|
|
|||
|
| |||
|
| |||
|
| |||
|
|
|||
|
Christina Brock, Mech-Sense, Department of Gastroenterology, Aalborg Hospital, DK-9000 Aalborg, Denmark Lars Arendt-Nielsen, Center for Sensory-Motor Interactions, Department of Health Science and Technology, Aalborg University, DK-9000 Aalborg, Denmark Oliver Wilder-Smith, Pain and Nociception Research Group, Department of Anaesthesiology, Radboud University Nijmegen Medical Centre, the Netherlands Asbjørn Mohr Drewes, Mech-Sense, Department of Gastroenterology, Aalborg Hospital, DK-9000 Aalborg, Denmark Author contributions: All authors have contributed to the manuscript. Supported by Det Obelske Familie fond and Spar Nord Fonden Correspondence to: Asbjørn Mohr Drewes, Professor, MD, PhD, DMSc, Mech-Sense, Department of Gastroenterology, Aalborg Hospital, DK-9000 Aalborg, Denmark. drewes@hst.aau.dk Telephone: +45-99321111 Fax: +45-99326507 Received: September 10, 2008 Revised: November 24, 2008 Accepted: November 31, 2008 Published online: January 14, 2009
Abstract The objective of this appraisal is to shed light on the various approaches to screen sensory information in the human gut. Understanding and characterization of sensory symptoms in gastrointestinal disorders is poor. Experimental methods allowing the investigator to control stimulus intensity and modality, as well as using validated methods for assessing sensory response have contributed to the understanding of pain mechanisms. Mechanical stimulation based on impedance planimetry allows direct recordings of luminal cross-sectional areas, and combined with ultrasound and magnetic resonance imaging, the contribution of different gut layers can be estimated. Electrical stimulation depolarizes free nerve endings non-selectively. Consequently, the stimulation paradigm (single, train, tetanic) influences the involved sensory nerves. Visual controlled electrical stimulation combines the probes with an endoscopic approach, which allows the investigator to inspect and obtain small biopsies from the stimulation site. Thermal stimulation (cold or warm) activates selectively mucosal receptors, and chemical substances such as acid and capsaicin (either alone or in combination) are used to evoke pain and sensitization. The possibility of multimodal (e.g. mechanical, electrical, thermal and chemical) stimulation in different gut segments has developed visceral pain research. The major advantage is involvement of distinctive receptors, various sensory nerves and different pain pathways mimicking clinical pain that favors investigation of central pain mechanisms involved in allodynia, hyperalgesia and referred pain. As impairment of descending control mechanisms partly underlies the pathogenesis in chronic pain, a cold pressor test that indirectly stimulates such control mechanisms can be added. Hence, the methods undoubtedly represent a major step forward in the future characterization and treatment of patients with various diseases of the gut, which provides knowledge to clinicians about the underlying symptoms and treatment of these patients.
© 2009 The WJG Press and Baishideng. All rights reserved.
Key words: Endoscopy; Intestine; Experimental; Neurophysiology; Pain
Peer reviewer: Yvette Taché, PhD, Digestive Diseases Research Center and Center for Neurovisceral Sciences and Women’s Health, Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine at UCLA, University of California, Los Angeles and VA Greater Los Angeles Healthcare System, 11301 Wilshire Boulevard, CURE Building 115, Room 117, Los Angeles, CA, 90073, United States
Brock C, Arendt-Nielsen L, Wilder-Smith O, Drewes AM. Sensory testing of the human gastrointestinal tract. World J Gastroenterol 2009; 15(2): 151-159 Available from: URL: http://www.wjgnet.com/1007-9327/15/151.asp DOI: http://dx.doi.org/10.3748/wjg.15.151
INTRODUCTION Abdominal pain is very common in the general population[1], and pain is the most prevalent symptom in the gastrointestinal (GI) clinic[2]. Gastroenterologists face a challenge in treating these symptoms. Consequently, characterization of visceral pain is one of the most important issues in the diagnosis and assessment of organ dysfunction, as diseases giving rise to deep pain often are difficult to diagnose. This is partly due to the sparse and diffuse termination of visceral afferents in the spinal dorsal horn that overlap several segments, which is further complicated by convergence with somatic afferents (spinal convergence), autonomic (involvement of vagal nerve and spinal afferents) and enteric nervous (homeostatic and secretory) systems. Hence, activation of peripheral sensory afferents may lead to symptoms related to GI motor function (sweating, vasodilation, nausea and vomiting), which blurs the clinical picture. Consequently, complaints related to the autonomic nervous system or related to referred somatic pain are a clinical challenge. To understand the sensory system and how it can be tested, it is important to understand the basic neurophysiological mechanisms behind GI pain. In healthy subjects, most visceral afferent activity does not reach higher brain centers, except information regarding filling of the esophagus, stomach, rectum and bladder. However, when the internal organs are potentially in danger - e.g. via inflammation and diseases - symptoms such as discomfort and pain are typically reported. The feeling is mostly vague and difficult to characterize, in contrast to distinct localization and characterization in somatic diseases. The different neuroanatomical structures of the two systems explain to some degree why visceral pain is more challenging to diagnose than its somatic counterpart (Figure 1). Visceral afferents that mediate conscious sensations run predominantly together with sympathetic nerves that reach the central nervous system (CNS), although some afferents join parasympathetic and parallel pathways. However, the upper esophagus and rectum also possess somatic innervation. The importance of this dual innervation is not clear, although the rectum has more complex functions than most other visceral organs and may need a more differentiated innervation. The peritoneum and parietal serous membranes of the lungs and heart possess their own parietal nerve supply, which is organized like the skin[3]. Hence, pain from these structures gives a distinct, intense and localized pain, which is comparable to the pain evoked by skin lesions. Most of the visceral afferents converge with laminaⅠ, Ⅱ and Ⅴ spino-thalamic tract (STT) neurons, which receive input from both superficial and deep somatic tissue as well as other visceral organs[4]. Although the neuronal mechanisms are more complex, this convergence leads to referred somatic pain as well as viscero-visceral hyperalgesia. The latter phenomenon may explain several comorbid conditions such as increased number of anginal attacks in patients with gallbladder calcinosis, and increased number painful sensations to normal air and feces in the gut in patients primarily suffering from dysmenorrhea[5-9]. Most visceral organs exhibit spinal representation overlapping multiple segmental levels[10]. This widespread and low-density nature of visceral sensory innervation explains why large areas of the gut appear to be relatively insensitive to pain stimuli. The extensive resulting CNS activation may also explain the diffuse and unpleasant nature of visceral pain. Finally, unlike the somatic system, where prolonged or summated stimuli such as during inflammation are necessary to activate the N-methyl-D-aspartate (NMDA) receptor, it seems as though - in the visceral context - the NMDA receptor can be more easily activated by short-lasting and low intensity stimuli[11,12]. The resulting amplification of nociceptive processing explains why the manifestation of visceral pain is so often unpleasant and intense in its clinical presentation.
