Evaluation of the antinociceptive activities of several sodium channel blockers using veratrine test in mice

Yoshizawa, Kazumi; Arai, Narumaki; Suzuki, Yukina; Nakamura, Toka; Takeuchi, Kota; Sakamoto, Reinii; Masuda, Ryosuke

doi:10.1002/syn.22056

Cited by 5 publications

(12 citation statements)

References 27 publications

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“…Despite its use over many decades, there still is no clear information on the mode of action of VPA at the molecular level. Proposed mechanisms have included effects on sodium channel-mediated currents, on GABA receptors, and the efficacy of excitatory neurotransmission (11)(12)(13)(14). Early studies on the administration of VPA to neuron cultures indicated its ability to modulate sodium and potassium ion conductance (15) and to modify sodium-dependent action potentials in neurons (16,17).…”

mentioning

confidence: 99%

Valproic acid interactions with the NavMs voltage-gated sodium channel

Zanatta

Sula

Miles

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Valproic acid (VPA) is an anticonvulsant drug that is also used to treat migraines and bipolar disorder. Its proposed biological targets include human voltage-gated sodium channels, among other membrane proteins. We used the prokaryotic NavMs sodium channel, which has been shown to be a good exemplar for drug binding to human sodium channels, to examine the structural and functional interactions of VPA. Thermal melt synchrotron radiation circular dichroism spectroscopic binding studies of the full-length NavMs channel (which includes both pore and voltage sensor domains), and a pore-only construct, undertaken in the presence and absence of VPA, indicated that the drug binds to and destabilizes the channel, but not the pore-only construct. This is in contrast to other antiepileptic compounds that have previously been shown to bind in the central hydrophobic core of the pore region of the channel, and that tend to increase the thermal stability of both pore-only constructs and full-length channels. Molecular docking studies also indicated that the VPA binding site is associated with the voltage sensor, rather than the hydrophobic cavity of the pore domain. Electrophysiological studies show that VPA influences the block and inactivation rates of the NavMs channel, although with lower efficacy than classical channel-blocking compounds. It thus appears that, while VPA is capable of binding to these voltage-gated sodium channels, it has a very different mode and site of action than other anticonvulsant compounds.

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mentioning

confidence: 99%

Valproic acid interactions with the NavMs voltage-gated sodium channel

Zanatta

Sula

Miles

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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“…In our previous study, we demonstrated that mexiletine reduced the veratrine-induced nociceptive response in mice [9]. However, milnacipran may have difficulty binding to sodium channels because its planar structure is fixed by the cyclopropane structure [19].…”

Section: Discussionmentioning

confidence: 99%

“…The veratrine test was performed as described previously [9]. Veratrine solution of 40 µL (1.0 µg) was injected under the skin of the dorsal surface of the right hind paw using a microsyringe with a 30-gage needle.…”

Section: Veratrine Testmentioning

confidence: 99%

“…Previously, we reported for the first time the production of a nociceptive response via an intraplantar injection of veratrine in mice; the nociceptive response was suppressed by the selective Nav1.7 inhibitor PF-04856264 [9]. Therefore, intraplantar injection of veratrine could activate Nav1.7, which was related to pain in the DRG sensory neurons.…”

Section: Introductionmentioning

confidence: 99%

“…Significantly, Nav1.7 is localized in the sensory endings and plays a major role in the transmission of painful stimuli [10]. Our results suggest that the veratrine test in mice might be a useful tool for assessing the analgesic potential of sodium channel blockers [9].…”

Section: Introductionmentioning

confidence: 99%

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Differences in the antinociceptive effects of serotonin–noradrenaline reuptake inhibitors via sodium channel blockade using the veratrine test in mice

Yoshizawa¹,

Suzuki²,

Nakamura³

et al. 2021

NeuroReport

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Antidepressants exert their analgesic effects by inhibiting the reuptake of noradrenaline. Several antidepressants have been shown to block the sodium channels, which might contribute to their analgesic potency. The aim of this study was to determine whether serotonin-noradrenaline reuptake inhibitors (SNRIs) could produce antinociceptive effects via sodium channel blockade using the veratrine test in mice. Furthermore, the effects of these agents on the veratrine test were examined to elucidate the effects of several antidepressants and tramadol on sodium channels. The administration of duloxetine (10 mg/kg) and venlafaxine (30 mg/kg) suppressed cuff-induced mechanical allodynia; however, these antinociceptive effects were only partially suppressed by atipamezole. Furthermore, duloxetine and venlafaxine demonstrated antinociceptive effects via sodium channel blockade, as assayed by the veratrine test. In addition, several antidepressants, including amitriptyline, paroxetine and mirtazapine, reduced veratrine-induced nociception.In contrast, milnacipran and tramadol did not alter the veratrine-induced nociception. These results indicated that, in addition to the primary action of SNRIs on monoamine transporters, sodium channel blockade might be involved in the antinociceptive activities of duloxetine and venlafaxine, but not milnacipran.

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