The pathogenesis of neuropathic pain includes hyperactivation of glutamatergic transmission. Earlier, we showed that the antidepressant inhibition of the NMDA receptor by potential-dependent mechanism leads to pain relief, and the sodium-calcium exchanger (NCX) is responsible for the calcium-dependent desensitization of the NMDA receptor. 
To study the analgesic mechanism of antidepressant action and the functional relationships of NCX and NMDAR as targets for neuropathic pain management, we used electrophysiological techniques (patch clamp registration of NMDAR transmembrane currents in the “whole cell” configuration) and molecular modeling methods (QSAR, docking, molecular dynamics).
Amitriptyline and desipramine in high concentrations (100 μM) have been shown to cause potential-dependent inhibition of NMDAR currents, which little depends on the concentration of extracellular calcium in the perfusion solution; they act as classical channel blockers. At low therapeutic concentrations (<10 μM), the drugs inhibit NMDAR currents along the calcium-dependent pathway, not blocking the receptor channel, but affecting the NCX, which greatly enhances the NMDAR-dependent desensitization. Molecular modeling methods have determined the binding sites of antidepressant molecules with NMDA and NCX. The interaction energies have been calculated. The antidepressant molecule binds inside the NMDAR channel near the site of Mg ion sorption; the NCX binding site is located outside and does not intersect with the binding sites of sodium and calcium ions. For both receptors, the binding strength of the antidepressant molecule is mainly determined by electrostatic interactions.
Desipramine is more strongly bound to NMDAR and NCX, which correlates with its higher analgesic efficacy compared to amitriptyline.
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The study is supported by RFBR grant 18-015-00023 and FASO АААА-А18-118012290427-7.

ANTI-GLUTAMATE MECHANISM OF ANALGESIC ACTION OF ANTIDEPRESSANTS AMITRIPTYLINE AND DESIPRAMINE