THE RATIONALE FOR EXPERIMENTAL STIMULATION OF THE HUMAN GUT In clinical practice, several symptoms of underlying diseases confound the characterization of pain. These may include complaints relating to psychological, cognitive and social aspects of the illness, as well as systemic reactions such as fever and general malaise[13]. Furthermore, analgesic treatment and other medications often cause sedation and/or other side effects, which invariably bias the clinical evaluation of pain-related symptoms. Consequently, most studies evaluating drug efficacy in sensory functions of the gut have included a large number of patients. As a result of the above factors, together with the heterogeneity of the material, complicated statistical models have frequently been used - albeit often with equivocal effects. In the clinical situation, this is not a major problem. But, in assessment of analgesics in clinical trials, these confounders can easily invalidate the outcome. However, in experimental pain models, the confounding factors can often be turned to advantages in the assessment of basic GI functions, mechanisms of disease and treatment efficacy. Under these circumstances, the investigator controls the experimentally induced pain (including the nature, location, intensity, frequency and duration of the stimulus), and provides quantitative measures of the psychophysical, behavioral or neurophysiological responses[13-15]. Different experimental animal models have been used in this context. The advantages of these models are obvious: neuronal activity can be studied directly in anesthetized or spinalized animals with invasive recording techniques or via assessment of behavior[16]. However, as neurobiology of the pain system differs substantially even between animal species, translation from animal studies to human pain studies has some major shortcomings. Human experimental pain studies have for those reasons gained much interest during recent years. In man, pain is closely related to culture, linguistic terms and expressions, and should be regarded as the net effect of complex multidimensional mechanisms that involve most parts of the CNS including intensity coding, affective, behavioral and cognitive components. This explains some of the difficulties and challenges in quantifying human sensory experiences with simple neurophysiological and/or behavioral methods, and why interest in more advanced human experimental pain studies has increased rapidly during the last decade[13,17]. The ultimate goal of advanced human experimental pain research is to obtain a better understanding of pain mechanisms involved in pain transduction, transmission and perception under normal and pathophysiological conditions, such as clinical pain. Obviously, the risk of perforation and other complications during invasive procedures limits the testing possibilities when stimulating the gut. As a result of these difficulties in accessing the GI tract, visceral experimental pain testing is far more resource-intensive and challenging than the more traditional somatic pain stimulations. As a result, most previous visceral studies have relied on relatively simple mechanical or electrical stimuli. These methods are easy to apply. But they have numerous limitations[13]. One should bear in mind that as pain is a multidimensional perception, the response to a single stimulus of a given modality only represents a limited fraction of the entire pain experience. Hence, the possibility of combining different methods to gut stimulation and induction of hyperalgesia will provide the possibility to more closely imitate the clinical situation, and provide extensive and differentiated information on the visceral nociceptive system[13,18]. Ideally, experimental stimuli to elicit gut pain in humans should be physiological, minimally invasive, reliable in test-retest experiments, and quantifiable. Preferably, the pain should mimic observations in diseased organs by inducing phenomena such as allodynia and hyperalgesia. Most experimental studies have been completed in functional diseases such as functional chest pain, non-ulcer dyspepsia and irritable bowel syndrome; but, to some degree organic diseases (e.g. ulcers, inflammatory bowel disease and chronic pancreatitis) have also been investigated[18-23]. The different types of stimulation (electrical, mechanical, thermal, chemical and ischemic) that evoke visceral pain in humans, as well as their limitations, have been described in detail previously[13,24]. In this review, we focus on novel developments regarding test systems that allow standardized stimulation of the GI tract and their applications.
