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Stretch-dependent sensitization of post-junctional neural effectors in colonic muscles.

ABSTRACT: The colon undergoes distension-induced changes in motor activity as luminal contents or feces increase wall pressure. Input from enteric motor neurons regulates this motility. Here we examined stretch-dependent responses in circular muscle strips of murine colon.Length ramps (6-31?m s(-1) ) were applied in the axis of the circular muscle layer in a controlled manner until 5 mN isometric force was reached.Length ramps produced transient membrane potential hyperpolarizations and attenuation of action potential (AP) complexes. Responses were reproducible when ramps were applied every 30 s. Stretch-dependent hyperpolarization was blocked by TTX, suggesting AP-dependent release of inhibitory neurotransmitter(s). Atropine did not potentiate stretch-induced hyperpolarizations, but increased compliance of the circular layer. N(?)-nitro-L-arginine (L-NNA) inhibited stretch-dependent hyperpolarization and decreased muscle compliance, suggesting release of NO mediates stretch-dependent inhibition. Control membrane potential was restored by the NO donor sodium nitorprusside. Stretch-dependent hyperpolarizations were blocked by L-methionine, an inhibitor of stretch-dependent K(+) (SDK) channels in colonic muscles. Loss of interstitial cells of Cajal, elicited by Kit neutralizing antibody, also inhibited responses to stretch. In presence of L-NNA and apamin, stretch responses became excitatory and were characterized by membrane depolarization and increased AP firing. A neurokinin-1 receptor antagonist inhibited this stretch-dependent increase in excitability.Our data show that stretch-dependent responses in colonic muscles require tonic firing of enteric inhibitory neurons, but reflex activation of neurons does not appear to be necessary. NO causes activation of SDK channels, and stretch of muscles further activates these channels, explaining the inhibitory response to stretch in colonic muscle strips.

SUBMITTER: Won KJ

PROVIDER: S-EPMC3552106 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature

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Stretch-dependent sensitization of post-junctional neural effectors in colonic muscles.

Won K-J KJ Sanders K M KM Ward S M SM

Neurogastroenterology and motility 20130102 2

<h4>Background</h4>The colon undergoes distension-induced changes in motor activity as luminal contents or feces increase wall pressure. Input from enteric motor neurons regulates this motility. Here we examined stretch-dependent responses in circular muscle strips of murine colon.<h4>Methods</h4>Length ramps (6-31μm s(-1) ) were applied in the axis of the circular muscle layer in a controlled manner until 5 mN isometric force was reached.<h4>Key results</h4>Length ramps produced transient membr ...[more]

PMID: 23279087

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Project description:Visceral pain is a leading cause of morbidity in gastrointestinal diseases, which is exacerbated by the gut-related side-effects of many analgesics. New treatments are needed and further understanding of the mediators and mechanisms underpinning visceral nociception in disease states is required to facilitate this. The pro-inflammatory cytokine TNFα is linked to pain in both patients with inflammatory bowel disease and irritable bowel syndrome, and has been shown to sensitize colonic sensory neurons. Somatic, TNFα-triggered thermal and mechanical hypersensitivity is mediated by TRPV1 signalling and p38 MAPK activity respectively, downstream of TNFR1 receptor activation. We therefore hypothesized that TNFR1-evoked p38 MAPK activity may also be responsible for TNFα sensitization of colonic afferent responses to the TRPV1 agonist capsaicin, and noxious distension of the bowel. Using Ca2+ imaging of dorsal root ganglion sensory neurons, we observed TNFα-mediated increases in intracellular [Ca2+ ] and sensitization of capsaicin responses. The sensitizing effects of TNFα were dependent on TNFR1 expression and attenuated by p38 MAPK inhibition. Consistent with these findings, ex vivo colonic afferent fibre recordings demonstrated an enhanced response to noxious ramp distention of the bowel and bath application of capsaicin following TNFα pre-treatment. Responses were reversed by p38 MAPK inhibition and absent in tissue from TNFR1 knockout mice. Our findings demonstrate a contribution of TNFR1, p38 MAPK and TRPV1 to TNFα-induced sensitization of colonic afferents, highlighting the potential utility of these drug targets for the treatment of visceral pain in gastrointestinal disease. KEY POINTS: The pro-inflammatory cytokine TNFα is elevated in gastrointestinal disease and sensitizes colonic afferents via modulation of TRPA1 and NaV 1.8 activity. We further develop this understanding by demonstrating a role for p38 MAPK and TRPV1 in TNFα-mediated colonic afferent sensitization. Specifically, we show that: TNFα sensitizes sensory neurons and colonic afferents to the TRPV1 agonist capsaicin. TNFα-mediated sensitization of sensory neurons and colonic nociceptors is dependent on TNFR1 expression. TNFα sensitization of sensory neurons and colonic afferents to capsaicin and noxious ramp distension is abolished by inhibition of p38 MAPK. Collectively these data support the utility of targeting TNFα, TNFR1 and their downstream signalling via p38 MAPK for the treatment of visceral pain in gastrointestinal disease.

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Dataset Information

Stretch-dependent sensitization of post-junctional neural effectors in colonic muscles.

Publications

Stretch-dependent sensitization of post-junctional neural effectors in colonic muscles.

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