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Visceral Pain: Spinal Afferents, Enteric Mast Cells, Enteric Nervous System and Stress

May 2011
Current Pharmaceutical Design 17(16):1573-5

DOI:10.2174/138161211796196918

Source
PubMed

Authors:

The Ohio State University

This review aims to examine current basic and clinical concepts, the results of which are expanding our understanding of visceral hypersensitivity and functional abdominal pain of intestinal origin in relation to the enteric nervous system (ENS), spinal sensory neurons and enteric mast cells. Advances in this sphere are translating to improved insight into chronic functional abdominal and pelvic pain syndromes in general.

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Current Pharmaceutical Design, 2011, 17, 1573-1575 1573

Visceral Pain: Spinal Afferents, Enteric Mast Cells, Enteric Nervous System and

Stress

Jackie D. Wood*

Department of Physiology & Cell Biology, The Ohio State University College of Medicine Columbus, Ohio, USA

Abstract: This review aims to examine current basic and clinical concepts, the results of which are expanding our understanding of vis-

ceral hypersensitivity and functional abdominal pain of intestinal origin in relation to the enteric nervous system (ENS), spinal sensory

neurons and enteric mast cells. Advances in this sphere are translating to improved insight into chronic functional abdominal and pelvic

pain syndromes in general.

Keywords: Stress, corticotropin releasing factor, irritable bowel syndrome, sensory afferents, abdominal pain.

INTRODUCTION

Functional abdominal/pelvic pain syndromes are those for

which no abnormal physical or metabolic processes can be found

that explain the symptoms. Functional pain syndromes include

urologic chronic pain, the irritable bowel syndrome (IBS), prostati-

tis, fibromyalgia and vulvodynia with overlapping morbidity occur-

ring for one or more of these. High comorbidity is reported, for

example, for IBS with the painful urinary bladder syndrome of

interstitial cystitis and with fibromyalgia [1,2] . These are debilitat-

ing syndromes, with unknown etiologies, which cause major mor-

bidity and economic impact. Patients with IBS have significantly

higher rates of urinary system problems including interstitial cysti-

tis [3]. Approximately one-third of patients attending urological

clinics for symptoms of pelvic pain are reported to have a diagnosis

of IBS [3]. Women are affected in a majority of the cases and the

symptoms can be sufficiently severe as to compromise ability to

function in daily life. Comorbidity of IBS with fibromyalgia is in-

teresting in terms of the underlying basic science because IBS is a

visceral pain syndrome with lowered threshold to bowel distension

while fibromyalgia is somatic with lowered thresholds for tactile

stimulation. Comorbidity is of interest for the present topic in that

only the subset of patients who have both IBS and fibromyalgia

experience both visceral and somatic hypersensitivity [4].

CROSS-SENSITIZATION

Presently, there is no clear explanation for how hypersensitivity

in one visceral organ might be transferred to another organ or for

that matter between a visceral organ and tactile allodynia in the

skin. Nevertheless, it is becoming clear in animal models that mast

cells, spinal afferents and neurogenic inflammation form a common

denominator in the sharing of hypersensitivity between abdominal

viscera. Uterine inflammation induced by either chemical irritation

or endometriosis in rat models induces inflammation and hypersen-

sitivity in the urinary bladder and colon and the inflammatory cros-

stalk is interrupted by resection of sensory afferents in the hypogas-

tric nerve [5]. Likewise, colonic irritation by either mucosal irritants

(e.g., TNBS colitis) or mechanical distension induces inflammation

associated with sensitization of spinal afferents and mast cell acti-

vation in the urinary bladder of rats [6,7].

Studies in which capsaicin is Instilled in the urinary blader to

stimulate the afferents, which transmit information out of the blad

der, evokes hypersensitivity to distention in the colon [8-10]. Instil-

lation of a local anesthetic (e.g., lidocaine), along with capsaicin,

*Address Correspondence to this author at the Department of Physiology

and Cell Biology, 304 Hamilton Hall, 1645 Neil Avenue, Columbus, Ohio

43210, U.S.A; Tel: 1-614-2925449; Fax: 1-614-2924888;

E-mail: wood.13@osu.edu

prevents the sensitizing cross talk to the colon. In similar manner

experimentally-induced inflammation in the bladder evokes tactile

cutaneous allodynia in mouse models. Investigators doing this kind

of research suggest that the evidence points to mast cell release of

histamine as the primary factor in the sensitization of the bladder

afferent innervation to distension [9,8].

