title: Cav1.2 and Cav1.3 L-type calcium channels independently control short- and long-term sensitization to pain.
abstract: L-type calcium channels in the CNS exist as two subunit forming channels, Cav1.2 and Cav1.3, which are involved in short- and long-term plasticity. We demonstrate that Cav1.3 but not Cav1.2 is essential for wind-up. These results identify Cav1.3 as a key conductance responsible for short-term sensitization in physiological pain transmission. We confirm the role of Cav1.2 in a model of long-term plasticity associated with neuropathic pain. Up-regulation of Cav1.2 and down-regultation of Cav1.3 in neuropathic pain underlies the switch from physiology to pathology. Finally, the results of the present study reveal that therapeutic targeting molecular pathways involved in wind-up may be not relevant in the treatment of neuropathy.
  
  
  
  Short-term central sensitization to pain temporarily increases the responsiveness of nociceptive pathways after peripheral injury. In dorsal horn neurons (DHNs), short-term sensitization can be monitored through the study of wind-up. Wind-up, a progressive increase in DHNs response following repetitive peripheral stimulations, depends on the post-synaptic L-type calcium channels. In the dorsal horn of the spinal cord, two L-type calcium channels are present, Cav1.2 and Cav1.3, each displaying specific kinetics and spatial distribution. In the present study, we used a mathematical model of DHNs in which we integrated the specific patterns of expression of each Cav subunits. This mathematical approach reveals that Cav1.3 is necessary for the onset of wind-up, whereas Cav1.2 is not and that synaptically triggered wind-up requires NMDA receptor activation. We then switched to a biological preparation in which we knocked down Cav subunits and confirmed the prominent role of Cav1.3 in both naive and spinal nerve ligation model of neuropathy (SNL). Interestingly, although a clear mechanical allodynia dependent on Cav1.2 expression was observed after SNL, the amplitude of wind-up was decreased. These results were confirmed with our model when adapting Cav1.3 conductance to the changes observed after SNL. Finally, our mathematical approach predicts that, although wind-up amplitude is decreased in SNL, plateau potentials are not altered, suggesting that plateau and wind-up are not fully equivalent. Wind-up and long-term hyperexcitability of DHNs are differentially controlled by Cav1.2 and Cav1.3, therefore confirming that short- and long-term sensitization are two different phenomena triggered by distinct mechanisms.
authors.affiliation: University of Bordeaux, Bordeaux, France.|CNRS, IINS, UMR5297, Bordeaux, France.|Faculty of Sciences, Abdelmalek Essaâdi University, Tetouan, Morocco.
authors.forename: Houda
authors.initials: H
authors.lastname: Radwani
authors.affiliation: University of Bordeaux, Bordeaux, France.|CNRS, IINS, UMR5297, Bordeaux, France.
authors.forename: Maria José
authors.initials: MJ
authors.lastname: Lopez-Gonzalez
authors.affiliation: University of Bordeaux, Bordeaux, France.|CNRS, INCIA, UMR 5287, Talence, France.
authors.forename: Daniel
authors.identifier: 0000-0003-4471-0525
authors.initials: D
authors.lastname: Cattaert
authors.affiliation: University of Bordeaux, Bordeaux, France.|CNRS, IINS, UMR5297, Bordeaux, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Roca-Lapirot
authors.affiliation: University of Bordeaux, Bordeaux, France.|Department of Pediatric Surgery, University Hospital of Bordeaux, Bordeaux, France.
authors.forename: Eric
authors.identifier: 0000-0002-6814-5420
authors.initials: E
authors.lastname: Dobremez
authors.affiliation: University of Bordeaux, Bordeaux, France.|CNRS, IINS, UMR5297, Bordeaux, France.
authors.forename: Rabia
authors.initials: R
authors.lastname: Bouali-Benazzouz
authors.affiliation: Department of Neurochemistry and Neurotoxicology, Stockholm University, Stockholm, Sweden.
authors.forename: Emelía
authors.initials: E
authors.lastname: Eiríksdóttir
authors.affiliation: Department of Neurochemistry and Neurotoxicology, Stockholm University, Stockholm, Sweden.
authors.forename: Ülo
authors.initials: Ü
authors.lastname: Langel
authors.affiliation: University of Bordeaux, Bordeaux, France.|CNRS, IINS, UMR5297, Bordeaux, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Favereaux
authors.affiliation: Faculty of Sciences, Abdelmalek Essaâdi University, Tetouan, Morocco.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Errami
authors.affiliation: University of Bordeaux, Bordeaux, France.|CNRS, IINS, UMR5297, Bordeaux, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Landry
authors.affiliation: University of Bordeaux, Bordeaux, France.|CNRS, IINS, UMR5297, Bordeaux, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Fossat
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000818:Animals; D015220:Calcium Channels / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D006930:Hyperalgesia / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D009437:Neuralgia / Q000378:metabolism* / Q000503:physiopathology; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D013116:Spinal Cord / Q000378:metabolism / Q000503:physiopathology; D066148:Spinal Cord Dorsal Horn / Q000378:metabolism / Q000503:physiopathology; D013127:Spinal Nerves / Q000378:metabolism / Q000503:physiopathology; D013569:Synapses / Q000378:metabolism
chemical_list: D015220:Calcium Channels; D020746:Calcium Channels, L-Type; C419385:L-type calcium channel alpha(1C); D016194:Receptors, N-Methyl-D-Aspartate; C093712:Cacna1d protein, rat