MECHANICAL STIMULATION OF THE GUT In the last decade, several studies have addressed the mechanical and sensory function of the GI tract by means of mechanical distension. Simple and physiological gut distension, such as ingestion of well-defined meals, may be useful in clinical studies[25]. Balloon or bag distension is, however, the favored method as the mechanical stimulation intensity is easier to control. Most recent studies have used the Barostat based on volume changes in an air-filled balloon kept at constant pressure levels, and several protocols and stimulation paradigms have been recommended for the Barostat, such as phasic and tonic distension. These stimulation paradigms have been thoroughly discussed, and will not be described here - for review see Whitehead et al[26] and van der Schaar et al[27]. The major advantages of the Barostat system and similar pressure-volume-based methods are the relatively low cost and the documented reproducibility between laboratories[28]. Furthermore, they are reliable and easy to use for routine purposes. Such systems have also been used for assessing sensory and pain thresholds, and under different conditions, attempts have been made to calculate the compliance and tension of the organs[26,27,29,30]. A major pitfall in early balloon distension studies was the use of latex balloons causing large errors because of latex deformability and lack of control of the stimulation field. Consequently, polyurethane or polyethylene bags are now recommended generally. There are, however, still several limitations and sources of error with systems based exclusively on volume and pressure. These include the fact that the data obtained must be corrected for compressibility of air as well as other major concerns, for further details see Drewes et al[31]. Basically, a common mistake in GI distension studies is to consider the mechanoreceptors as pressure, volume or tension receptors. In fact, the sensory rating may not be strictly related to pressure (or tension) during gut distension. Circumferential strain or stress are more likely parameters correlating with receptor responses to stimulus intensity[32]. This is partly due to the fact that strain is a non-dimensional parameter independent of the geometry of the organ and directly associated with tissue deformation. In fact, recent studies have clearly demonstrated that circumferential strain is an important determinant of mechanoreceptor-mediated responses[33-36]. Correspondingly, studies providing tension calculations based on Barostat methods have shown conflicting results, e.g. in a recent study of the stomach, the estimated tension seemed to correlate with the sensation[29,37], whereas another study showed a high inter-individual variability in the sensation score to the applied tension, which suggests that factors other than wall tension influence the sensation[38]. However, uncertainties in the assumptions given above, and lack of adequate geometric and biomechanical considerations can also explain these findings[39]. Methods based on impedance planimetry allows recordings of luminal cross-sectional area directly and calculation of the radius in the distended GI segment[33,35,36,40-42]. As an example, a schematic drawing of the multimodal rectal probe is shown in Figure 2. Estimates of circumferential wall tension, stretch and strain based on measured radius are more accurate than estimates based on volume exclusively[32]. Findings during rectal distension support this theory, as stretch ratio at pain detection threshold produces an excellent intra-class coefficient of 0.98, both with and without administration of the antimuscarinic drug butylscopolamine[43]. An example of a rectum probe is shown in Figure 3. To reliably compute, e.g. rectal stress and strain, more complex modeling is necessary. Thus, in future studies mechanical distension combined with, for example, ultrasound methods or magnetic resonance imaging may offer the possibility of a better anatomical characterization of the GI tract[44,45].
ELECTRICAL STIMULATION OF THE GUT Electrically induced depolarization of sensory afferents has been widely used as an experimental stimulus in humans. Electrical stimuli have proved to be safe in all parts of the GI system; however, it is recommended to monitor the heart during esophageal stimulation, as previous experiments have documented that atrial capture may occur[46]. Electrical stimulation of the GI tract has been used to study, for example, basic pain mechanisms[7,42,47-49] via evoked brain potentials to gut stimuli[50-52], and the effect of analgesics in both healthy volunteers and patients[53]. The main advantage of electrical stimulation is its reproducibility[43,54]. Also, its dynamic range (i.e. the range from sensation to pain threshold) is relatively high, which allows more robust assessment of sensory thresholds. A further advantage is that electrodes are easily implemented on different GI probes[13,43,54]. The well defined on- and offset of the stimulus makes it suitable to study pain mechanisms related to time, such as temporal summation[48,55] and cerebral evoked potentials. There are, however, also limitations and drawbacks. Depending on the probe design and the electrodes, it may be difficult to obtain optimal mucosal contact between the electrodes and the GI tract because of, for example, longitudinal esophageal mucosal folds. Hence, it is necessary to measure and control the impedance between electrodes during stimulation, preferably at different frequencies. Further, electrical stimuli are neither natural nor specific for any sensory modality, and the electrical stimulation bypasses receptors, which stimulates all afferent nerves directly, including silent fibers. Consequently, electrical stimulation reflects the central nervous response rather than peripheral afferents. However, as most gut afferents are polymodal[56] and respond to a wide range of stimuli, specificity may be of minor importance. The electrical stimulation creates an electrical field, and the action potential is partly determined by the extracellular electrical potential, and partly by the nerve properties, including myelin and ion-channel configuration. Thus, there may be some selectivity relating to fiber type as the non-myelinated afferents (C-fibers) possess a higher activation threshold than myelinated fibers[17,57,58]. Hence, increasing stimulation intensity may depolarize myelinated fibers first, followed by C-fiber recruitment at higher stimulation intensities. Electrodes can be either unipolar with a reference placed on the skin or bipolar with a set of electrodes. As a result of safety considerations, bipolar stimulation is recommended because the electrical field is more localized. Cardiac arrhythmia may theoretically be evoked by stimulation of nearby organs. Normally, atrial captures can be seen; but, this has no clinical significance. Arrhythmia can be avoided by either turning patch-electrodes away from the dorsal side of the heart, or by using bipolar ring electrodes that exhibit good mucosal contact[42]. Impedance should preferably be less than 3 kΩ before stimulation is initiated. Numerous stimulation paradigms have been recommended and no general consensus exists with respect to the configuration of the optimal electrical pulse. In fact, the stimulus should reflect the purpose, e.g. it is crucial to use single pulses in electrophysiological studies, where early peaks of evoked brain potentials are wanted. On the other hand, a single stimulus in the gut demands rather high intensity to evoke pain, and trains or continuous series of pulses can be used in order to investigate temporal summation to a repeated series of stimuli (termed “wind-up” in animal experiments). Based on this experience, we use either: (1) single square pulses (duration 0.2-2 ms) in electrophysiological studies assessing evoked brain responses; (2) trains of five constant current pulses (rectangular with a duration of 1 ms applied at 200 Hz termed “single burst stimuli”), as such stimuli demand less current to evoke sensory responses; (3) “repeated burst stimuli” given as a series of single burst stimuli to investigate, for example, the central amplification of the repeated stimuli[48,55,59]; or (4) tetanic stimulation to be used for sensory thresholds of temporal summation[60]. This is applied as a train of pulses (0.2 ms, 100 Hz) that is linearly increased from zero. The advantage of this stimulation is that it is precise and less time-consuming. Blind, untargeted stimulation is avoided by integrating electrodes onto endoscopic biopsy forceps, which makes stimulation of well-defined areas in the esophagus, stomach, duodenum, terminal ileum and colon possible[48,55]. An example of targeted colonic stimulation is shown in Figure 4. The major advantage of this modification is that electrode position is controllable and can be altered in case of stimulation in the vicinity of somatic structures and nerves. Further, mucosal contact is secured and evoked motor phenomena such as secondary contractions can be studied directly. Hence, the method allows characterization of local and referred pain to stimuli in most areas of the intestine relevant to localized pathology. However, the subjects have to cope with the rather thick endoscopes during experiments, which may be unpleasant especially in the upper GI tract, and which may cause bias in the pain assessment. As gut segments exhibit differences in anatomy and innervation, a general consensus regarding stimulation location is warranted. Consequently, as described above, stimulation paradigms have a major influence on pain assessment. Thus, future studies should include standardized and validated optimal parameters such as stimulus duration, shape, polarity, frequency and intensity, which allows comparison between different laboratories.
