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Abstract
Gastrointestinal (GI) pain - a form of visceral pain - is common in some disorders, such as irritable bowel syndrome, Crohn's disease and pancreatitis. However, identifying the cause of GI pain frequently represents a diagnostic challenge as the clinical presentation is often blurred by concomitant autonomic and somatic symptoms. In addition, GI pain can be nociceptive, neuropathic and associated with cancer, but in many cases multiple aetiologies coexist in an individual patient. Mechanisms of GI pain are complex and include both peripheral and central sensitization and the involvement of the autonomic nervous system, which has a role in generating the symptoms that frequently accompany pain. Treatment of GI pain depends on the precise type of pain and the primary disorder in the patient but can include, for example, pharmacological therapy, cognitive behavioural therapies, invasive surgical procedures, endoscopic procedures and lifestyle alterations. Owing to the major differences between organ involvement, disease mechanisms and individual factors, treatment always needs to be personalized and some data suggest that phenotyping and subsequent individual management of GI pain might be options in the future.
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Kaddumi EG. Effect of distal esophageal irritation on the changes of cystometry parameters to esophagus and colon distentions in rats. Can J Physiol Pharmacol 2019; 97:766-772. [PMID: 31013433 DOI: 10.1139/cjpp-2019-0122] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
The coexistence of different visceral pathologies in patients suffering from irritable bowel syndrome, interstitial cystitis, and other pathologies, necessitates the study of these pathologies under complicated conditions. In the present study, cystometry recordings were used to investigate the effect of distal esophageal chemical irritation on the urinary bladder interaction with distal colon distention, distal esophageal distention, and electrical stimulation of abdominal branches of vagus nerve. Distal esophageal chemical irritation significantly decreased the intercontraction time via decreasing the voiding time. Also, distal esophageal chemical irritation significantly decreased the pressure amplitude by decreasing the maximum pressure. Following distal esophageal chemical irritation, distal esophageal distention was able to significantly decrease the intercontraction time by decreasing the storage time. However, 3 mL distal colon distention significantly increased the intercontraction time by increasing the storage time. On the other hand, following distal esophageal chemical irritation, electrical stimulation of abdominal branches of vagus nerve did not have any significant effect on intercontraction time. However, electrical stimulation of abdominal branches of vagus nerve significantly increased the pressure amplitude by increasing the maximum pressure. The results of this study demonstrate that urinary bladder function and interaction of bladder with other viscera can be affected by chemical irritation of distal esophagus.
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Affiliation(s)
- Ezidin G Kaddumi
- Department of Basic Medical Sciences, Faculty of Medicine, Al-Balqa Applied University, Al-Salt, Jordan.,Department of Basic Medical Sciences, Faculty of Medicine, Al-Balqa Applied University, Al-Salt, Jordan
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Changes in responses of neurons in spinal and medullary subnucleus reticularis dorsalis to acupoint stimulation in rats with visceral hyperalgesia. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2014; 2014:768634. [PMID: 25525449 PMCID: PMC4262754 DOI: 10.1155/2014/768634] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/06/2014] [Accepted: 09/23/2014] [Indexed: 12/29/2022]
Abstract
The purpose of this study was to explore the mechanism of acupoints sensitization phenomenon at the spinal and medulla levels. Experiments were performed on adult male Sprague-Dawley rats and visceral noxious stimuli was generated by colorectal distension (CRD). The activities of wide dynamic range (WDR) and subnucleus reticularis dorsalis (SRD) neurons were recorded. The changes of the reactions of WDR and SRD neurons to electroacupuncture (EA) on acupoints of “Zusanli-Shangjuxu” before and after CRD stimulation were observed. The results showed that visceral nociception could facilitate the response of neurons to acupoints stimulation. In spinal dorsal horn, EA-induced activation of WDR neurons further increased to 106.84 ± 17.33% (1.5 mA) (P < 0.001) and 42.27 ± 13.10% (6 mA) (P < 0.01) compared to the neuronal responses before CRD. In medulla oblongata, EA-induced activation of SRD neurons further increased to 63.28 ± 15.96% (1.5 mA) (P < 0.001) and 25.02 ± 7.47% (6 mA) (P < 0.01) compared to that before CRD. Taken together, these data suggest that the viscerosomatic convergence-facilitation effect of WDR and SRD neurons may underlie the mechanism of acupoints sensitization. But the sensitizing effect of visceral nociception on WDR neurons is stronger than that on SRD neurons.
