Pregabalin acts on Na⁺-Ca²⁺ exchanger, which promotes Ca²⁺ extrusion from human Merkel cell line

Pregabalin, a first-line treatment for neuropathic pain, binds to the voltage-gated calcium channel auxiliary subunit alpha2delta-1, reducing neurotransmitter release. Transdermal pregabalin has also shown analgesic effects in neuropathic mouse models. However, its effects on epidermal cells remain unclear.

We aimed to investigate the action of pregabalin on the human Merkel cell line (MC).

We used the cultured human Merkel cell line MCC 14/2 to measure intracellular free calcium concentration ([Ca²⁺]_i) levels using fura-2 and to perform immunofluorescence analysis.

To examine effect of pregabalin on a chronic pain condition, we applied Lys-(Des-Arg⁹) bradykinin (BK) for 48 hours (BK group), BK for 48 hours with pregabalin for 24 hours (BK + pregabalin group), or none (as control group) before measuring the direct mechanical stimulation-induced [Ca²⁺]_i response in the MCs. The area under the curve (AUC) of the transient increase in [Ca²⁺]_i was significantly increased in the BK group than that in the control group. Area under the curve did not show any significant differences between control group and BK + pregabalin group. When the Na⁺-Ca²⁺ exchanger (NCX) inhibitor KB-R7943 and SEA0400 were applied just before mechanical stimulation in the BK + pregabalin group, AUC was significantly increased compared to that in the absence of KB-R7943 and SEA0400. We could not observe any significant differences in the peak values of mechanical stimulation-induced [Ca²⁺]_i increases among the groups. Merkel cells predominantly expressed the NCX1 isoform.

These results suggested that the site of action of pregabalin to MCs is Ca²⁺ extrusion mechanism via NCX1.