THERMAL STIMULATION In contrast to mechanical and electrical stimuli, thermal stimuli activate selectively, for example, being either mucosal heat-responsive TRPV1 receptors with temperatures above 43℃, or mucosal cold-responsive TRPA1 with temperatures less than 17℃[61]. Thermal stimulation has been used to study basic pain mechanisms[42,43,48,49,54,61,62], functional[63] and organic gut disorders[22] and analgesic efficacy in healthy volunteers and patients[53]. Rectal heat pain stimulation has been performed using a Peltier device[61]. To improve thermal stimulation in the gut, we have developed the multimodal esophageal probe - for details see Drewes and Gregersen[24]. Thermal stimulation is based on recirculation of cooled and/or heated water in the bag with a temperature sensor placed inside the bag. The method has also been integrated onto a multimodal rectal probe. In both cases, the most reliable proxy of the thermal energy applied is the area under the temperature curve[43,64]. In the esophagus, the method aims at having a constant high or low temperature in the bag until the pain threshold is reached. This method has been shown to be reliable and robust in drug experiments[54]. In studies of healthy subjects, it has shown some limitations, as not all subjects reach a pain threshold during the 2 min stimulation that were empirically found to be safe. To improve control over the stimulation intensity and duration, the method has recently been changed in order to obtain a linear increase in temperature, with an adjustable temperature ramp. Such stimulation is shown in Figure 5. In these experiments, the stimulation intensity can continue until the subject reaches the pain threshold, an improvement that is expected to result in better validity and reliability of the method.
CHEMICAL STIMULATION Chemical stimulation of the GI tract resembles clinical inflammation and approaches the ideal experimental visceral pain stimulus[7]. Such stimuli have successfully been applied to the skin[14,17,65] and muscles[66], but are also widely used in the gut. As an example, esophageal acidification is commonly used as a method to sensitize the gut evoking allodynia/hyperalgesia[67,68], but the model may also be used for direct stimulation[69]. The major relevance of the model may be induction of sensitization of visceral afferents to subsequent experimental stimulation. Chemical stimulation has been used to study, for example, basic pain mechanisms[42,43,48-50,62,70,71] and functional gut disorders[22,50]. However, drawbacks of chemical stimuli include a relative long latency time to onset of effects, and that the effects are often not reproducible[7]. Other stimuli such as glycerol, alcohol, bradykinin and other chemicals[72-75] have been used in uncontrolled studies, but their applicability has yet to be established. Recently, capsaicin has been used to evoke pain in the small and large intestine[76-78]. Chemical stimulation has also been used to explore basic functions such as autonomic changes in referred pain[79]. Hammer et al[77] have shown that activation of chemosensitive pathways induces symptoms that differ from those induced by mechanical activation, although animal data do not allow such a strict separation[80,81]. As a result of the relative inconsistency of the effects of acid perfusion in the esophagus[82], we recently used perfusion of a combination of acid and capsaicin in the human esophagus[83]. It is believed that capsaicin has an additional effect on acid because of synergistic mechanisms on the transient receptor potential vanilloid type 1 (TRPV1) channels[83]. The perfusion induced locally reproducible hyperalgesia to subsequent heat and electrical stimulation, and an expansion of referred pain in all subjects. The increased referred pain reflects convergence mechanisms on second-order neurons in the spinal cord, and can be used to elucidate the central component of hyperalgesia. A further step is achieved by the demonstration of viscero-visceral hyperalgesia in the rectum following esophageal perfusion with acid and capsaicin[84]. Hence, the model may be more robust than acid perfusion alone, but further studies are needed.
SPATIAL AND TEMPORAL SUMMATION Lewis[85] has found that distension of the gut is most painful when long, continuous segments of the gut are distended simultaneously. Even greater pressures within smaller segments of the gut are not as efficacious in producing painful sensations. Hence, spatial summation is clearly an important contributor to visceral pain mechanisms. An experimental design to achieve spatial summation is mounting either multiple inflatable bags or one long bag on a probe, and then assessing the distension volume at pain detection threshold (PDT) derived from each bag, compared to the distension volume at PDT during simultaneous distension of multiple bags or the long bag. Also, integration over time-temporal summation-is important. If electrical stimuli are repeated over time, both pain and the area of referred pain increase progressively[47]. The same phenomenon is seen following repeated distensions[7].
ACTIVATION OF INHIBITORY MECHANISMS Pain inhibits pain, and impairment of descending control mechanisms is believed to be an important part of the pathogenesis of chronic pain[86]. Descending inhibition involves a spinal-supraspinal-spinal feedback mechanism, which results in direct or indirect inhibition of spinal neuronal responses[87,88]. Supraspinal sites can, however, also facilitate nociception, and the measured net output is either predominantly facilitation or inhibition[89]. Hence, experimental studies assessing human inhibitory processes measure the balance between these phenomena. The most common method to provoke the noxious inhibitory system is the cold pressor test that is performed by immersing a hand or foot in 2.0 ± 0.3℃ ice-cooled water for at least 2 min. Efficacy of the descending control can then be investigated by comparing two stimuli separated by the cold pressor test. The cold pressor test has been used to study basic pain mechanisms and functional gut disorders[90].
