Cav1.2 and Cav1.3 L-type calcium channels independently control short- and long-term sensitization to pain.

Autor: Radwani H; University of Bordeaux, Bordeaux, France.; CNRS, IINS, UMR5297, Bordeaux, France.; Faculty of Sciences, Abdelmalek Essaâdi University, Tetouan, Morocco., Lopez-Gonzalez MJ; University of Bordeaux, Bordeaux, France.; CNRS, IINS, UMR5297, Bordeaux, France., Cattaert D; University of Bordeaux, Bordeaux, France.; CNRS, INCIA, UMR 5287, Talence, France., Roca-Lapirot O; University of Bordeaux, Bordeaux, France.; CNRS, IINS, UMR5297, Bordeaux, France., Dobremez E; University of Bordeaux, Bordeaux, France.; Department of Pediatric Surgery, University Hospital of Bordeaux, Bordeaux, France., Bouali-Benazzouz R; University of Bordeaux, Bordeaux, France.; CNRS, IINS, UMR5297, Bordeaux, France., Eiríksdóttir E; Department of Neurochemistry and Neurotoxicology, Stockholm University, Stockholm, Sweden., Langel Ü; Department of Neurochemistry and Neurotoxicology, Stockholm University, Stockholm, Sweden., Favereaux A; University of Bordeaux, Bordeaux, France.; CNRS, IINS, UMR5297, Bordeaux, France., Errami M; Faculty of Sciences, Abdelmalek Essaâdi University, Tetouan, Morocco., Landry M; University of Bordeaux, Bordeaux, France.; CNRS, IINS, UMR5297, Bordeaux, France., Fossat P; University of Bordeaux, Bordeaux, France.; CNRS, IINS, UMR5297, Bordeaux, France.
Jazyk: angličtina
Zdroj: The Journal of physiology [J Physiol] 2016 Nov 15; Vol. 594 (22), pp. 6607-6626. Date of Electronic Publication: 2016 Jul 03.
DOI: 10.1113/JP272725
Abstrakt: Key Points: 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.
Abstract: 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.
(© 2016 University of Bordeaux & CNRS. The Journal of Physiology © 2016 The Physiological Society.)
Databáze: MEDLINE
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