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NEUROREGULATION AND MOTILITY

Two TTX-resistant Na⁺ currents in mouse colonic dorsal root ganglia neurons and their role in colitis-induced hyperexcitability

¹Gastrointestinal Diseases Research Unit and ²Department of Anatomy and Cell Biology, Queen's University, Kingston, Ontario, Canada K7L 5G2

Submitted 7 April 2004 ; accepted in final form 16 June 2004

The composition of Na⁺ currents in dorsal root ganglia (DRG) neurons depends on their neuronal phenotype and innervation target. Two TTX-resistant (TTX-R) Na⁺ currents [voltage-gated Na channels (Na_v)] have been described in small DRG neurons; one with slow inactivation kinetics (Na_v1.8) and the other with persistent kinetics (Na_v1.9), and their modulation has been implicated in inflammatory pain. This has not been studied in neurons projecting to the colon. This study examined the relative importance of these currents in inflammation-induced changes in a mouse model of inflammatory bowel disease. Colonic sensory neurons were retrogradely labeled, and colitis was induced by instillation of trinitrobenzenesulfonic acid (TNBS) into the lumen of the distal colon. Seven to ten days later, immunohistochemical properties were characterized in controls, and whole cell recordings were obtained from small (<40 pF) labeled DRG neurons from control and TNBS animals. Most neurons exhibited both fast TTX-sensitive (TTX-S)- and slow TTX-R-inactivating Na⁺ currents, but persistent TTX-R currents were uncommon (<15%). Most labeled neurons were CGRP (79%), tyrosine kinase A (trkA) (84%) immunoreactive, but only a small minority bind IB4 (14%). TNBS-colitis caused ulceration, thickening of the colon and significantly increased neuronal excitability. The slow TTX-R-inactivating Na current density (Na_v1.8) was significantly increased, but other Na currents were unaffected. Most small mouse colonic sensory neurons are CGRP, trkA immunoreactive, but not isolectin B₄ reactive and exhibit fast TTX-S, slow TTX-R, but not persistent TTX-R Na⁺ currents. Colitis-induced hyperexcitability is associated with increased slow TTX-R (Na_v1.8) Na⁺ current. Together, these findings suggest that colitis alters trkA-positive neurons to preferentially increase slow TTX-R Na⁺ (Na_v1.8) currents.

tyrosine kinase A-positive neurons; sodium channels; nociception colon

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