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

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.

Etiology and Pharmacology of Neuropathic Pain

“…Ca v 1 channels as therapeutic targets. In addition to the established role of changes in N-type Ca 2+ channels, certain lines of evidence support an additional contribution of L-type Ca 2+ channels in the maintenance of neuropathic pain (Balasubramanyan and Smith, 2005;Fossat et al, 2010;Chang et al, 2015;Radwani et al, 2016). This has led to increased interest in broad-spectrum dihydropyridine-related Ca 2+ channel blockers such as M4, which blocks Ca v 1.2 (L-type), Ca v 2.2 (N-type), and Ca v 3.2 and 3.3 (T-type channels) Zamponi et al, 2015 Snutch and Zamponi, 2017).…”

Calcium signalling through L‐type calcium channels: role in pathophysiology of spinal nociceptive transmission

“…As the dendritic tree is the preferential target of synaptic inputs, Ca v 1.3 channels are strategically located to elicit plateau potentials and amplify nociceptive inputs. In fact, a model of DHNs strongly suggests that the Ca v 1.3 channels are the major contributors to plateau potentials (Radwani et al ., ; Figure C).…”

“…Ca v 1.2 and Ca v 1.3 LTCs are expressed in the spinal cord both in the dorsal and the ventral horn (Perrier et al , ; Simon et al , ; Dobremez et al , ; Fossat et al , ; Radwani et al ., ). They carry slowly inactivating calcium currents allowing the expression of regenerative membrane properties in dorsal horn neurons (DHNs), called plateau potentials.…”

“…In the CNS, Ca v 1.2 and Ca v 1.3 channelsare predominantly post‐synaptic channels and are expressed in the soma and dendrites (Di Biase et al , ; Jenkins et al , ). In the spinal cord, Ca v 1.2 and Ca v 1.3 channels differ in their neuronal distribution, with Ca v 1.3 channels being expressed in the dendritic tree, in ventral horn neurons and in the whole somato‐dendritic compartment up to the distal dendrites in the dorsal horn (DH) while Ca v 1.2 channels are mostly restricted to the soma and proximal dendrites (Westenbroek et al , ; Simon et al , ; Dobremez et al , ; Radwani et al ., ). The lower voltage‐activated Ca v 1.3 subunit carries inward currents at threshold electrical membrane potentials and shapes neuronal firing (Striessnig et al , ).…”

“…They also contribute to pathologies such as Parkinson's disease (Striessnig et al , ) and developmental disorders such as autism syndromes (Striessnig et al , ). There is now strong evidence that LTCs actually subsume pain processing in the DH of the spinal cord (Schaible et al , ; Fossat et al , ; Fossat et al , ; Favereaux et al , ; Radwani et al , ).…”