Gastroenterology

Gastroenterology

Volume 138, Issue 1, January 2010, Pages 294-304.e3
Gastroenterology

Basicā€”Alimentary Tract
Adrenergic Stimulation Mediates Visceral Hypersensitivity to Colorectal Distension Following Heterotypic Chronic Stress

https://doi.org/10.1053/j.gastro.2009.09.054Get rights and content

Background & Aims

Chronic stress exacerbates or causes relapse of symptoms such as abdominal pain and cramping in patients with irritable bowel syndrome. We investigated whether chronic stress increases plasma norepinephrine and sensitizes colon-specific dorsal root ganglion (DRG) neurons by increasing expression of nerve growth factor (NGF) in the colon wall.

Methods

Heterotypic chronic stress (HeCS) was applied to male Wistar rats and neurologic and molecular responses were analyzed. Tissues were analyzed for NGF expression.

Results

HeCS significantly increased visceromoter response to colorectal distension; expression of NGF increased in colonic muscularis externa and mucosa/submucosa. Rheobase decreased, resting membrane potential was depolarized, and electrogenesis of action potentials increased in colon-specific thoracolumbar DRG neurons. Luminal administration of resiniferatoxin in distal colon, systemic administration of anti-NGF antibody, or inhibition of the NGF receptor trkA by k252a or antisense oligonucleotides in thoracolumbar DRG blocked the chronic stress-induced visceral hypersensitivity to colorectal distension. Blockade of Ī±1/Ī±2- and Ī²1/Ī²2-adrenergic receptors prevented the stress-induced visceral hypersensitivity and increased expression of NGF in the colon wall. HeCS did not induce any inflammatory response in the colon wall.

Conclusions

The peripheral stress mediator norepinephrine induces visceral hypersensitivity to colorectal distension in response to HeCS by increasing the expression of NGF in the colon wall, which sensitizes primary afferents in the absence of an inflammatory response.

Section snippets

Animals

We used 6- to 10-week-old male Wistar rats housed at 22Ā°C with a 12-hour light/dark cycle. The Institutional Animal Care and Use Committee at University of Texas Medical Branch approved all procedures performed on animals.

Heterotypic Chronic Stress Protocol

Rats were subjected to 9 consecutive days of a heterotypic stress protocol comprised of 3 randomly arranged stressors, 60 minutes of water avoidance stress, 45 minutes of cold restraint stress at 4Ā°C, or 20 minutes of forced swimming stress, as described previously.5 Control

Chronic Stress-Induced Visceral Hypersensitivity Is Associated With Increase in Excitability of Colon-Specific Thoracolumbar DRG Neurons

We found that 9-day HeCS significantly increases the visceromoter response to graded CRD at pressures of 40, 50, 60, and 80 mmHg, compared to prestressed baseline response (Figure 1A) (n = 14 rats). The increase in visceromoter response persists for at least 8 hours after the last stressor, but it returns to basal levels 24-hours post-HeCS. By contrast, 9-day sham stress in age-matched control rats had no significant effect on the visceromoter response to CRD (Figure 1B) at 8 and 24 hours (n =

Discussion

Our findings show that HeCS induces visceral hypersensitivity to CRD that lasts for at least 8 hours, but it returns to baseline by 24 hours. Choudhury et al5 found that HeCS induces colonic circular smooth muscle hyperreactivity to acetylcholine, which also lasts for about 8 hours and returns to baseline by 24 hours. We found that adrenergic stimulation mediates induction of visceral hypersensitivity by HeCS. The blockade of Ī±1/Ī±2- and Ī²1/Ī²2-adrenergic receptors before the daily application of

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    Conflicts of interest The authors disclose no conflicts.

    Funding Supported by National Institute of Diabetes and Digestive and Kidney Diseases grants DK 032346 and DK 072414 (SKS).

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