The purpose of this study is to test the hypothesis that the analgesic and antipruritic efficacy of antidepressants is associated with their ability to block NMDA and AMPA receptors.
Electrophysiological measurement of the effects of 6 antidepressants on the ionic currents through NMDA and AMPA channels in neurons of the rat brain are performed by the method of fixation of the membrane potential of a neuron in the whole cell configuration. None of the compounds tested did not showed significant blocking ability against AMPA receptors. It has been shown that desipramine, chlorpromazine, and amitriptyline block voltage-dependently NMDA receptors by the mechanism of the trap. IC50 values for these compounds are equal to 1.57 ± 0.13 mM; 4.3 ± 1.0 mM; 14.1 ± 0.7 mM, respectively. Analysis of 3D models of desipramine, chlorpromazine and amitriptyline has showed that the structure of these compounds or their metabolites has V-like group formed by aromatic rings. Aromatic groups of molecules of clozapine, methiothepine and fluoxetine have other configurations. Their blocking efficiency is much lower: IC50 value of the voltage-independent blocking by fluoxetine is equal to 36.2 ± 1,7 mM, and clozapine - 70 ± 10 mM; methiothepin blocks the receptor voltage-dependently weakly. Using molecular docking methods it has been shown that blocking ability of antidepressants against the NMDA receptor is determined by their interaction with the channel, but not with the individual subunits. Desipramine, chlorpromazine and amitriptyline are effective for the management of neuropathic pain and itch syndromes; clozapine, methiothepine and fluoxetine are not.
It has been concluded that the postsynaptic ionotropic glutamate AMPA receptors are not the main target of analgesic and antipruritic action of antidepressants. The dependence of the analgesic and antipruritic efficacy of antidepressants on their structure and the ability to block voltage-dependent NMDA receptors has been shown.
The research is supported by RFBR grant 12-04-00454-a.