It has long been known that antidromic stimulation and backfir-

ing of the sensory innervation inside the lungs or skeletal joints

evoke neurogenic inflammation and hypersensitivity in the airways

and arthritic pain in the joints [11,12]. The evidence suggests that

this might be the case also for the urinary bladder and the gut. Sub-

stance P release from the afferent innervation is implicated as the

stimulus for neurogenic inflammation in both the joints and airways

[13].

A logical explanation for the cross talk between the intestine

and neighboring pelvic organs (e.g., urinary bladder) is that infor-

mation transmitted by sensitized intestinal afferents project to the

same spinal interneurons that receive input from bladder afferents.

Earlier studies showed that the majority of spinal neurons that re-

spond to bladder stimulation also respond to colon stimulation and

vice versa, and that activity in the colonic nerves modulates the

neural control of micturition [14,15]. Based on the available litera-

ture (see next two topics), it can be logically assumed that sensitiza-

tion of intestinal afferents by mediators released from enteric mast

cells underlies both the well documented hypersensitivity to colonic

distension associated with inflammation or stress in rodent models

and the neurogenic cross talk now known to take place between the

colon and urinary bladder.

SPINAL AFFERENTS

Noxious stimulation in the intestinal tract is detected by specific

sensory neurons that have their cell bodies located in dorsal root

ganglia (DRG). Beyak et al. (2004; 2005) [16,17] reported evidence

from a mouse model for colitis that hyperalgesia develops as a re-

sult of enhanced excitability of subsets of neurons in the DRG [16].

This kind of sensory information from the bowel is transmitted by

mesenteric afferents to the DRG and on to second order interneu-

rons in the dorsal horn of the spinal cord. Anterograde tracing tech-

niques for following sensory afferents into the intestinal wall show

how the afferents branch within the ENS myenteric plexus and send

projections into the ganglia where some form synapses with neuron

cell somas and others form specialized endings that discharge ac-

tion potentials in response to mechanical stimulation [18,19]. Elec-

trical stimulation of mesenteric afferents, at the same time as re-

cording from neurons in the ENS, evokes excitatory responses in

the neurons [20]. These responses reflect release of substance P and

calcitonin gene related peptide from presynaptic sensory terminals

1574 Current Pharmaceutical Design, 2011, Vol. 17, No. 16 Jackie D. Wood

on ENS neurons within the ganglia that are seen in the anterograde

tracings of Tassicker et al. [18].

Receptors for bradykinin, ATP, adenosine, prostaglandins, leu-

kotrienes, histamine and mast cell proteases are expressed on sen-

sory nerve terminals in the intestine, which include the terminal

endings found inside myenteric ganglia [21]. Any of these mast cell

or ischemia-related mediators fire the afferent terminal when ap-

plied experimentally and have potential for elevating the sensitivity

of the terminal to its preferred stimulus modality, especially in the

disordered conditions associated with inflammation or ischemia.

This suspicion is reinforced by findings that a reduced threshold for

painful responses to balloon distension in the large bowel is associ-

ated with degranulation of mast cells in animal models. Treatment

with mast cell stabilizing drugs prevents lowering of the pain

threshold to distension, which occurs during mucosal inflammation

in the animal models [22]. Based on discoveries of this nature, it

has been suggested that mast cell stabilization might prove to be an

efficacious treatment in human IBS [23, 24].

ENTERIC MAST CELLS

Signaling between enteric mast cells and the neural elements of

the ENS in food allergies and parasitic infections is a significant

aspect of neurogastroenterology [25-27]. Enteric mast cells are

packed with granules that are sites of storage for a broad mix of

preformed chemical mediators. Antigens stimulate the mast cells to

release the mediators, which then diffuse in paracrine manner into

the extracellular space inside the ENS. Evidence that enteric mast

cells express receptors for corticotropin releasing factor (CRF) and

that CRF stimulates release of mediators from mast cells is accumu-

lating. This includes evidence that subepithelial mast cells in mu-

cosal biopsies from human colon express immunoreactivity for

CRF1 and CRF2 receptors [28,29] and early results in my laboratory

at Ohio State University shows coexpression of CRF1 and CRF2

receptors by mast cells in guinea pig colon and human jejunum

[29].

