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.

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 (Nav) 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 Nav1.2, Nav1.3, Nav1.6, Nav1.7, and Nav1.8 with a ß1 subunit by using whole-cell, two-electrode, voltage clamp techniques. We also studied the role of the ß3 subunit on the effect of antidepressants on Nav1.3. All antidepressants inhibited sodium currents in an inactivated state induced by all five α subunits with ß1. The inhibitory effects were more potent for Nav1.3, Nav1.7, and Nav1.8, which are distributed in dorsal root ganglia, than Nav1.2 and Nav1.6, which are distributed primarily in the central nervous system. The effect of amitriptyline on Nav1.7 with ß1 was most potent with a half-maximal inhibitory concentration (IC50) 4.6 µmol/L. IC50 for amitriptyline on Nav1.3 coexpressed with ß1 was lowered from 8.4 to 4.5 µmol/L by coexpression with ß3. 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 ß3 subunit appears important for inhibition of Nav1.3. These findings may aid better understanding of the mechanisms underlying the pain relieving effects of antidepressants.

Blockage of the upregulation of voltage-gated sodium channel nav1.3 improves outcomes after experimental traumatic brain injury.

Excessive active voltage-gated sodium channels are responsible for the cellular abnormalities associated with secondary brain injury following traumatic brain injury (TBI). We previously presented evidence that significant upregulation of Nav1.3 expression occurs in the rat cortex at 2 h and 12 h post-TBI and is correlated with TBI severity. In our current study, we tested the hypothesis that blocking upregulation of Nav1.3 expression in vivo in the acute stage post-TBI attenuates the secondary brain injury associated with TBI. We administered either antisense oligodeoxynucleotides (ODN) targeting Nav1.3 or artificial cerebrospinal fluid (aCSF) at 2 h, 4 h, 6 h, and 8 h following TBI. Control sham animals received aCSF administration at the same time points. At 12 h post-TBI, Nav1.3 messenger ribonucleic acid (mRNA) levels in bilateral hippocampi of the aCSF group were significantly elevated, compared with the sham and ODN groups (p<0.01). However, the Nav1.3 mRNA levels in the uninjured contralateral hippocampus of the ODN group were significantly lowered, compared with the sham group (p<0.01). Treatment with antisense ODN significantly decreased the number of degenerating neurons in the ipsilateral hippocampal CA3 and hilar region (p<0.01). A set of left-to-right ratio value analyzed by magnetic resonance imaging T2 image on one day, three days, and seven days post-TBI showed marked edema in the ipsilateral hemisphere of the aCSF group, compared with that of the ODN group (p<0.05). The Morris water maze memory retention test showed that both the aCSF and ODN groups took longer to find a hidden platform, compared with the sham group (p<0.01). However, latency in the aCSF group was significantly higher than in the ODN group (p<0.05). Our in vivo Nav1.3 inhibition studies suggest that therapeutic strategies to block upregulation of Nav1.3 expression in the brain may improve outcomes following TBI.

Pharmacological kinetics of BmK AS, a sodium channel site 4-specific modulator on Nav1.3.

OBJECTIVE: In this study, the pharmacological kinetics of Buthus martensi Karsch (BmK) AS, a specific modulator of voltage-gated sodium channel site 4, was investigated on Na(v)1.3 expressed in Xenopus oocytes. METHODS: Two-electrode voltage clamp was used to record the whole-cell sodium current. RESULTS: The peak currents of Na(v)1.3 were depressed by BmK AS over a wide range of concentrations (10, 100, and 500 nmol/L). Most remarkably, BmK AS at 100 nmol/L hyperpolarized the voltage-dependence and increased the voltage-sensitivity of steady-state activation/inactivation. In addition, BmK AS was capable of hyperpolarizing not only the fast inactivation but also the slow inactivation, with a greater preference for the latter. Moreover, BmK AS accelerated the time constant and increased the ratio of recovery in Na(v)1.3 at all concentrations. CONCLUSION: This study provides direct evidence that BmK AS facilitates steady-state activation and inhibits slow inactivation by stabilizing both the closed and open states of the Na(v)1.3 channel, which might result from an integrative binding to two receptor sites on the voltage-gated sodium channels. These results may shed light on therapeutics against Na(v)1.3-targeted pathology.