MULTIMODAL APPROACH Five to ten years ago, the available probes did not possess the ability to produce more than a few of the above-mentioned stimuli. Some authors have combined mechanical and electrical stimuli[91,92], and others have used electrical stimuli combined with sensitization to acid[50]. The esophageal multimodal probe and its use in basic, pharmacological and clinical studies has been reviewed recently, and the reader is referred to Drewes et al[18]. Recently, the model has been used in basic science, including other gut segments such as the duodenum[62] and rectum[43]. We are currently using the multimodal rectal approach in pharmacological and clinical studies of functional and organic disorders. One limitation of multimodal pain stimulation in the gut is that it is done without visualization of the inside of the intestine. Hence, diseases such as esophageal erosions cannot be excluded. Recently, we have made an attempt to combine the multimodal probe with endoscopy, as illustrated in Figure 6, by passing a small (2.8 mm) video-endoscope into a multimodal probe, which allows mechanical, thermal and chemical stimulation. A schematic drawing of the probe is shown in Figure 6. As electrical stimulation can be done with electrodes attached at the biopsy forceps for the endoscope[48], the probe allows full multimodal stimulation including mucosal inspection and biopsies (albeit small) for histology and specific immunohistochemical staining. In diseases such as esophagitis, the TRPV1 receptor has been shown to be important[71] and the receptor also seems to play a role in sensation to heat and acid[93]. Hence, combined information about the sensory profile and histological findings may be important in evaluation of the pathogenesis in diseases. Theoretically, the endoscope can be replaced with an ultrasound probe that allows assessment of the gut wall and, therefore, can be used for advanced mechanical modeling[94].
CONCLUSION Over the last few years, the technical limitations of sensory testing in the GI tract have been increasingly surmounted. Multimodal esophageal, duodenal and rectal probes have been developed, which allow the investigator to use different stimulus modalities in the gut. The probes have proved to be robust across sessions, and have shown high reproducibility in all modalities. Future experiments using experimental testing will undoubtedly shed light on the pathogenesis of GI disorders, as well as assisting in finding new treatment modalities.
REFERENCES
1
Sandler RS, Stewart WF,
Liberman JN, Ricci JA, Zorich NL. Abdominal pain, bloating, and diarrhea in
the 2 Russo MW, Wei JT, Thiny MT, Gangarosa LM, Brown A, Ringel Y, Shaheen NJ, Sandler RS. Digestive and liver diseases statistics, 2004. Gastroenterology 2004; 126: 1448-1453 PubMed DOI 3 Bonica JJ. Anatomic and Physiologic Basis of Nociception and Pain. In: Bonica JJ, editor. The management of pain. Philidelphia: Lea and Febiger, 1990: 1186-1213 4 Giamberardino MA. Recent and forgotten aspects of visceral pain. Eur J Pain 1999; 3: 77-92 5 Giamberardino MA, De Laurentis S, Affaitati G, Lerza R, Lapenna D, Vecchiet L. Modulation of pain and hyperalgesia from the urinary tract by algogenic conditions of the reproductive organs in women. Neurosci Lett 2001; 304: 61-64 PubMed
6
Giamberardino MA. Visceral
Hyperalgesia. In: Devor M, Rowbotham MC, Wiesenfeld-Hallin Z, editors. Proc.9th World Congress on
Pain, Progr Pain Res
7
8 Foreman RD. Mechanisms of cardiac pain. Annu Rev Physiol 1999; 61: 143-167 PubMed DOI 9 Brinkert W, Dimcevski G, Arendt-Nielsen L, Drewes AM, Wilder-Smith OH. Dysmenorrhoea is associated with hypersensitivity in the sigmoid colon and rectum. Pain 2007; 132 Suppl 1: S46-S51 PubMed 10 Bielefeldt K, Christianson JA, Davis BM. Basic and clinical aspects of visceral sensation: transmission in the CNS. Neurogastroenterol Motil 2005; 17: 488-799 11 Olivar T, Laird JM. Differential effects of N-methyl-D-aspartate receptor blockade on nociceptive somatic and visceral reflexes. Pain 1999; 79: 67-73 PubMed DOI 12 Gebhart GF. Visceral pain-peripheral sensitisation. Gut 2000; 47 Suppl 4: iv54-iv55; discussion iv58 PubMed 13 Drewes AM, Gregersen H, Arendt-Nielsen L. Experimental pain in gastroenterology: a reappraisal of human studies. Scand J Gastroenterol 2003; 38: 1115-1130
14
Arendt-Nielsen L. Induction and Assessment of Experimental Pain From Human Skin, Muscle, and Viscera. In: Jensen TS,
Turner JA, Wiesenfeld-Hallin Z, editors. Proceedings of the 8th World
Congress of Pain, Progress in Pain Research and Management. 15 Andersen OK, Graven-Nielsen T, Matre D, Arendt-Nielsen L, Schomburg ED. Interaction between cutaneous and muscle afferent activity in polysynaptic reflex pathways: a human experimental study. Pain 2000; 84: 29-36 PubMed DOI
16
Sengupta
JN, Gebhart GF. Gastrointestinal Afferent Fibers and
Sensation. In: Johnson LR, editor. Physiology of the Gastrointestinal Tract.