Release of mast cell proteases (e.g., mast cell protease II) into

the systemic circulation and intestinal lumen is a marker for de-

granulation of enteric mucosal mast cells. Release of proteases into

the circulation occurs as a conditioned response in laboratory ani-

mals to either light or auditory stimuli after pairing with antigenic

sensitization [30]. In humans release of mast cell proteases into the

lumen of the small intestine occurs as a response to stress [31],

which like the animal studies, reflects a brain to enteric mast cell

connection [31]. Stimulation of neurons in the brain stem by intrac-

erebroventricular injection of thyrotropin-releasing hormone evokes

degranulation of mast cells in the rat small intestine and adds to the

evidence in support of a CNS to mast cell connection [32]. Electri-

cal stimulation to backfire sensory afferents in the intestinal mesen-

tery evokes release of mast cell mediators (e.g., histamine and mast

cell proteases) inside the walls of the small and large intestine [29].

Restraint stress exacerbates nociceptive responses to distension that

are associated with increased release of histamine from mast cells

[33]. The brain-to-mast cell connection is significant because mast

cell hyperplasia is associated with the diarrhea-predominant form of

IBS [34](Barbara et al., 2004) and the gastrointestinal symptoms of

cramping lower abdominal pain, urgency and diarrhea, which are

associated with mast cell degranulation, are expected to be the same

whether the mast cells are degranulated by antigen-antibody cross-

linking as in food allergies or input from the brain during stress.

CORTICTROPIN RELEASING FACTOR AND STRESS

CRF is expressed predominantly in the hypothalamic paraven-

tricular nucleus in the brain where it is released during stress. The

majority of the endocrine, neurochemical, electrophysiological and

behavioral effects, which are reported to occur after experimental

injection of CRF into the brain, are essentially the same as those

associated with experimentally-induced stress in one form or the

other in animal models. Virtually all of the effects of intra-brain

applications of CRF can be reduced or abolished by administration

of CRF receptor antagonists and this reinforces belief in a predomi-

nant central role for CRF in stress [35]. Gastric and small intestinal

motility in animals are suppressed by CRF injection in the brain

[36-38]. Unlike the inhibitory effects in the upper GI tract, stress

evokes neurogenic secretory diarrhea, increases permeability of the

mucosal epithelial barrier, and accelerates colon transit in animal

models, human volunteers, and IBS patients [40,41]. Intracerebral

administration of non-selective or selective CRF1 receptor antago-

nists suppresses the effects of both stress and administration of CRF

[40,42, 43].

CONCLUSION

Release of CRF inside the “big brain” and inside the ENS in

concert with ENS/spinal afferent interactions with enteric mast cells

during stress are transformed into symptoms of cramping abdomi-

nal pain, fecal urgency and watery diarrhea, which are hallmarks of

diarrhea-predominant irritable bowel syndrome, infectious enteritis,

food allergy, and inflammatory bowel disease in humans. Interac-

tive signaling between the ENS, spinal sensory afferent nerves and

enteric mast cells is a key to understanding visceral pain. A positive

feed-back signaling loop connecting spinal afferents, ENS neurons

and enteric mast cells amplifies nociceptive and other forms of

sensory input from the gut to the central nervous system. This trans-

lates to basic understanding of visceral hypersensitivity, sensory

crosstalk among pelvic viscera and the emerging recognition that

functional abdominal pain can involve comorbidity of gut hyper-

sensitivity with other pain syndromes elsewhere in the body (e.g.,

interstitial cystitis, prostatitis, vulvodynia, vulvar vestibulitis and

fibromyalgia). This suggests that ENS, mast cells and spinal affer-

ents might be productive targets for pharmacotherapy in human

functional gastrointestinal symptoms associated with psychogenic

stress, postinfectious enteritis and anti-enteric autoimmune events.

ACKNOWLEDGMENT

The opinions expressed in this review are my own. Neverthe-

less, they are based on work and interactions in my laboratory with

a progression of outstanding students and visiting scientists whose

discoveries have helped shape current concepts of Neurogastroen-

terology. Work on enteric neurophysiology in my laboratory has

been supported continuously by the National Institutes of Health

NIDDK Institute since 1973.

