drug effects; D004525:Efferent Pathways / Q000378:metabolism; D006930:Hyperalgesia / Q000523:psychology; D007278:Injections, Spinal; D008026:Ligation; D008297:Male; D051379:Mice; D009437:Neuralgia / Q000473:pathology / Q000503:physiopathology; D009543:Nifedipine / Q000494:pharmacology; D059225:Nociception / Q000187:drug effects*; D010147:Pain Measurement / Q000187:drug effects; D013127:Spinal Nerves / Q000293:injuries; D020866:omega-Conotoxin GVIA / Q000494:pharmacology
chemical_list: C512066:CACNA2D1 protein, mouse; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D020864:Calcium Channels, N-Type; D020866:omega-Conotoxin GVIA; D009543:Nifedipine