Abstract
Voltage-gated sodium channels are known to play a pivotal role in perception and transmission of pain sensations. Gain-of-function mutations in the genes encoding the peripheral neuronal sodium channels, hNav1.7–1.9, cause human painful diseases. Thus while treatment of chronic pain remains an unmet clinical need, sodium channel blockers are considered as promising druggable targets. In a previous study, we evaluated the analgesic activity of sumatriptan, an agonist of serotonin 5HT1B/D receptors, and some new chiral bioisosteres, using the hot plate test in the mouse. Interestingly, we observed that the analgesic effectiveness was not necessarily correlated to serotonin agonism. In this study, we evaluated whether sumatriptan and its congeners may inhibit heterologously expressed hNav1.7 sodium channels using the patch-clamp method. We show that sumatriptan blocks hNav1.7 channels only at very high, supratherapeutic concentrations. In contrast, its three analogs, namely 20b, (R)-31b, and (S)-22b, exert a dose and use-dependent sodium channel block. At 0.1 and 10 Hz stimulation frequencies, the most potent compound, (S)-22b, was 4.4 and 1.7 fold more potent than the well-known sodium channel blocker mexiletine. The compound induces a negative shift of voltage dependence of fast inactivation, suggesting higher affinity to the inactivated channel. Accordingly, we show that (S)-22b likely binds the conserved local anesthetic receptor within voltage-gated sodium channels. Combining these results with the previous ones, we hypothesize that use-dependent sodium channel blockade contributes to the analgesic activity of (R)-31b and (S)-22b. These later compounds represent promising lead compounds for the development of efficient analgesics, the mechanism of action of which may include a dual action on sodium channels and 5HT1D receptors.
Highlights
Neuropathic pain arises as a direct consequence of a lesion or disease affecting the somatosensory system (Treede et al, 2008)
Sumatriptan and its analogs, as well as mexiletine, were tested on hNav1.7 channels permanently expressed in HEK293 cell line
Using the patch-clamp technique to evaluate the effects of sumatriptan and its analogs on peripheral neuronal sodium channels, we observed that sumatriptan is a weak sodium channel blocker, since the concentration necessary to produce a significant sodium current reduction is greater than 100 μM, whereas the therapeutic blood concentration range is 61–203 nM (Schulz and Schmoldt, 2003)
Summary
Neuropathic pain arises as a direct consequence of a lesion or disease affecting the somatosensory system (Treede et al, 2008). Voltage-gated sodium channel have a major role in the generation and conduction of the electrical pain information in the central and peripheral nervous system (Dib-Hajj et al, 2010; Catterall, 2012). Gain-of-function mutations in the genes encoding these channels induce DRG neuron hyperexcitability and cause human painful disorders, while loss-of-function mutations of Nav1.7 cause congenital insensitivity to pain (Hoeijmakers et al, 2015). These observations strongly suggest a promising role for sodium channels as druggable targets in pain treatment (Cummins and Rush, 2007; Priest and Kaczorowski, 2007; Dib-Hajj et al, 2009; Theile and Cummins, 2011). We recently demonstrated that orphenadrine, a muscle relaxant with analgesic properties, partially inhibits peripheral nerve sodium channels at clinical concentrations (Desaphy et al, 2009)
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