3rd. 17 Curatolo M, Petersen-Felix S, Arendt-Nielsen L. Sensory assessment of regional analgesia in humans: a review of methods and applications. Anesthesiology 2000; 93: 1517-1530 PubMed DOI 18 Drewes AM, Arendt-Nielsen L, Funch-Jensen P, Gregersen H. Experimental human pain models in gastro-esophageal reflux disease and unexplained chest pain. World J Gastroenterol 2006; 12: 2806-2817 PubMed 19 Mertz H, Fullerton S, Naliboff B, Mayer EA. Symptoms and visceral perception in severe functional and organic dyspepsia. Gut 1998; 42: 814-822 PubMed 20 Bernstein CN, Niazi N, Robert M, Mertz H, Kodner A, Munakata J, Naliboff B, Mayer EA. Rectal afferent function in patients with inflammatory and functional intestinal disorders. Pain 1996; 66: 151-161 PubMed DOI 21 Munakata J, Naliboff B, Harraf F, Kodner A, Lembo T, Chang L, Silverman DH, Mayer EA. Repetitive sigmoid stimulation induces rectal hyperalgesia in patients with irritable bowel syndrome. Gastroenterology 1997; 112: 55-63 PubMed DOI 22 Drewes AM, Reddy H, Pedersen J, Funch-Jensen P, Gregersen H, Arendt-Nielsen L. Multimodal pain stimulations in patients with grade B oesophagitis. Gut 2006; 55: 926-932 PubMed 23 Dimcevski G, Schipper KP, Tage-Jensen U, Funch-Jensen P, Krarup AL, Toft E, Thorsgaard N, Arendt-Nielsen L, Drewes AM. Hypoalgesia to experimental visceral and somatic stimulation in painful chronic pancreatitis. Eur J Gastroenterol Hepatol 2006; 18: 755-764 PubMed DOI 24 Drewes AM, Gregersen H. Multimodal pain stimulation of the gastrointestinal tract. World J Gastroenterol 2006; 12: 2477-2486 PubMed 25 Hjelland IE, Hausken T, Svebak S, Olafsson S, Berstad A. Vagal tone and meal-induced abdominal symptoms in healthy subjects. Digestion 2002; 65: 172-176
26
Whitehead WE, Delvaux M.
Standardization of barostat procedures for testing smooth muscle tone and
sensory thresholds in the gastrointestinal tract. The Working Team of
Glaxo-Wellcome Research, 27 van der Schaar PJ, Lamers CB, Masclee AA. The role of the barostat in human research and clinical practice. Scand J Gastroenterol Suppl 1999; 230: 52-63 PubMed 28 Cremonini F, Houghton LA, Camilleri M, Ferber I, Fell C, Cox V, Castillo EJ, Alpers DH, Dewit OE, Gray E, Lea R, Zinsmeister AR, Whorwell PJ. Barostat testing of rectal sensation and compliance in humans: comparison of results across two centres and overall reproducibility. Neurogastroenterol Motil 2005; 17: 810-820 PubMed 29 Distrutti E, Azpiroz F, Soldevilla A, Malagelada JR. Gastric wall tension determines perception of gastric distention. Gastroenterology 1999; 116: 1035-1042 PubMed DOI 30 Camilleri M. Testing the sensitivity hypothesis in practice: tools and methods, assumptions and pitfalls. Gut 2002; 51 Suppl 1: i34-i40 31 Drewes AM, Schipper KP, Dimcevski G, Petersen P, Andersen OK, Gregersen H, Arendt-Nielsen L. Multi-modal induction and assessment of allodynia and hyperalgesia in the human oesophagus. Eur J Pain 2003; 7: 539-549 32 Gregersen H, Kassab G. Biomechanics of the gastrointestinal tract. Neurogastroenterol Motil 1996; 8: 277-297 PubMed 33 Gao C, Petersen P, Liu W, Arendt-Nielsen L, Drewes AM, Gregersen H. Sensory-motor responses to volume-controlled duodenal distension. Neurogastroenterol Motil 2002; 14: 365-374 PubMed DOI 34 Barlow JD, Gregersen H, Thompson DG. Identification of the biomechanical factors associated with the perception of distension in the human esophagus. Am J Physiol Gastrointest Liver Physiol 2002; 282: G683-G689 35 Drewes AM, Pedersen J, Liu W, Arendt-Nielsen L, Gregersen H. Controlled mechanical distension of the human oesophagus: sensory and biomechanical findings. Scand J Gastroenterol 2003; 38: 27-35 36 Petersen P, Gao C, Arendt-Nielsen L, Gregersen H, Drewes AM. Pain intensity and biomechanical responses during ramp-controlled distension of the human rectum. Dig Dis Sci 2003; 48: 1310-1316 37 Piessevaux H, Tack J, Wilmer A, Coulie B, Geubel A, Janssens J. Perception of changes in wall tension of the proximal stomach in humans. Gut 2001; 49: 203-208 PubMed 38 Thumshirn M, Camilleri M, Choi MG, Zinsmeister AR. Modulation of gastric sensory and motor functions by nitrergic and alpha2-adrenergic agents in humans. Gastroenterology 1999; 116: 573-585 PubMed DOI 39 Gregersen H, Christensen J. Gastrointestinal tone. Neurogastroenterol Motil 2000; 12: 501-508 40 Gregersen H, Stodkilde-Jorgensen H, Djurhuus JC, Mortensen SO. The four-electrode impedance technique: a method for investigation of compliance in luminal organs. Clin Phys Physiol Meas 1988; 9 Suppl A: 61-64 41 Gregersen H, Barlow J, Thompson D. Development of a computer-controlled tensiometer for real-time measurements of tension in tubular organs. Neurogastroenterol Motil 1999; 11: 109-118 PubMed DOI 42 Drewes AM, Schipper KP, Dimcevski G, Petersen P, Andersen