The gastrointestinal (GI) organs of the human body are responsible for transporting and extracting nutrients from food and drink, as well as excreting solid waste. Biomechanical experimentation of the GI organs provides insight into the mechanisms involved in their normal physiological functions, as well as understanding of how diseases can cause disruption to these. Additionally, experimental findings form the basis of all finite element (FE) modelling of these organs, which have a wide array of applications within medicine and engineering. This systematic review summarises the experimental studies that are currently in the literature (n = 247) and outlines the areas in which experimentation is lacking, highlighting what is still required in order to more fully understand the mechanical behaviour of the GI organs. These include (i) more human data, allowing for more accurate modelling for applications within medicine, (ii) an increase in time-dependent studies, and (iii) more sophisticated in vivo testing methods which allow for both the layer- and direction-dependent characterisation of the GI organs. The findings of this review can also be used to identify experimental data for the readers' own constitutive or FE modelling as the experimental studies have been grouped in terms of organ (oesophagus, stomach, small intestine, large intestine or rectum), test condition (ex vivo or in vivo), number of directions studied (isotropic or anisotropic), species family (human, porcine, feline etc.), tissue condition (intact wall or layer-dependent) and the type of test performed (biaxial tension, inflation-extension, distension (pressure-diameter), etc.). Furthermore, the studies that investigated the time-dependent (viscoelastic) behaviour of the tissues have been presented.

Intestinal stenosis is a common complication of Crohn's Disease (CD). Stenosis is associated with alteration of bowel mechanical properties. This study aims to quantitate the mechanical properties of the intestinal stenosis and to explore associations between histology and mechanical remodeling at stenotic intestinal sites in CD patients.

Intestinal segments from stenotic sites were studied in vitro from 19 CD patients. A luminal catheter with a bag was used to stepwise pressurize the intestinal segments from 0-100 cmH₂O with 10 cmH₂O increments. B-mode ultrasound images were obtained at the narrowest part of the stenosis at each pressure level and morphometric parameters were obtained from ultrasound images. The mechanical behavior of the stenotic tissue were characterized by using an isotropic three dimensional strain energy function in Demiray model form, the mechanical constants were obtained by fitting the model to the recorded intraluminal pressure and the inner radius of the stenotic segment of the small bowel. Grading scores were used for histological analysis of inflammation, fibrosis, muscular hypertrophy and adipocyte proliferation in the intestinal layers. The collagen area fraction in intestinal layers was also calculated. Associations between histological and the mechanical constants (stiffness) were analyzed.

Chronic inflammation was mainly located in mucosa whereas fibrosis was found in submucosa. The mechanical remodeling was performed with changed mechanical constants ranged between 0.35-13.68kPa. The mechanical properties changes were associated mainly with chronic inflammation, fibrosis and combination of inflammation and fibrosis (R>0.69, P<0.001). Furthermore, the mechanical properties correlated with the collagen fraction in submucosa and muscular layers (R>0.53, P<0.05).

We quantitated the intestinal stenosis stiffness. Associations were found between bowel mechanical remodeling and histological changes at the stenotic site in CD patients.

Although intestinal ultrasonography, CT and MRI can be used to diagnose Crohn's Disease (CD)-associated bowel strictures, these techniques may not have sufficient accuracy and resolution to differentiate predominantly inflammatory strictures from predominantly fibrotic strictures. The present study aims to quantitate the mechanical remodeling of intestinal stenosis and to explore the associations between histological parameters and mechanical properties at the intestinal stenotic sites in CD patients. For the first time, we quantitatively demonstrated that the mechanical properties of the intestinal wall in CD stenosis are associated with the chronic inflammation, fibrosis and collagen fraction in the intestinal layers. The results of this study may facilitate design and development of artificial biomaterials for gastrointestinal organs. The potential clinical implication of this study is that the histological characteristics in patients with CD can be predicted clinically by means of inflammation and fibrosis assessment in conjunction with tissue stiffness measurement.

Defecation is a complex process that is difficult to study and analyze.

Here, we present new analytical tools to calculate frictional force and tension during expulsion of the Fecobionics simulated stool in human subjects.

The 12-cm-long Fecobionics device contained pressure sensors, motion processor units for measurement of orientation and bending, and impedance rings for measurement of cross-sectional areas. Eight normal subjects defecated Fecobionics. The bending angle of the device, frictional force between the device and the surrounding tissue, and the stretch tensions were calculated.

