State-dependent properties of a new T-type calcium channel blocker enhance CaV3.2 selectivity and support analgesic effects
| العنوان: | State-dependent properties of a new T-type calcium channel blocker enhance CaV3.2 selectivity and support analgesic effects |
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| المؤلفون: | Amaury François, Alain Eschalier, Emmanuel Bourinet, Nicolas Kerckhove, Denis Ardid, Agathe Gelot, Christian Barrère, Abdelkrim Alloui, Mathieu Meleine, Victor N. Uebele, John J. Renger |
| المساهمون: | Institut de Génomique Fonctionnelle (IGF), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Neuro-Dol (Neuro-Dol), Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Nutrition, inflammation et dysfonctionnement de l'axe intestin-cerveau (ADEN), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Pharmacologie fondamentale et clinique de la douleur, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Neuro-Dol (Neuro-Dol), Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM) |
| المصدر: | PAIN PAIN, Elsevier, 2013, 154 (2), pp.283-293. ⟨10.1016/j.pain.2012.10.023⟩ Pain Pain, 2013, 154 (2), pp.283-293. ⟨10.1016/j.pain.2012.10.023⟩ |
| بيانات النشر: | Ovid Technologies (Wolters Kluwer Health), 2013. |
| سنة النشر: | 2013 |
| مصطلحات موضوعية: | Male, Pyridines, Analgesic, Benzeneacetamides, Pharmacology, Rats, Sprague-Dawley, Calcium Channels, T-Type, Mice, 03 medical and health sciences, 0302 clinical medicine, In vivo, medicine, Animals, Humans, Potency, 030304 developmental biology, Mice, Knockout, Neurons, 0303 health sciences, Dose-Response Relationship, Drug, Voltage-dependent calcium channel, business.industry, T-type calcium channel, Antagonist, Calcium Channel Blockers, Rats, HEK293 Cells, Anesthesiology and Pain Medicine, Nociception, Neurology, Hyperalgesia, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neurology (clinical), medicine.symptom, business, 030217 neurology & neurosurgery |
| الوصف: | International audience; T-type calcium channels encoded by the Ca V 3.2 isoform are expressed in nociceptive primary afferent neurons where they contribute to hyperalgesia and thus are considered as a potential therapeutic target to treat pathological pain. Here we report that the small organic state-dependent T-type channel antagonist TTA-A2 efficiently inhibits recombinant and native Ca V 3.2 currents. Although TTA-A2 is a pan Ca V 3 blocker, it demonstrates a higher potency for Ca V 3.2 compared to Ca V 3.1. TTA-A2 selectivity for T-type currents was demonstrated in sensory neurons where it lowered cell excitability uniquely on neurons expressing T-type channels. In vivo pharmacology in Ca V 3.2 knockout and wild type mice reveal that TTA-A2-mediated antinociception critically depends on Ca V 3.2 expression. The pathophysiology of irritable bowel syndrome (IBS) was recently demonstrated to involve Ca V 3.2 in a rat model of this disease. Oral administration of TTA-A2 produced a dose-dependent reduction of hypersensitivity in an IBS model, demonstrating its therapeutic potential for the treatment of pathological pain. Overall, our results suggest that the high potency of TTA-A2 in the depolarized state strengthen its analgesic efficacy and selec-tivity toward pathological pain syndromes. This characteristic would be beneficial for the development of analgesics targeting T-type channels, in particular for the treatment of pain associated with IBS. Ó |
| تدمد: | 0304-3959 1872-6623 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::c4f4c457dddda9b0fcc292ab8d8f00ffTest https://doi.org/10.1016/j.pain.2012.10.023Test |
| رقم الانضمام: | edsair.doi.dedup.....c4f4c457dddda9b0fcc292ab8d8f00ff |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 03043959 18726623 |
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