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Received: April 8, 2011 Accepted: April 27, 2011

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Galanin is a neuropeptide expressed by sensory neurones innervating the gastrointestinal (GI) tract. Galanin displays inhibitory effects on vagal afferent signaling within the upper GI tract, and the goal of this study was to determine the actions of galanin on colonic spinal afferent function. Specifically, we sought to evaluate the effect of galanin on lumbar splanchnic nerve (LSN) mechanosensitivity to noxious distending pressures and the development of hypersensitivity in the presence of inflammatory stimuli and colitis. Using ex vivo electrophysiological recordings we show that galanin produces a dose‐dependent suppression of colonic LSN responses to mechanical stimuli and prevents the development of hypersensitivity to acutely administered inflammatory mediators. Using galanin receptor (GalR) agonists, we show that GalR1 activation, but not GalR2/3 activation, suppresses mechanosensitivity. The effect of galanin on colonic afferent activity was not observed in tissue from mice with dextran sodium sulfate‐induced colitis. We conclude that galanin has a marked suppressive effect on colonic mechanosensitivity at noxious distending pressures and prevents the acute development of mechanical hypersensitivity to inflammatory mediators, an effect not seen in the inflamed colon. These actions highlight a potential role for galanin in the regulation of mechanical nociception in the bowel and the therapeutic potential of targeting galaninergic signaling to treat visceral hypersensitivity. Galanin inhibits lumbar splanchnic nerve activity in response to mechanical distension via GalR1 and also abolishes the mechanical hypersensitivity induced by inflammatory mediators. However, galanin loses this inhibitory effect in a model of colitis.

Early life stress in mice is a suitable model for Irritable Bowel Syndrome but does not predispose to colitis nor increase susceptibility to enteric infections

Article

May 2018

Neonatal period is characterized by an immature intestinal barrier. Scattered evidence suggests that early life stressful events induce long lasting alterations of intestinal homeostasis mimicking Irritable Bowel Syndrome (IBS). Those observations highlighting defect of intestinal barrier by early life stress questioned its potential role as a risk factor for gastrointestinal disorders such as colitis and infections. In this study, we aimed to analyze if maternal separation (MS) in mice gathers IBS main features. We next addressed whether MS could trigger or exacerbate colitis in genetically predisposed mice and/or enhance susceptibility to gastrointestinal infections in wild type mice. MS induced main features of IBS in adult wild type male mice i.e. intestinal hyperpermeability, visceral hypersensitivity, microbiota dysbiosis, bile acid malabsorption and low grade inflammation in intestine associated with a defect of Paneth cells and the ILC3 population. This breach in mucosal barrier functions in adults was associated with a systemic IgG response against commensal E. coli and increased IFNγ secretion by splenocytes. However, in IL10-/- mice, MS did not trigger nor worsen colitis. Furthermore, wild type mice submitted to MS did not show increase susceptibility to gastrointestinal infections (S. Typhimurium, L. monocytogenes or T. gondii) compared to controls. Altogether, our results identify MS in mice as a good experimental model for IBS mimicking all the main features. In addition, early life stress, even though it has long lasting consequences on intestinal homeostasis, does not constitute a facilitating factor to colitis in predisposed individuals nor to gastrointestinal infections in wild type mice.

Neural Secretions and Regulation of Gut Functions

Chapter

Jun 2018

Menizibeya Osain Welcome

Neural secretions of the gut are substances released from the neurons or nerve terminals of the gastrointestinal (GI) tract to regulate the functioning of the GI system as well as extragut tissues and organs. The neural secretions may be mediated and released centrally or peripherally to act on the GI tract and extragut tissues/organs. The central neural secretions that act on the gut are mediated by the brain and spinal cord, whereas peripherally mediated neural secretions are regulated and released from the intrinsic nervous system of the gut (enteric nervous system) and extrinsic nervous system. Progressive advancement of knowledge on neural secretions of the gut was dictated mainly by technological progress. This area of study (regarding neural secretions and regulation of gut) has increasingly been recognized as a new field of science called neurogastroenterology. The science of neural secretions and regulation of GI functioning began around the eighteenth to nineteenth centuries. The founding fathers of this new science were William Maddock Bayliss (1860–1924), Ernest Henry Starling (1866–1927), Georg Meissner (1829–1905), Leopold Auerbach (1828–1897), Santiago Ramón y Cajal (1852–1934), Alexander Stanislavovich Dogiel (1852–1922), John Newport Langley (1852–1925), Paul Trendelenburg (1884–1931), and Harold Hirschsprung (1830–1916) among others. The second half of the twentieth century was marked by substantial advancement in neurogastroenterology, and generally in science. Development of the broader field “gastroenteroneuro endocrinology,” which comprises neurogastroenterology and gut endocrinology, was enhanced by progress in genetics and molecular biology pioneered by James Watson (1928–), Francis Crick (1916–2004), and Maurice Hugh Frederick Wilkins (1916–2004); peptide biochemistry, and the invention of the radioimmunoassay, which enabled the measurement of minute quantities of neuropeptides. The gut produces over 50 types of neural secretions (neurotransmitters, neuromodulators), and tens of different types of neurons have been identified in the gut alone. This makes the gut one of the most important organs that can mediate neural signals at the peripheral level and in extragut tissues and organs such as the brain and adipose tissues. With extensively growing data on neurotransmitters of the gut and their functions, it is necessary to provide state-of-the-art information on neural secretions of the gut and their mechanisms of regulation. This chapter provides contemporary information on fundamental aspects of the neural secretions of the gut, gives an account of the course of discovery of these secretions (neurotransmitters) of the gut, and provides the mechanisms of neural regulation of GI functions. The clinical importance of the neurotransmitters is systematically described.