The bending angle and pressures changed during expulsion with the maximum pressure recorded at the rear. The averaged circumferential tension, longitudinal tension and friction force in each subject were associated with the front-rear pressure difference (r > 0.7, p < 0.005). The peak circumferential tension, longitudinal tension, and friction force immediately before expulsion of the rear were significantly higher compared to when the front entered the anal canal (F = 164.7, p < 0.005; F = 152.1, p < 0.005; F = 71.4, p < 0.005; respectively.).

This study shows that Fecobionics obtained reliable data under physiological conditions. Mechanical features such as frictional force and stretch tensions were assessable during Fecobionics expulsion.

Many lower gastrointestinal diseases are associated with altered mechanical movement and deformation of the large intestine, i.e., the colon and rectum. The leading reason for patients' visits to gastrointestinal clinics is visceral pain, which is reliably evoked by mechanical distension rather than non-mechanical stimuli such as inflammation or heating. The macroscopic biomechanics of the large intestine were characterized by mechanical tests and the microscopic by imaging the load-bearing constituents, i.e., intestinal collagen and muscle fibers. Regions with high mechanical stresses in the large intestine (submucosa and muscularis propria) coincide with locations of submucosal and myenteric neural plexuses, indicating a functional interaction between intestinal structural biomechanics and enteric neurons. In this review, we systematically summarized experimental evidence on the macro- and micro-scale biomechanics of the colon and rectum in both health and disease. We reviewed the heterogeneous mechanical properties of the colon and rectum and surveyed the imaging methods applied to characterize collagen fibers in the intestinal wall. We also discussed the presence of extrinsic and intrinsic neural tissues within different layers of the colon and rectum. This review provides a foundation for further advancements in intestinal biomechanics by synergistically studying the interplay between tissue biomechanics and enteric neurons.

Testing of biomechanical properties of intestine requires the tissue to be preconditioned by applying cyclic loading to obtain repeatable mechanical data. However, little is known about the mechanosensory properties during intestinal preconditioning. We aimed to study the relationship between mechanical preconditioning of the human rectum and sensory response. Three fast rectal bag distensions to the pain threshold were done in seven healthy females. A visual analog scale (VAS) was used for sensory assessment. At each distension, we determined (1) time, bag cross-sectional area (CSA), radius (r), r/r₀, pressure and tension to reach VAS = 1, 3 and 5 (pain threshold); (2) the same parameters at induced contraction start; (3) CSA where the pressure started to increase (CSA_P>baseline) and (4) the number of contractions. The time, CSA, r/r₀ and tension to reach VAS = 1 and VAS = 3 increased from distension 1 to 3 (4.9 < F < 11.5, 0.05 > P > 0.007), primarily due to difference between the first and second distension. For VAS = 5, r/r₀ was smaller in distension 3 than distension 1 (P < 0.05), whereas time, CSA and tension did not differ between distensions (P > 0.5). Compared with distension 1, CSA, r/r₀ and tension at contraction start, and CSA_P>baseline were bigger in distensions 2 and 3 (5.5 < F < 10.9, 0.05 > P > 0.009). The pressure to reach the VAS levels, the contraction numbers and pressure at contraction start did not differ among distensions (P > 0.6). During mechanical preconditioning, CSA, tension and deformation increased at sub-pain levels, reflecting sensory adaptation. The data point to acute remodeling of a strain-dependent mechanism in the rectal wall.

Sacral nerve stimulation (SNS) has been demonstrated to alleviate symptoms and improve quality of life in selected patients with irritable bowel syndrome (IBS). The mechanisms of action, however, remain unknown. The aim of the study was to evaluate the effects of SNS on rectal sensitivity and biomechanical properties in patients with IBS.

Twenty patients with diarrhea-predominant (n = 11) or mixed (n = 9) IBS were treated with SNS in a controlled, randomized crossover trial. They were randomized to either 1 month of SNS (ON) or placebo (OFF) with the opposite setting for the next month. Sensory and biomechanical parameters were assessed by multimodal rectal stimulation at the end of each period. IBS-specific symptoms were evaluated at baseline and at the end of each treatment period.