OK, Gregersen H, Arendt-Nielsen L. Multimodal assessment of pain in the esophagus: a new experimental model. Am J Physiol Gastrointest Liver Physiol 2002; 283: G95-G103 PubMed 43 Brock C, Nissen TD, Gravesen FH, Frokjaer JB, Omar H, Gale J, Gregersen H, Svendsen O, Drewes AM. Multimodal sensory testing of the rectum and rectosigmoid: development and reproducibility of a new method. Neurogastroenterol Motil 2008; 20: 908-918 PubMed 44 Gregersen H, Gilja OH, Hausken T, Heimdal A, Gao C, Matre K, Odegaard S, Berstad A. Mechanical properties in the human gastric antrum using B-mode ultrasonography and antral distension. Am J Physiol Gastrointest Liver Physiol 2002; 283: G368-G375 45 Frokjaer JB, Liao D, Bergmann A, McMahon BP, Steffensen E, Drewes AM, Gregersen H. Three-dimensional biomechanical properties of the human rectum evaluated with magnetic resonance imaging. Neurogastroenterol Motil 2005; 17: 531-540 46 Frobert O, Arendt-Nielsen L, Bak P, Funch-Jensen P, Bagger JP. Oesophageal sensation assessed by electrical stimuli and brain evoked potentials--a new model for visceral nociception. Gut 1995; 37: 603-609 PubMed 47 Arendt-Nielsen L, Drewes AM, Hansen JB, Tage-Jensen U. Gut pain reactions in man: an experimental investigation using short and long duration transmucosal electrical stimulation. Pain 1997; 69: 255-262 PubMed DOI 48 Drewes AM, Arendt-Nielsen L, Jensen JH, Hansen JB, Krarup HB, Tage-Jensen U. Experimental pain in the stomach: a model based on electrical stimulation guided by gastroscopy. Gut 1997; 41: 753-757 PubMed 49 Drewes AM, Arendt-Nielsen L, Krarup HB, Hansen JB, Tage-Jensen U. Pain evoked by electrical stimulation of the prepyloric region of the stomach: cutaneous sensibility changes in the referred pain area. Pain Res Manag 1999; 4: 131-137
50
Sarkar S, Aziz Q, Woolf
CJ, 51 Hollerbach S, Tougas G, Frieling T, Enck P, Fitzpatrick D, Upton AR, Kamath MV. Cerebral evoked responses to gastrointestinal stimulation in humans. Crit Rev Biomed Eng 1997; 25: 203-242 52 Sami SA, Rossel P, Dimcevski G, Nielsen KD, Funch-Jensen P, Valeriani M, Arendt-Nielsen L, Drewes AM. Cortical changes to experimental sensitization of the human esophagus. Neuroscience 2006; 140: 269-279 53 Staahl C, Christrup LL, Andersen SD, Arendt-Nielsen L, Drewes AM. A comparative study of oxycodone and morphine in a multi-modal, tissue-differentiated experimental pain model. Pain 2006; 123: 28-36 PubMed DOI
54
Staahl C, Reddy H, 55 Drewes AM, Petersen P, Qvist P, Nielsen J, Arendt-Nielsen L. An experimental pain model based on electric stimulations of the colon mucosa. Scand J Gastroenterol 1999; 34: 765-771 PubMed 56 Su X, Gebhart GF. Mechanosensitive pelvic nerve afferent fibers innervating the colon of the rat are polymodal in character. J Neurophysiol 1998; 80: 2632-2644 PubMed 57 Handwerker HO, Kobal G. Psychophysiology of experi-mentally induced pain. Physiol Rev 1993; 73: 639-671 58 Tougas G, Hudoba P, Fitzpatrick D, Hunt RH, Upton AR. Cerebral-evoked potential responses following direct vagal and esophageal electrical stimulation in humans. Am J Physiol 1993; 264: G486-G491 59 Arendt-Nielsen L, Graven-Nielsen T, Svensson P, Jensen TS. Temporal summation in muscles and referred pain areas: an experimental human study. Muscle Nerve 1997; 20: 1311-1313 PubMed 60 Buscher HC, Wilder-Smith OH, van Goor H. Chronic pancreatitis patients show hyperalgesia of central origin: a pilot study. Eur J Pain 2006; 10: 363-370 PubMed DOI
61
Chan CL, Scott SM,
Birch MJ, Knowles CH, Williams NS, Lunniss PJ. Rectal heat thresholds: a
novel test of the sensory afferent pathway. Dis 62 Frokjaer JB, Andersen SD, Gale J, Arendt-Nielsen L, Gregersen H, Drewes AM. An experimental study of viscero-visceral hyperalgesia using an ultrasound-based multimodal sensory testing approach. Pain 2005; 119: 191-200 63 Drewes AM, Pedersen J, Reddy H, Rasmussen K, Funch-Jensen P, Arendt-Nielsen L, Gregersen H. Central sensitization in patients with non-cardiac chest pain: a clinical experimental study. Scand J Gastroenterol 2006; 41: 640-649 PubMed 64 Pedersen J, Reddy H, Funch-Jensen P, Arendt-Nielsen L, Gregersen H, Drewes AM. Cold and heat pain assessment of the human oesophagus after experimental sensitisation with acid. Pain 2004; 110: 393-399 PubMed DOI 65 Andersen OK, Gracely RH, Arendt-Nielsen L. Facilitation of the human nociceptive reflex by stimulation of A beta-fibres in a secondary hyperalgesic area sustained by nociceptive input from the primary hyperalgesic area. Acta Physiol Scand 1995; 155: 87-97 PubMed 66 Babenko VV, Graven-Nielsen T, Svensson P, Drewes AM, Jensen TS, Arendt-Nielsen L. Experimental human muscle pain induced by intramuscular injections of bradykinin, serotonin, and substance P. Eur J Pain 1999; 3: 93-102
67