A Pharmacological Rationale to Reduce t...d Tolerance and Hyperalgesia- A Review

Article

Full-text available

Mar 2018

Chronic pain is an important health and social problem. Misuse and abuse of opioids in chronic non-cancer pain management seem to be a huge problem, in some countries. This could probably affect the normal use of such analgesics in patients in need of them. Basic and clinical researches should find the solution to mitigate the potential damage. Dysregulation of mast cell and microglia activation plays an important role in the pathogenesis and management of chronic pain. Persistent mast cell activation sensitizes nociceptors and initiates central nervous system inflammatory processes, involving microglial cell activation and sensitization of spinal somatosensory neurons. Exposure of mast cells and microglia to opioids is well known to provoke activation of these nonneuronal immune cell populations, thereby contributing to an exacerbation of pro-inflammatory and pro-nociceptive processes and promoting, over the long-term, opioid-induced hyperalgesia and tolerance. This review is intended to provide the reader with an overview of the role for these non-neuronal cells in opioid- induced chronic pain and tolerance as a consequence of prolonged exposure to these drugs. In addition, we will examine a potential strategy with the aim to modulate opioid-induced over-activation of glia and mast cells, based on endogenous defense mechanisms and fatty acid amide signaling molecules.

Conditioned emotional response in rats enhances colonic motility through the central release of corticotropin-releasing factor

Article

Apr 1991
GASTROENTEROLOGY

The effect of a mental stress model corresponding to conditioned fear on cecocolonic motility was evaluated electromyographically in intact and hypophy-sectomized rats equipped with electrodes implanted in the cecum and proximal colon over a long period and a small polyethylene catheter inserted into the right lateral ventricle of the brain. Intact fasted and fed rats showed an increase of 82.3% and 67.2%, respectively, in colonic spike-burst frequency when placed for 30 minutes in a box in which they had previously received electrical shocks in their feet. Intracerebroventricular administration of corticotropin-releasing factor (0.5 μg/kg) mimicked the effects of mental stress and increased cecocolonic spikeburst frequency by 75.8%. The specific corticotropin-releasing factor receptor antagonist α-helical CRF9–41 given intracerebroventricularly (5 μ/kg) prevented both the effects of mental stress and corticotropin-releasing factor (0.5 μg/kg intracerebroventricularly) on colonic spike-burst frequency. In contrast, diazepam (0.5 mg/kg IM) suppressed colonic hypermotility induced by mental stress but not that resulting from intracerebroventricular injection of corticotropin-releasing factor (0.5 (μg/kg). Increased colonic spike-burst frequency induced either by stress or by central administration of corticotropin-releasing factor was not prevented by hypophysectomy. It was concluded that mental stress increases the frequency of cecocolonic spike-burst activity and that these effects are related to the central release of corticotropin-releasing factor because they are blocked by a corticotropin-releasing factor antagonist and reproduced by intracerebroventricular administration of corticotropin-releasing factor. Moreover, mental stress-induced colonic motor alterations are mediated by the autonomic nervous system rather than by the hypothalamopituitary axis because they are not abolished by hypophysectomy.