Cold stimuli were better tolerated in the ON period (19.9 °C[± 0.6]) compared to the OFF period (21.8 °C[± 0.6]; p = 0.03). Significantly lower cross-sectional areas were needed to elicit sensory responses in the ON period (1545 mm(2) [± 95]) compared to the OFF period (1869 mm(2) [± 92]; p = 0.015). The association between reduced sensory threshold and improvement of constipation was of borderline significance (p = 0.05). Wall stiffness was significantly lower in the ON period (192 mmHg[± 10]) compared to the OFF period (234 mmHg[± 10]; p = 0.004). Reduced wall stiffness was significantly associated with improved overall GSRS-IBS symptom score (p = 0.01). Reduced sensory threshold to stretch (p = 0.02) and reduced wall stiffness (p < 0.001) were predictors of the GSRS-IBS symptom score.

SNS for diarrhea-predominant and mixed IBS relaxes the rectal wall, while making it more sensitive to stretch and less sensitive to cold. Reduced wall stiffness and increased sensitivity to stretch are associated with improved GSRS-IBS symptom score.

PPC-5650 is a new pharmacological agent that can modulate acid-sensing ion channel activity, leading to a reduction in the pain signal under up-regulated conditions. The non-clinical programme for PPC-5650 supported a role for this novel agent in the treatment of pain in patients with irritable bowel syndrome (IBS). In patients with IBS, the aims of the study were: (1) to assess the efficacy of a single bolus of PPC-5650 locally applied in the rectum using multi-modal stimulations of the recto sigmoid and (2) to assess the safety profile of PPC-5650. The study was a randomized, double-blind, placebo-controlled, cross-over trial in patients with IBS, excluding females of child-bearing potential. The study consisted of a training visit, study visit 1 and 2 and a follow-up visit. Rectosigmoid electrical, thermal and mechanical stimulations were performed, pain perception was rated on a pain intensity scale and referred pain areas were assessed. All adverse events were registered. Twenty-five patients with IBS were enrolled and completed the study (9 women and 16 men; mean age 50.4 ± 12.7 years). No effects of the study drug were found on any of the rectal stimulations or for referred pain areas (all p > 0.05). No significant or clinically relevant treatment-related differences were seen for the laboratory safety variables or any other reported adverse event. In conclusion, in patients with IBS on rectal sensitivity to multi-modal stimulations, PPC-5650 did not produce efficacy relative to placebo. The overall safety and tolerability of PPC-5650 was acceptable.

Measurements of anorectal function using high-resolution anorectal manometry (HR-ARM) and rectal barostat technology provide more reliable results than standard ARM with an elastic balloon; however, HR-ARM results have not been compared to ARM and standard barostat protocols are impractical in routine clinical practice. The aim of this study was to validate HR-ARM against standard ARM and standard barostat against a novel Rapid Barostat Bag (RBB) measurement and elastic balloon measurements of rectal function.

Twenty-six healthy volunteers (15 female, 11 male, 19-52 years) were studied. Measurements of anal function and simulated defecation were compared for 12-sensor HR-ARM and 6-sensor standard ARM using line plots from the same recording. Rectal capacity, compliance, and sensation (volume threshold) were measured by elastic balloon, standard barostat, and RBB methods using stepwise inflation of a 700-mL polyethylene bag to 40 mmHg distension by electronic barostat and handheld syringe monitored by sphygmo-manometer, respectively. Results are reported as mean ± SD. Bland-Altman plots and correlation coefficients (r) for measurements were calculated.

There was excellent agreement between HR- and standard ARM measurements (r > 0.86, <25 mmHg difference) and between standard barostat and RBB measurements of rectal capacity (r = 0.97, <25 mL difference). Correlation coefficients of threshold volumes for initial perception, urgency and discomfort were 0.37, 0.71, and 0.95, respectively. No significant correlation was present with elastic balloon measurements. Time to complete studies was shorter for HR-ARM than standard ARM and for RBB than standard barostat in historical controls.

HR-ARM with RBB measurements of anorectal function provides quick and reasonably accurate measurements of continence function suitable for use in routine clinical practice (ClinicalTrial.gov NCT01456442).

Faecal continence depends on several factors, including rectal wall properties. Stimulation of the dorsal genital nerve (DGN) can suppress bladder contraction and similar effects are anticipated for the rectum. In this study, the acute effect of DGN stimulation on the rectal cross-sectional area is investigated.

