Antidepressants inhibit Nav1.3, Nav1.7, and Nav1.8 neuronal voltage-gated sodium channels more potently than Nav1.2 and Nav1.6 channels expressed in Xenopus oocytes

Abstract

Tricyclic antidepressants (TCAs) and duloxetine are used to treat neuropathic pain. However, the mechanisms underlying their analgesic effects remain unclear. Although many investigators have shown inhibitory effects of antidepressants on voltage-gated sodium channels (Na) as a possible mechanism of analgesia, to our knowledge, no one has compared effects on the diverse variety of sodium channel α subunits. We investigated the effects of antidepressants on sodium currents in Xenopus oocytes expressing Na1.2, Na1.3, Na1.6, Na1.7, and Na1.8 with a β subunit by using whole-cell, two-electrode, voltage clamp techniques. We also studied the role of the β subunit on the effect of antidepressants on Na1.3. All antidepressants inhibited sodium currents in an inactivated state induced by all five α subunits with β. The inhibitory effects were more potent for Na1.3, Na1.7, and Na1.8, which are distributed in dorsal root ganglia, than Na1.2 and Na1.6, which are distributed primarily in the central nervous system. The effect of amitriptyline on Na1.7 with β was most potent with a half-maximal inhibitory concentration (IC) 4.6 μmol/L. IC for amitriptyline on Na1.3 coexpressed with β was lowered from 8.4 to 4.5 μmol/L by coexpression with β. Antidepressants predominantly inhibited the sodium channels expressed in dorsal root ganglia, and amitriptyline has the most potent inhibitory effect. This is the first evidence, to our knowledge, showing the diverse effects of antidepressants on various α subunits. Moreover, the β subunit appears important for inhibition of Na1.3. These findings may aid better understanding of the mechanisms underlying the pain relieving effects of antidepressants.

The Microglial Activation Inhibitor Minocycline, Used Alone and in Combination with Duloxetine, Attenuates Pain Caused by Oxaliplatin in Mice

“…It was also shown that the increased density of microglial cells and astrocytes correlates with pain hypersensitivity due to oxaliplatin administration [24], and decreased activation of the microglia and astrocytes relieved pain and stimulated neuroprotection [23,25]. Based on these findings [26][27][28][29][30][31][32][33], in this present research minocycline was used alone or in combination with a Na v channel inhibitor, i.e., ambroxol [34][35][36], or a serotonin/noradrenaline reuptake inhibitor with Na v -channel blocking properties, duloxetine [37,38], to attenuate tactile allodynia and cold hyperalgesia caused by oxaliplatin.…”

Sodium Channel Blockers Modulate Abnormal Activity of Regenerating Nociceptive Corneal Nerves After Surgical Lesion

“…Of note, lidocaine, carbamazepine, and amitriptyline have been reported to inhibit all the aforementioned Nav channel subtypes expressed by nociceptors. 30,34,[48][49][50] In addition, in corneal nociceptive nerve terminals, functional evidence suggests that tetrodotoxin-resistant sodium currents are the primary determinant of their excitability, 51 which leads to the presumption that tetrodotoxin-resistant sodium channels are the main contributors to the onset of membrane hyperexcitability in corneal nociceptive terminals after injury, and in turn they are the main molecular targets of the sodium channel blockers assessed in this work.…”

Analgesic Effects of Topical Amitriptyline in Patients With Chemotherapy-Induced Peripheral Neuropathy: Mechanistic Insights From Studies in Mice

“…Amitriptyline is an antagonist of the histamine, muscarinic, adrenergic, and serotonin receptors, and leads to blockade of voltage-gated sodium ion channels 30,41 . It also appears to interact with calcium ion channels 37 .…”