Extrinsic Sensory Afferent Nerves Innervating the Gastrointestinal Tract

Chapter

Dec 2006

Effect of a corticotropin releasing hormone receptor antagonist on colonic sensory and motor function in patients with irritable bowel syndrome

Article

Jul 2004

Yasuhiro Sagami

Background and aims Corticotropin releasing hormone (CRH) is a major mediator of the stress response in the brain-gut axis. Irritable bowel syndrome (IBS) is presumed to be a disorder of the brain-gut link associated with an exaggerated response to stress. We hypothesised that peripheral administration of α-helical CRH (αhCRH), a non-selective CRH receptor antagonist, would improve gastrointestinal motility, visceral perception, and negative mood in response to gut stimulation in IBS patients. Methods Ten normal healthy subjects and 10 IBS patients, diagnosed according to the Rome II criteria, were studied. The tone of the descending colon and intraluminal pressure of the sigmoid colon were measured at baseline, during rectal electrical stimulation (ES), and at recovery after administration of saline. Visceral perception after colonic distension or rectal ES was evaluated as threshold values on an ordinate scale. The same measurements were repeated after administration of αhCRH (10 μg/kg). Results ES induced significantly higher motility indices of the colon in IBS patients compared with controls. This response was significantly suppressed in IBS patients but not in controls after administration of αhCRH. Administration of αhCRH induced a significant increase in the barostat bag volume of controls but not in that of IBS patients. αhCRH significantly reduced the ordinate scale of abdominal pain and anxiety evoked by ES in IBS patients. Plasma adrenocorticotropic hormone and serum cortisol levels were generally not suppressed by αhCRH. Conclusion Peripheral administration of αhCRH improves gastrointestinal motility, visceral perception, and negative mood in response to gut stimulation, without affecting the hypothalamo-pituitary-adrenal axis in IBS patients.

T2047 Mast Cell Activation by Corticotropin Releasing Factor (CRF) in Guinea Pig and Human Intestine

Article

May 2010

Release of mast cell mediators into the jejunum by cold pain stress in humans

Article

Apr 1998
GASTROENTEROLOGY

The central nervous system regulates gut functions via complex interactions between the enteric nervous and immune systems. The aim of this study was to investigate whether mast cell mediators are released into the human jejunal lumen during stress. A closed-segment perfusion technique was used to investigate jejunal release of tryptase, histamine, prostaglandin D2, and water flux in response to the cold pressor test in 8 healthy subjects and 9 patients with food allergy. In 6 food-allergic patients, jejunal biochemical responses to cold pain stress were compared with those induced by food intraluminal challenge. Cold pain stress elevated heart rate and blood pressure and increased luminal release of mast cell mediators and jejunal water secretion in both groups. Stress-induced release of tryptase and histamine, but not of prostaglandin D2 and water flux, was greater in food-allergic patients than in healthy volunteers. In food-allergic patients, jejunal biochemical responses induced by cold pain stress were similar to those induced by antigen challenge. These results show the ability of the central nervous system to modulate intestinal mast cell activity and suggest that mast cells have a role in stress-related gut dysfunction.

Cross-Talk and Sensitization of Bladder Afferent Nerves

Article

Jan 2010
NEUROUROL URODYNAM

The coordination of pelvic physiologic function requires complex integrative sensory pathways that may converge both peripherally and/or centrally. Following a focal, acute irritative or infectious pelvic insult, these same afferent pathways may produce generalized pelvic sensitization or cross-sensitization as we show bi-directionally for the bladder and bowel in an animal model. Single unit bladder afferent recordings following intracolonic irritation reveal direct sensitization to both chemical and mechanical stimuli that's dependent upon both intact bladder sensory (C-fiber) innervation and neuropeptide content. Concurrent mastocytosis (preponderantly neurogenic) likely plays a role in long-term pelvic organ sensitization via the release of nociceptive and afferent-modulating molecules. Prolonged pelvic sensitization as mediated by these convergent and antidromic reflexive pathway may likewise lead to chronic pelvic pain and thus the overlap of chronic pelvic pain disorders.