Ten female patients (median age 60 years) with idiopathic faecal incontinence were included in the study. Stimulation was applied via plaster electrodes with the maximum tolerable amplitude (pulse width was 200 μs at a pulse rate of 20 Hz). Three series of pressure-controlled phasic (10, 20 and 30 cm H(2) O) and stepwise (5-30 cm H(2) O in steps of 5 cm H(2) O) rectal distensions were conducted (unstimulated, stimulated, unstimulated), and the rectal cross-sectional area (CSA) was measured with impedance planimetry.

All patients completed the investigation. The median stimulation amplitude was 21 (8.5-27) mA. Comparing stimulated with unstimulated phasic distension, there was no significant difference in the median rectal CSA. Comparing stimulated with unstimulated stepwise distension, there was no significant difference in the median rectal CSA. Neither the rectal pressure-CSA relationship (CSA/P(R) ) nor the rectal wall tension changed during stimulation.

No acute effect on rectal CSA during pressure-controlled distension was demonstrated during DGN stimulation.

It has been reported that different brain activation areas are demonstrated during somatosensory and visceral stimulation. However, no study thus far has investigated how activated patterns in the human brain differ during visceral stimulation of different sites of the digestive tracts. The aim of this study was to determine possible site-specific differences in brain responses and perceptions during visceral stimulation of two different sites, the intraluminal distentions of the rectum and descending colon.

Regional cerebral blood flow was assessed in 32 healthy right-handed male subjects using H(2)(15)O positron emission tomography during distention of the rectum (R group, n = 16) or descending colon (DC group, n = 16) at 40 or 20 mmHg.

R group reported significantly higher scores of abdominal pain (P < 0.05) and urge to defecate (P < 0.001) during the application of stimulus at 40 mmHg compared with DC group but not of abdominal bloating or anxiety. In comparisons of response to the 40-mmHg stimulus, R group showed significantly greater activation in posterior midcingulate cortex (MCC) and right anterior and posterior insula, whereas DC group showed greater activation in subgenual anterior cingulate cortex (ACC), perigenual ACC and left orbitofrontal and superior temporal cortices.

These findings suggest that central projections of painful visceral stimulation from the rectum and descending colon differ in affective, cognitive and nociceptive processing in the brain, which may result in different perceptions of visceral stimulation from different sites.

It has been claimed that recognizable organized sensory nerve endings could not be detected in the rectal wall. Hence the identification of cold receptors sensitive to cold temperature in the rectal wall has so far not been reported in the literature. We investigated the hypothesis that rectal cooling effected an increase of the rectal tone.

Twenty-eight healthy volunteers (18 men, 10 women, age 26-50 years) were studied. The rectal wall tone was assessed by the barostat system during infusion of normal saline at 30 degrees C and at 4 degrees C. The test was repeated after rectal anesthetization with lidocaine.

The rectal tone on rectal saline infusion showed no response at a temperature of 30 degrees C, and asignificant increase (p < 0.05) at 4 degrees C. The latency measured by the switch-inflation apparatus recorded a mean of 15.3 +/- 1.2 ms. Iced saline infusion into the anesthetized rectum effected no significant change in the rectal tone.

The current study has demonstrated that rectal infusion of iced saline produced an increase of the rectal tone. This effect is suggested to be a reflex and mediated through the 'rectal cooling reflex'. The reflex is suggested to act as an investigative tool in the diagnosis of rectal motile disorders provided further studies are performed.

To investigate possible differences between patients with non-erosive gastroesophageal reflux disease (NERD) and controls in a) sensitivity of the distal esophagus after mechanical and thermal stimuli and b) the referred pain areas.

Fifteen healthy subjects (mean age 39+/-19.4 years) and 13 NERD patients (mean age 44.4+/-21 years) were enrolled in the study. Pain evoked by mechanical and thermal stimuli was assessed using a newly designed multimodal stimulation probe.

The patients were less sensitive to mechanical stimulation as assessed by the cross-sectional area (p<0.001) and volume (p=0.007). After thermal stimulation, the patients were hypersensitive to heat stimuli (p=0.04), whereas no significant difference was seen to cold stimuli. The referred pain areas were larger in patients compared with the pain areas in controls after mechanical (p=0.03) and heat stimuli (p=0.01), but not after cold stimuli. Balloon distension resulted in a significant higher number of reactive esophageal contractions in patients as compared with controls (p=0.001).

The present study showed that NERD patients were hypersensitive to heat stimuli of the esophagus, with an increase in referred pain to the evoked visceral pain. The data indicate that peripheral sensitization of heat-sensitive pathways together with facilitation of central pain mechanisms are important in the pathogenesis of NERD.