Bernstein LM, 68 Tack JF. Chest Pain of Oesophageal Origin. In: Corazziari E, editor. Approach to the patient with chronic gastrointestinal disorders. 1st. Milano: Messaggi, 1999: 153-170 69 Fass R, Naliboff B, Higa L, Johnson C, Kodner A, Munakata J, Ngo J, Mayer EA. Differential effect of long-term esophageal acid exposure on mechanosensitivity and chemosensitivity in humans. Gastroenterology 1998; 115: 1363-1373 PubMed DOI 70 Hobson AR, Khan RW, Sarkar S, Furlong PL, Aziz Q. Development of esophageal hypersensitivity following experimental duodenal acidification. Am J Gastroenterol 2004; 99: 813-820 PubMed 71 Matthews PJ, Knowles CH, Chua YC, Delaney C, Hobson AR, Aziz Q. Effects of the concentration and frequency of acid infusion on the development and maintenance of esophageal hyperalgesia in a human volunteer model. Am J Physiol Gastrointest Liver Physiol 2008; 294: G914-G917 PubMed DOI 72 Louvel D, Delvaux M, Staumont G, Camman F, Fioramonti J, Bueno L, Frexinos J. Intracolonic injection of glycerol: a model for abdominal pain in irritable bowel syndrome? Gastroenterology 1996; 110: 351-361 PubMed DOI
73
Stürup GK. Visceral Pain. 74 Hertz AF. The sensibility of the alimentary tract in health and disease. Lancet 1911; 1: 1051-1056
75
Lim RK, Miller DG,
Guzman F, Rodgers DW, 76 Drewes AM, Schipper KP, Dimcevski G, Petersen P, Gregersen H, Funch-Jensen P, Arendt-Nielsen L. Gut pain and hyperalgesia induced by capsaicin: a human experimental model. Pain 2003; 104: 333-341 PubMed DOI 77 Hammer J, Vogelsang H. Characterization of sensations induced by capsaicin in the upper gastrointestinal tract. Neurogastroenterol Motil 2007; 19: 279-287 PubMed 78 Lee KJ, Vos R, Tack J. Effects of capsaicin on the sensorimotor function of the proximal stomach in humans. Aliment Pharmacol Ther 2004; 19: 415-425 PubMed DOI 79 Arendt-Nielsen L, Svensson P, Sessle BJ, Cairns BE, Wang K. Interactions between glutamate and capsaicin in inducing muscle pain and sensitization in humans. Eur J Pain 2008; 12: 661-670 PubMed DOI 80 Rong W, Hillsley K, Davis JB, Hicks G, Winchester WJ, Grundy D. Jejunal afferent nerve sensitivity in wild-type and TRPV1 knockout mice. J Physiol 2004; 560: 867-881 PubMed DOI 81 Tack J. Chemosensitivity of the human gastrointestinal tract in health and in disease. Neurogastroenterol Motil 2007; 19: 241-244 PubMed DOI 82 Drewes AM, Reddy H, Staahl C, Funch-Jensen P, Arendt-Nielsen L, Gregersen H, Lundbye-Christensen S. Statistical modeling of the response characteristics of mechanosensitive stimuli in the human esophagus. J Pain 2005; 6: 455-462 83 Olesen AE, Staahl C, Arendt-Nielsen L, Drewes AM. Perfusion of the oesophagus with capsaicin and acid: a new human experimental pain model of visceral hyperalgesia. In: Abstracts of the 12th World Congress on Pain, International Association for the Study of Pain (IASP), 17-22 August 2008, Glasgow, Scotland [CD-ROM] 84 Brock C, Andresen T, Frøkjær J, Gale J, Arendt-Nielsen L, Drewes A. Central sensitization: induction of rectal hypersensitivity and activation of diffuse noxious inhibitory control (DNIC) following oesophageal acid and capsaicin infusion. In: Abstracts of the 12th World Congress on Pain, International Association for the Study of Pain (IASP), 17-22 August 2008, Glasgow, Scotland [CD-ROM]
85
Lewis T. Pain. 86 Mitchell LA, MacDonald RA, Brodie EE. Temperature and the cold pressor test. J Pain 2004; 5: 233-237 PubMed DOI 87 Le Bars D. The whole body receptive field of dorsal horn multireceptive neurones. Brain Res Brain Res Rev 2002; 40: 29-44 PubMed 88 Millan MJ. Descending control of pain. Prog Neurobiol 2002; 66: 355-474 PubMed 89 Calvino B, Grilo RM. Central pain control. Joint Bone Spine 2006; 73: 10-16 PubMed DOI 90 Wilder-Smith CH, Schindler D, Lovblad K, Redmond SM, Nirkko A. Brain functional magnetic resonance imaging of rectal pain and activation of endogenous inhibitory mechanisms in irritable bowel syndrome patient subgroups and healthy controls. Gut 2004; 53: 1595-1601 PubMed 91 Accarino AM, Azpiroz F, Malagelada JR. Symptomatic responses to stimulation of sensory pathways in the jejunum. Am J Physiol 1992; 263: G673-G677 PubMed 92 Hollerbach S, Hudoba P, Fitzpatrick D, Hunt R, Upton AR, Tougas G. Cortical evoked responses following esophageal balloon distension and electrical stimulation in healthy volunteers. Dig Dis Sci 1998; 43: 2558-2566 PubMed 93 Matthews PJ, Aziz Q, Facer P, Davis JB, Thompson DG, Anand P. Increased capsaicin receptor TRPV1 nerve fibres in the inflamed human oesophagus. Eur J Gastroenterol Hepatol 2004; 16: 897-902 PubMed DOI 94 Frokjaer JB, Andersen SD, Drewes AM, Gregersen H. Ultrasound-determined geometric and biomechanical properties of the human duodenum. Dig Dis Sci 2006; 51: 1662-1669 PubMed DOI
S- Editor Li LF L- Editor Kerr C E- Editor Ma WH
| |||
|
|
