Cav3.2 calcium channel inhibition: 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 the remission phase. Current treatments are generally weakly effective. Therefore, new therapeutic approaches are needed. The role of Cav3.2 voltage-dependent calcium channels, which have been shown to be important in other chronic pain contexts, was investigated in a murine model of colonic hypersensitivity (CHS) associated with low-grade inflammation.

EXPERIMENTAL APPROACH: A chronic low dose of dextran sulfate sodium (DSS 0.5%) was administered to mice via drinking water. The inflammation status of the mice was assessed by systemic and local measures of IL-6, myeloperoxidase and lipocalin-2 using ELISA. The colonic sensitivity was evaluated by measuring the visceromotor responses to colorectal distension. The functional involvement of Cav3.2 channels was investigated using different pharmacological (TTA-A2, ABT-639, and ethosuximide) and genetic tools.

KEY RESULTS: DSS (0.5%) induced low-grade inflammation associated with CHS in mice. The genetic and pharmacological Cav3.2 channel inhibition reduced CHS. The Cav3.2 channel deletion in primary nociceptive neurons in the dorsal root ganglion (Cav3.2Nav1.8 KO mice) suppressed CHS. The spinal, but not systemic, administration of ABT-639, which is a peripherally acting T-type blocker, reduced CHS. Administered intrathecally to Cav3.2Nav1.8 KO mice, ABT-639 had no effect, demonstrating the involvement of Cav3.2 channels located presynaptically in afferent fibre terminals. Finally, ethosuximide, which is a T-type blocker used clinically, reduced CHS.

CONCLUSIONS AND IMPLICATIONS: These results suggest that ethosuximide represents a promising drug reposition strategy and that Cav3.2 inhibition is an attractive therapeutic approach for relieving CHS in IBS or IBD.