The aim of this study was to use magnetic resonance imaging (MRI) to evaluate the three-dimensional geometry and mechanosensory properties of the sigmoid colon. The sigmoid colon was stepwise distended by a water-filled bag in eight subjects. Simultaneous MRI, bag pressure recording and sensory assessment were performed before and after smooth muscle relaxation with butylscopolamine. The surface distributions of principal curvature radii, wall thickness, tension, stress and circumferential strain were calculated. The geometry of the distended sigmoid colon was complex and the spatial distributions of the biomechanical parameters were non-homogeneous. The circumferential length, strain, pressure and wall stress increased as a function of bag volume (all P < 0.001). In response to butylscopolamine, the pressure and wall stress were reduced (P < 0.05) and the stress-strain curves were shifted to the right. The sensory response was a linear function of the biomechanical parameters (all P < 0.001) and decreased in response to butylscopolamine as a function of volume (P = 0.02). The stimulus-response data indicate that the mechanosensitive afferents are affected by smooth muscle tone. The present study provides a method for characterizing the complex geometry and mechanical properties of the sigmoid colon, including the role of smooth muscle tone. This may be valuable in understanding of the biomechanical and mechanosensory functions in colonic diseases.

To gain more information of the pain mechanisms in chronic pancreatitis we applied standardized experimental pain stimulation of the duodenum, oesophagus and the skin in 12 healthy controls and 13 patients with chronic pancreatitis and typical pain attacks.

Using endoscopy a guide wire was positioned into the horizontal part of the duodenum, and a probe with a distal balloon was introduced over the guide wire. Mechanical stimuli were given as tonic (38 ml/min) or phasic (increasing volume steps of 5 ml delivered for 60 s) distensions of the balloon. After stimulation of the duodenum, the distal oesophagus was stimulated with the same protocol. Finally, the skin was stimulated with 'single and repeated burst' electrical stimuli reflecting activation of peripheral and central pain mechanisms.

The stimuli reliably evoked both painful and non-painful local and referred sensations. The patients had hyposensitivity to both tonic and phasic mechanical stimuli of the duodenum and the oesophagus (P=0.001). Hypoalgesia was also observed to single and repeated electrical skin stimuli in the patients, most evident for repeated stimuli (P=0.001). The evoked referred pain did not differ between the groups, but the patients used on average more words from the McGill Pain Questionnaire to describe the pain evoked in the duodenum (P=0.02).

Generalized hypoalgesia to experimental visceral and somatic stimulations was found in chronic pancreatitis. The findings suggest that the activation and modulation of central mechanisms is fundamental in pancreatic pain, and future studies should address the effect of analgesics with central effects in the treatment of these patients.

The pain, urgency, and incontinence in ulcerative colitis may be related to changes in viscoelastic properties of the gut wall or to alterations of the sensory pathways. In the present study, we used an advanced rectal probe to study the mechanosensory and smooth muscle properties in patients with active disease.

Nine patients with ulcerative colitis (mean age 39.5 years) with exacerbation limited to the rectum and sigmoid colon and 17 age-matched healthy subjects were included. The rectum was distended before and after pharmacological relaxation of the smooth muscle until moderate pain was reported, and the cross-sectional area, volume, pressure, tension, and strain were computed. To investigate central integration of a tonic stimulus, the bag was finally distended to the pain threshold; then, the cross-sectional area was held constant for 2 min.

The patients were hypersensitive to mechanical stimuli as assessed by the cross-sectional area (F = 21.7; P < 0.001). There were no differences in compliance or stiffness between the 2 groups, but the hypersensitivity was abolished after muscle relaxation. Together with the muscle analysis, this finding demonstrated that the smooth muscles were tonically contracted in the inflamed rectum, resulting in a decreased rectal circumference. The tonic distensions did not evoke central integration of the pain response, indicating that hyperalgesia is more likely related to peripheral factors.

Patients with active ulcerative colitis have hypersensitivity and increased tone of the smooth muscles, which may explain the symptoms. Drugs that affect smooth muscle contraction may be helpful in difficult cases.

Fecal continence requires relaxation of the rectal wall and a reservoir of adequate capacity. Rectal compliance provides an assessment of rectal wall stiffness; however, compliance is also affected by rectal capacity. We developed and validated a barostat measurement of rectal capacity. By accounting for variation in rectal capacity, we aimed to improve the inconsistent relationship between rectal compliance, sensation, and continence reported in the literature.

