Tetrodotoxin: A New Strategy to Treat Visceral Pain?
Abstract
:1. Introduction
2. Primary Sensory Innervation of the Viscera
3. VGSCs
3.1. TTX-S Channels
3.2. TTX-R Channels
4. VGSC Blockade by TTX as a New Pain Therapy
5. Concluding Remarks
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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VGSCs | Gene | Tetrodotoxin | Associated Pain | Alteration | References |
---|---|---|---|---|---|
Nav1.1 | SCN1A | Sensitive | Irritable bowel syndrome | Upregulation | [61] |
Nav1.5 | SCN5A | Resistant | Irritable bowel syndrome, cardiac syndrome | Loss of function | [38,48,72,73] |
Nav1.6 | SCN8A | Sensitive | Colorectal pain | Activation | [74] |
Nav1.7 | SCN9A | Sensitive | Erythromelalgia, paroxysmal extreme pain | Gain of function or altered functional levels | [45,71,75] |
Nav1.8 | SCN10A | Resistant | Chronic jejunitis pain | Change in function or expression | [76] |
Nav1.9 | SCN11A | Resistant | Chronic inflammatory pain | Potentiation | [77] |
Model | Administration of Tetrodotoxin (TTX) | Outcome | References | |
---|---|---|---|---|
Clinical evidence | Cancer-related pain patients | Subcutaneous injection (30 µg) | Long-lasting analgesia (56.7 days) | [87,109] |
Experimental evidence | Wild-type and Nav1.7 knock-out mouse models of pain | Subcutaneous injection (0.1, 0.3, 1, 3, 6 µM) | - TTX reduced both visceral pain-behaviour and referred hyperalgesia - Dose-dependent actions - Antinociceptive effect | [11,92] |
Dorsal root ganglion (DRG) neurons | Perfusion (0.5 µM) | TTX diminished Nav1.1 activated by Hm1a | [79] | |
Colorectal distension model of pain | Mucosal and serosal application (1, 3, 10 µM) | - 10 μM TTX on the mucosal side and 1 µM on the serosal side attenuated afferent responses to stretch - TTX predominantly inhibited Nav1.6 | [70] | |
Colorectal afferents sensitized by IL-2 | Perfusion (1 µM) | TTX blocked Nav1.7 | [89] | |
Chemical sensitized afferent splanchnic fibers | Perfusion (0.1 µM) | - TTX blocked pain-related behaviour - TTX failed to inhibit Nav1.7 | [93] | |
Vagus nerve of rats | Perfussion (10 µM) | TTX blocked action potential propagation | [95] | |
Pelvic vaginal afferents | Perfusion (0.5 µM) | TTX significantly reduced vaginal afferent responses to mechanical stimuli | [57] | |
Vagina-innervating DRG neurons | Perfusion (0.1 µM) | TTX decreased neuronal excitability by blocking TTX-S channels | ||
Vaginal pain mouse model | Intravaginal administration (0.5 µM) | TTX reduced spinal cord neuronal activation | ||
Bladder afferents of mice | Instillation (1 µM) | TTX supresed mechanical distension and reduced firing | [107] | |
Bladder-innervating DRG neurons | Incubation (100 nM) | TTX reduced Na+ current density and excitability | ||
In vivo bladder of mice | Intravesical infusion (1 µM) | TTX reduced noxious bladder distension-induced nociceptive signalling |
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Campos-Ríos, A.; Rueda-Ruzafa, L.; Herrera-Pérez, S.; Rivas-Ramírez, P.; Lamas, J.A. Tetrodotoxin: A New Strategy to Treat Visceral Pain? Toxins 2021, 13, 496. https://doi.org/10.3390/toxins13070496
Campos-Ríos A, Rueda-Ruzafa L, Herrera-Pérez S, Rivas-Ramírez P, Lamas JA. Tetrodotoxin: A New Strategy to Treat Visceral Pain? Toxins. 2021; 13(7):496. https://doi.org/10.3390/toxins13070496
Chicago/Turabian StyleCampos-Ríos, Ana, Lola Rueda-Ruzafa, Salvador Herrera-Pérez, Paula Rivas-Ramírez, and José Antonio Lamas. 2021. "Tetrodotoxin: A New Strategy to Treat Visceral Pain?" Toxins 13, no. 7: 496. https://doi.org/10.3390/toxins13070496