Inhibition of Ca_v 3.2 calcium channels: A new target for colonic hypersensitivity associated with low-grade inflammation.

BACKGROUND AND PURPOSE:Abdominal pain associated with low-grade inflammation is frequently encountered in irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD) during remission. Current treatments are not very effective and new therapeutic approaches are needed. The role of Ca_V 3.2 channels, which are important in other chronic pain contexts, was investigated in a murine model of colonic hypersensitivity (CHS) associated with low-grade inflammation. EXPERIMENTAL APPROACH:Low doses of dextran sulfate sodium (DSS; 0.5%) were chronically administered to C57BL/6j mice in drinking water. Their inflammatory state was assessed by systemic and local measures of IL-6, myeloperoxidase, and lipocalin-2 using elisa. Colonic sensitivity was evaluated by the visceromotor responses to colorectal distension. Functional involvement of Ca_V 3.2 channels was assessed with different pharmacological (TTA-A2, ABT-639, and ethosuximide) and genetic tools. KEY RESULTS:DSS induced low-grade inflammation associated with CHS in mice. Genetic or pharmacological inhibition of Ca_V 3.2 channels reduced CHS. Cav3.2 channel deletion in primary nociceptive neurons in dorsal root ganglia (Ca_V 3.2^Nav1.8 KO mice) suppressed CHS. Spinal, but not systemic, administration of ABT-639, a peripherally acting T-type channel blocker, reduced CHS. ABT-639 given intrathecally to Ca_V 3.2^Nav1.8 KO mice had no effect, demonstrating involvement of Ca_V 3.2 channels located presynaptically in afferent fibre terminals. Finally, ethosuximide, which is a T-type channel blocker used clinically, reduced CHS. CONCLUSIONS AND IMPLICATIONS:These results suggest that ethosuximide represents a promising drug reposition strategy and that inhibition of Ca_V 3.2 channels is an attractive therapeutic approach for relieving CHS in IBS or IBD.

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