Barostat measurements of rectal compliance and capacity were validated in 41 healthy, continent subjects. Slow staircase (0-40 mmHg) and rapid phasic (12-40 mmHg) distentions were performed on two separate days, filling sensations were assessed by visual analog score. A stool substitute retention test of rectal filling sensation and continence was performed.

Variance of volume measurements decreased with pressure comparing conditioning vs. index distentions, staircase vs. phasic distentions, and measurements on different days (all P < 0.001). Correction for rectal capacity measured at 40 mmHg reduced the "normal range" of compliance measurements (P < 0.01) but not vice versa. Compared with unadjusted volume measurements, normalized rectal volume (percentage filling relative to rectal capacity) improved the description of rectal sensation visual analog score (P < 0.01). Rectal capacity correlated with filling sensations and the volume retained on retention testing (P < 0.01).

Barostat measurements of rectal capacity at 40 mmHg are highly reproducible and not affected by distention protocol. The assessment of rectal capacity complements that of rectal compliance. Correction for rectal capacity provides an assessment of rectal wall stiffness independent of rectal geometry and improves the association of barostat volume measurements with rectal sensitivity and continence.

Our aims were to investigate gender differences to multimodal stimulations of the esophagus after experimentally induced sensitization. Thirty healthy age-matched subjects, 13 males and 17 females, were included. Pain evoked by mechanical and thermal stimuli was assessed before and after perfusion of the lower esophagus with 0.1 N hydrochloric acid. Males were more sensitive to the baseline mechanical stimuli (P < 0.01) and tolerated a lower volume of acid (P = 0.04). After acid perfusion, males were more sensitive than females to distensions (cross-sectional area P = 0.001 and volume P = 0.001). Acid perfusion sensitized both males (P = 0.03) and females (P = 0.04) to heat stimulation but not to cold stimulation (males, P = 0.09; females, P = 0.8). The referral areas for pain evoked by mechanical and thermal stimuli were larger in females compared with males both before and after acid perfusion (P = 0.002). In females only the referred pain area increased to heat stimulations (P = 0.02). Acid infusion resulted in a more hyperreactive esophagus (P = 0.03) but the hyperreactivity was not gender-dependent. In conclusion, males were more sensitive to mechanical and chemical esophageal stimuli and showed acid-evoked mechanical hyperalgesia. Females had significantly larger referred pain areas to the stimulations. The differentiated response to peripheral and central pain mechanisms may explain the gender-related differences seen in several gastrointestinal disorders.

The identification in the rectal wall of warm receptors sensitive to warm temperature has not been found in the literature. Therefore, we investigated the hypothesis that rectal warming effects rectal dilation, which seems to indicate the existence of warm receptors.

The rectal wall tone was studied in 24 healthy volunteers (14 men, 10 women, mean age 36.7+/-10.4 years). It was assessed by a barostat system during rectal infusion with normal saline at 30 degrees C, 40 degrees C, 45 degrees C, and 50 degrees C. The test was repeated after rectal anesthetization with lidocaine.

The rectal tone on rectal saline infusion at a temperature of 30 degrees C showed no response (P>0.05), whereas at a temperature of 40 degrees C, 45 degrees C, and 50 degrees C, it exhibited a significant decrease (P<0.05, <0.01, <0.001, respectively), which was proportional to the rising degree of temperature. Warm saline infusion into the anesthetized rectum resulted in no significant change in the rectal wall tone.

Rectal infusion with warm saline produced rectal dilation that increased with temperature elevation. This effect is suggested to be mediated through a reflex called "rectal warming reflex: and advances the possibility of the existence of warm receptors in the rectal wall; however, further studies are needed to confirm the issue.

A method to evaluate the three-dimensional (3-D) geometry of the human gastrointestinal wall may be valuable for understanding tissue biomechanics, mechano-sensation and function. In this paper we present a magnetic resonance imaging (MRI) based method to determine rectal geometry and validation of data obtained in three volunteers. A specially designed rectal bag was filled in a stepwise manner while MRI and bag pressure were recorded. 3-D models of curvatures, radii of curvature, tension and stress were generated and the circumferential and longitudinal strains were calculated. The computed bag volumes corresponded to the infused volumes. A pronounced bag elongation and decrease in wall thickness was observed during the bag filling. The spatial distributions of the biomechanical parameters were distinctly different between individuals and non-homogeneous throughout the rectal wall due to its complex geometry. The average tension and stress increased as a function of infused volume and circumferential strain. The present study provides a method for characterizing the complex in vivo 3-D geometry of the human rectum. The non-homogenous spatial curvature distribution suggests that simple estimates of tension based on pressure and volume do not reflect the true 3-D biomechanical properties of the rectum.

