Objective Increased faecal butyrate levels have been reported in irritable bowel syndrome. Rectal instillation of sodium butyrate (NaB) increases visceral sensitivity in rats by an unknown mechanism. We seek to examine the signal transduction pathways responsible for the enhanced neuronal excitability in the dorsal root ganglion (DRG) following NaB enemas and demonstrate that this is responsible for the colonic hypersensitivity reported in this animal model.
Design Colorectal distention (CRD) studies were performed in rats treated with NaB rectal instillation with/without intrathecal or intravenous administration of mitogen-activated protein (MAP) kinase kinase inhibitor U0126. Western blot analysis and immunocytochemistry studies elucidated intracellular signalling pathways that modulate IA. Patch-clamp recordings were performed on isolated DRG neurons treated with NaB, with/without U0126.
Results Visceromotor responses (VMR) were markedly enhanced in NaB-treated rats. Western blot analysis of DRG neurons from NaB-treated rats showed a 2.2-fold increase in phosphorylated ERK1/2 (pEKR1/2) and 1.9-fold increase in phosphorylated voltage-gated potassium channel subunit 4.2 (pKv4.2). Intrathecal or intravenous administration of U0126 reduced VMR to CRD in NaB-treated rats and prevented increases in pERK1/2 and pKv4.2. Patch-clamp recordings of isolated DRG neurons showed that NaB caused a reduction in IA to 48.9%±1.4% of control and an increase in neuronal excitability, accompanied by a twofold increase in pERK1/2 and pKv4.2. Concurrent U0126 administration prevented these changes.
Conclusions Visceral hypersensitivity induced by colonic NaB treatment is mediated by activation of the MAP kinase–ERK1/2 pathway, which phosphorylates Kv4.2. This results in a reduction in IA and an enhancement of DRG neuronal excitability.
- Sensory neurons
- visceral hypersensitivity
- irritable bowel syndrome
- Kv4.2 potassium channel
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Funding This work was supported by the National Institutes of Health grants R01 NS51466 and P30 DK34933.
Competing interests None.
Ethics approval All animal procedures were performed in accordance with National Institutes of Health guidelines and were approved by the University Committee on Use and Care of Animals at the University of Michigan.
Provenance and peer review Not commissioned; externally peer reviewed.
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