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

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 windup. Windup, a progressive increase in DHNs response following repetitive peripheral stimulations, depends on the post-synaptic L-type calcium channels (LTCs). In the dorsal horn of the spinal cord, two LTCs are present, Cav1.2 and Cav1.3, each displaying specific kinetics and spatial distribution. We used here 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 windup while Cav1.2 is not and that synaptically triggered windup requires NMDA receptor activation. We then switched to a biological preparation in which we knocked down Cav subunits, we confirmed the prominent role of Cav1.3 in both naive and spinal nerve ligation model of neuropathy (SNL). Interestingly, while a clear mechanical allodynia dependant on Cav1.2 expression was observed after SNL, the amplitude of windup 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 windup amplitude is decreased in SNL, plateau potentials are not altered, suggesting that plateau and windup are not fully equivalent. Windup and long-term hyperexcitability of DHNs are differentially controlled by Cav1.2 and Cav1.3, therefore, confirming that short-term and long-term sensitization are two different phenomena triggered by distinct mechanisms.

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