A hallmark symptom of irritable bowel syndrome (IBS) is a lower pain threshold during rectal distension, but the mechanism underlying this disorder remains unclear. Examining the relationship between physiological and perceptual responses to rectal distension can provide insight into the underlying peripheral or central dysfunction in IBS. Therefore, we carried out a study of the rectal sensations of urge to defecate, pain and unpleasantness in relation to the varying states of the rectum. Ten IBS patients and 13 healthy controls underwent six sets of isobaric rectal distensions. The first set was ascending stepwise distensions terminating upon report of moderate pain where verbal ratings of urge, pain, and unpleasantness were acquired. The remaining sets were phasic or tonic distensions at a single pressure eliciting either moderate urge or moderate pain intensity where subjects gave continuous ratings of urge or pain percepts. The McGill Pain Questionnaire (MPQ) was used to assess different qualities of the pain experience during single pressure distensions. Abnormalities in IBS patients included: (1) higher incidence of distensions where unpleasantness is greater than pain intensity, (2) significantly longer persistence of ratings after stimulus termination during phasic distensions eliciting either moderate urge or moderate pain, (3) significantly smaller ratings fluctuations during tonic distensions, and (4) significantly higher MPQ scores for painful tonic distensions. Our study demonstrates that IBS patients have abnormal temporal and intensity properties of rectal sensation. These can be accounted for by either altered peripheral neuromuscular processing and/or processing of ascending rectal input in the central nervous system.

Experimental pain models based on single stimuli have to some degree limited visceral pain studies in humans. Hence, the aim of this study was to investigate the effect of multi-modal visceral pain stimuli of the oesophagus in healthy subjects before and after induction of visceral hyperalgesia. We used a multi-modal psychophysical assessment regime and a neurophysiological method (nociceptive reflex) for the characterisation of the experimentally induced hyperalgesia.

A probe for multi-modal (cold, warm, electrical, and mechanical) visceral stimulation was positioned in the lower part of the oesophagus in eleven healthy subjects. Mechanical stimuli were applied as distensions with a bag, which also had electrodes mounted for electrical stimulation. Thermal stimulation with temperatures from 0 to 60 degrees C was applied with re-circulating water in the bag. To assess the interaction between visceral and somatic pathways, the nociceptive withdrawal reflex to electrical stimuli at the ankle was measured with and without simultaneous mechanical oesophageal distension to painful levels. Finally, the oesophageal sensitisation was induced by perfusion with hydrochloric acid. Multimodal responses (pain threshold, stimulus response function, size of nociceptive reflex, and referred pain areas) were assessed before and after the induced hyperalgesia.

The multi-modal psychophysical responses and reflex sizes were assessed twice before sensitisation, and the parameters were reproducible. Sensitisation of the oesophagus resulted in hyperalgesia to electrical and mechanical stimuli (29 and 35% decrease in pain threshold) and allodynia to cold and warmth stimuli (11% increase in sensory rating). After sensitisation, the referred pain area to mechanical stimuli increased more than 300% with a change in the localisation of the referred pain to all stimuli, and the amplitude of nociceptive reflex increased 100%, all indicating the presence of central hyperexcitability.

Visceral hyperalgesia/allodynia can be induced experimentally and assessed quantitatively by the newly introduced multi-modal psychophysical assessment approach. The significant changes of the experimentally evoked referred pain patterns and of the nociceptive reflex evoked from a distant somatic structure indicate that even short-lasting visceral hyperalgesia can generate generalised sensitisation.

Vagal afferent mechanoreceptors in the upper gut have recently been identified morphologically as intraganglionic laminar endings (IGLEs), but little is known about the structure of mechanoreceptive endings elsewhere in the gastrointestinal tract. We have morphologically characterized the nerve endings of specialized mechanoreceptors in the rectum.

Extracellular recordings from guinea pig rectal and colonic nerves were made, in vitro, in combination with rapid anterograde transport of biotinamide, to reveal the morphology of recorded fibers. Controlled distentions were used to activate mechanoreceptive afferent units, and von Frey hairs were used to identify their transduction sites.