Inhibition of the micturition reflex by stimulation of pelvic nerve afferents from the colon

Article

Dec 1978

Mental stress in rats enhances colonic motility through the central release of corticotropin-releasing factor

Article

May 1991
GASTROENTEROLOGY

The effect of a mental stress model corresponding to conditioned fear on cecocolonic motility was evaluated electromyographically in intact and hypophysectomized rats equipped with electrodes implanted in the cecum and proximal colon over a long period and a small polyethylene catheter inserted into the right lateral ventricle of the brain. Intact fasted and fed rats showed an increase of 82.3% and 67.2%, respectively, in colonic spike-burst frequency when placed for 30 minutes in a box in which they had previously received electrical shocks in their feet. Intracerebroventricular administration of corticotropin-releasing factor (0.5 micrograms/kg) mimicked the effects of mental stress and increased cecocolonic spike-burst frequency by 75.8%. The specific corticotropin-releasing factor receptor antagonist alpha-helical CRF9-41 given intracerebroventricularly (5 micrograms/kg) prevented both the effects of mental stress and corticotropin-releasing factor (0.5 micrograms/kg intracerebroventricularly) on colonic spike-burst frequency. In contrast, diazepam (0.5 mg/kg IM) suppressed colonic hypermotility induced by mental stress but not that resulting from intracerebroventricular injection of corticotropin-releasing factor (0.5 micrograms/kg). Increased colonic spike-burst frequency induced either by stress or by central administration of corticotropin-releasing factor was not prevented by hypophysectomy. It was concluded that mental stress increases the frequency of cecocolonic spike-burst activity and that these effects are related to the central release of corticotropin-releasing factor because they are blocked by a corticotropin-releasing factor antagonist and reproduced by intracerebroventricular administration of corticotropin-releasing factor. Moreover, mental stress-induced colonic motor alterations are mediated by the autonomic nervous system rather than by the hypothalamopituitary axis because they are not abolished by hypophysectomy.

Long-duration stress - Immediate and late effects on small and large bowel motility in rat

Article

May 1990

No extensive information exists in literature concerning the late or residual effects of stress on motility of small bowel and colon. Moreover, the duration and magnitude of the intestinal motor response to stress are still ignored. Therefore, the aim of our work was to determine, in rat, the effect of long-duration stress induced by restraint on the motility of small bowel and colon. Observations were made during physical restraint and 60 h later. Bipolar electrodes were implanted on the gastrointestinal serosa from the pylorus to the sigmoid colon in male Wistar rats. Electromyographic (EMG) recordings were made during fasting state, and a control EMG recording session was performed during 12 hr, followed by a 12-hr recording during restraint stress. After a 60-hr resting period, another EMG recording session was performed during 3 hr. During stress in the pylorus and small bowel, the recurrence of migrating myoelectrical complexes (MMCs) was immediately interrupted and replaced by a continuous and irregular activity. The motility index (number of spike bursts/10 min) was augmented rapidly on the jejunum and ileum, but it increased only gradually on the pylorus. Only on the transverse colon were the number of spike bursts/hour and their relative duration increased after 7 hr of physical restraint. In contrast, the sigmoid colon displayed a gradual decrease in the relative duration of contractile activity during the first 6-7 hr of stress. At 60 hr after stress in the pylorus and small bowel, a normal control motor activity was restored (MMC, motility index) on the jejunum and on the ileum, but the motility index on the pylorus was decreased.(ABSTRACT TRUNCATED AT 250 WORDS)

Stress-Induced Gastrointestinal Secretory and Motor Responses in Rats Are Mediated by Endogenous Corticotropin-Releasing Factor

Article

Jan 1989
GASTROENTEROLOGY

Corticotropin-releasing factor (CRF) has been implicated as a central nervous system mediator of stress. This study examined the effects of CRF and stress on gastric secretory and gastrointestinal motor functions in rats. Partial body restraint as a stress-producing stimulus significantly decreased gastric acid secretion, gastric emptying, and small bowel transit but markedly increased large bowel transit. Corticotropin-releasing factor given cerebroventricularly mimicked the gastrointestinal secretory and motor responses induced by partial body restraint. Cerebroventricular administration of a specific CRF receptor antagonist, alpha-helical CRF-(9-41), but not of the CRF fragment CRF-(1-20), prevented the gastrointestinal secretory and motor responses elicited either by partial body restraint or by exogenous administration of CRF in a dose-dependent fashion. These results suggest that the gastrointestinal secretory and motor responses in rats produced by stress (partial body restraint) are mediated by the endogenous release of CRF. They also indicate that CRF exerts its central nervous system actions on the gastrointestinal tract by a receptor-mediated event.

Visceral Pain: Spinal Afferents, Enteric Mast Cells, Enteric Nervous System and Stress

Abstract

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