T-type calcium channels contribute to colonic hypersensitivity in a rat model of irritable bowel syndrome
| Autor: | Juan F. Sanguesa Ferrer, Emilie Muller, Fabrice Marger, Abdelkrim Alloui, Terrance P. Snutch, Joël Nargeot, Emmanuel Bourinet, Julien Matricon, Denis Ardid, Christian Barrère, Anne Pizzoccaro, Alain Eschalier, Agathe Gelot |
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| Rok vydání: | 2011 |
| Předmět: |
Male
Abdominal pain Colon Pharmacology Irritable Bowel Syndrome Rats Sprague-Dawley Calcium Channels T-Type medicine Animals RNA Small Interfering Irritable bowel syndrome Multidisciplinary Base Sequence Voltage-dependent calcium channel business.industry Calcium channel T-type calcium channel Nociceptors Pain Perception Visceral pain Biological Sciences Calcium Channel Blockers medicine.disease Electrophysiological Phenomena Rats Butyrates Disease Models Animal Gene Knockdown Techniques Anesthesia Neuropathic pain Nociceptor Neuralgia medicine.symptom business |
| Zdroj: | Proceedings of the National Academy of Sciences. 108:11268-11273 |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | The symptoms of irritable bowel syndrome (IBS) include significant abdominal pain and bloating. Current treatments are empirical and often poorly efficacious, and there is a need for the development of new and efficient analgesics aimed at IBS patients. T-type calcium channels have previously been validated as a potential target to treat certain neuropathic pain pathologies. Here we report that T-type calcium channels encoded by the Ca V 3.2 isoform are expressed in colonic nociceptive primary afferent neurons and that they contribute to the exaggerated pain perception in a butyrate-mediated rodent model of IBS. Both the selective genetic inhibition of Ca V 3.2 channels and pharmacological blockade with calcium channel antagonists attenuates IBS-like painful symptoms. Mechanistically, butyrate acts to promote the increased insertion of Ca V 3.2 channels into primary sensory neuron membranes, likely via a posttranslational effect. The butyrate-mediated regulation can be recapitulated with recombinant Ca V 3.2 channels expressed in HEK cells and may provide a convenient in vitro screening system for the identification of T-type channel blockers relevant to visceral pain. These results implicate T-type calcium channels in the pathophysiology of chronic visceral pain and suggest Ca V 3.2 as a promising target for the development of efficient analgesics for the visceral discomfort and pain associated with IBS. |
| Databáze: | OpenAIRE |
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