Rectal mechanoreceptors were present in high density, had low thresholds, and adapted slowly to maintained distention. Each afferent unit had multiple small (<200 microm diameter) transduction sites ("hot spots") at which they could be activated locally by application of a light von Frey hair (0.08-7 mN). Anterograde dye filling revealed characteristic rectal intraganglionic laminar endings (rIGLEs) in myenteric ganglia, significantly associated with hot spots, comparable to the IGLEs of vagal tension receptors, but smaller and less complex. Afferent fibers with these morphologic and physiologic features could not be recorded from colonic nerves innervating the large bowel proximal to the rectum.

The rectum receives a dense afferent innervation by a distinct population of low-threshold, slowly adapting mechanoreceptors with specialized intraganglionic laminar endings (rIGLEs), which are not found more proximally in the colon.

Distension of the intestine is commonly used to elicit reflex responses at other sites in the gastrointestinal tract, and also to evaluate pain of intestinal origin. The sensory neurones, that initiate the reflexes or pain responses, react to the forces generated in the wall of the intestine. Thus, the responses of the intestine at the site of distension, particularly changes in contractile activity, influence the signals from the gut. In the present work we have analysed the relationship between distension and pressure changes in the jejunum of the rat, in vivo. Isovolumic distension for 5 min caused an initial pressure increase which declined quickly in the first 30 s, and then declined more slowly. Phasic pressure increases were superimposed on the baseline pressure change. Hexamethonium blocked the phasic pressure increases, whereas the initial rapid and subsequent slower pressure decline during distension persisted. Inhibition of nitric oxide synthase (NOS) increased intraluminal pressure and caused increased frequency and irregularity of phasic pressure increases. However, the decline in jejunal pressure during distension was not changed by inhibition of NOS. The pressure decline during isovolumic distension was similar whether saline or paraffin oil were used to distend the intestine, indicating that the decline was not due to increased hydrostatic pressure causing water and electrolyte to cross the mucosal epithelium from the lumen to the intestinal interstitium. Hyoscine had no significant effect on the pressure profile when the intestine was distended. However, when the systemic or the local circulation of the jejunum was infused with nicardipine, the pressure that was achieved during isovolumic distension was less, although the rate of change in pressure during the slow decline was similar. It is concluded that distension evokes phasic pressure increases in the jejunum, that are nerve-mediated, and increases the tension in the wall through a stretch-activated increase in contractile force generated by the circular muscle. The decline in pressure during maintained distension is primarily a consequence of visco-elastic properties of the wall of the intestine.

The past decade has seen major advances in the pharmacological understanding of the nervous system of the gastrointestinal tract, the enteric nervous system, and its importance for gut functions in several states of disease. Indeed, the enteric nervous system has become a promising target in the treatment of many gastrointestinal symptoms and disorders. Some of these new therapeutic concepts, such as botulinum toxin for achalasia and serotonergic drugs for functional bowel diseases, are already in clinical use. This paper is part 3 of three Minireviews in Pharmacology & Toxicology, and presents the neurogastrointestinal pharmacological therapeutic options in gastrointestinal pain, functional gastrointestinal disorders, inflammatory bowel diseases, cancer and related conditions with focus on future drug targets. The diagnosis of gastrointestinal neuropathy, the role of serotonin and related neuroendocrine transmitters, serotonergic drugs, and neurotrophic factors in neurogastrointestinal pharmacology will be addressed in this context.

A new multimodal pain assessment model was developed integrating electrical, mechanical, cold, and warmth stimuli into the same device. The device, with a bag and electrodes for electrical stimulation, was positioned in the lower part of the esophagus in 11 healthy subjects. Mechanical stimuli were delivered with an impedance planimetric system. Thermal stimuli were performed by circulating water of different temperatures (5-50 degrees C) inside the bag. All subjects reported both nonpainful and painful local and referred sensations to all stimuli. Temporal summation to repeated electrical stimuli could be studied. For all stimuli, there was a relationship between stimulus intensity and pain intensity. The referred pain area increased with increasing intensity of the electrical and mechanical stimuli. There were several differences between the sensations evoked by the four stimulus modalities, indicating activation of different visceral nerve pathways. This model offers the possibility for controlled multimodal stimuli activating the superficial and deeper layers of the human gut and should be used in basic, clinical, and pharmacological pain studies.