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McCormick Z, Bouffard KJ, Neudorf D, Casey E. A mediastinal mass presenting with unilateral periscapular and arm pain. PM R 2014; 6:560-3. [PMID: 24412635 DOI: 10.1016/j.pmrj.2013.11.012] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2013] [Revised: 11/12/2013] [Accepted: 11/14/2013] [Indexed: 11/28/2022]
Abstract
We describe a case of a patient with mediastinal lymphoma who presented with arm and scapular pain, which is an atypical referral pattern for pain originating from the mediastinum. We use this case as a platform to discuss mediastinal pain referral patterns and the importance of maintaining a broad differential diagnosis of arm and scapular pain, especially when symptoms atypical of pure neuromusculoskeletal structural disease are present.
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Affiliation(s)
- Zack McCormick
- Department of Physical Medicine and Rehabilitation, Rehabilitation Institute of Chicago, 345 East Superior St, Chicago, IL 60611(∗).
| | - Karina J Bouffard
- Physical Medicine and Rehabilitation/Pain Medicine Rehabilitation Institute of Chicago, Chicago, IL (ad interim)(†)
| | - Daniel Neudorf
- Chicago College of Osteopathic Medicine, Midwestern University, Chicago, IL(‡)
| | - Ellen Casey
- Department of Physical Medicine and Rehabilitation, Rehabilitation Institute of Chicago, Chicago, IL(§)
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A systematic review of the evidence for central nervous system plasticity in animal models of inflammatory-mediated gastrointestinal pain. Inflamm Bowel Dis 2014; 20:176-95. [PMID: 24284415 DOI: 10.1097/01.mib.0000437499.52922.b1] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND Abdominal pain frequently accompanies inflammatory disorders of the gastrointestinal tract (GIT), and animal models of GIT inflammation have been developed to explore the role of the central nervous system (CNS) in this process. Here, we summarize the evidence from animal studies for CNS plasticity following GIT inflammation. METHODS A systematic review was conducted to identify studies that: (1) used inflammation of GIT organs, (2) assessed pain or visceral hypersensitivity, and (3) presented evidence of CNS involvement. Two hundred and eight articles were identified, and 79 were eligible for analysis. RESULTS Rats were most widely used (76%). Most studies used adult animals (42%) with a bias toward males (74%). Colitis was the most frequently used model (78%) and 2,4,6-trinitrobenzenesulfonic acid the preferred inflammatory agent (33%). Behavioral (58%), anatomical/molecular (44%), and physiological (24%) approaches were used alone or in combination to assess CNS involvement during or after GIT inflammation. Measurement times varied widely (<1 h-> 2 wk after inflammation). Blinded outcomes were used in 42% studies, randomization in 10%, and evidence of visceral inflammation in 54%. Only 3 studies fulfilled our criteria for high methodological quality, and no study reported sample size calculations. CONCLUSIONS The included studies provide strong evidence for CNS plasticity following GIT inflammation, specifically in the spinal cord dorsal horn. This evidence includes altered visceromotor responses and indices of referred pain, elevated neural activation and peptide content, and increased neuronal excitability. This evidence supports continued use of this approach for preclinical studies; however, there is substantial scope to improve study design.
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Visceral nociceptive afferent facilitates reaction of subnucleus reticularis dorsalis to acupoint stimulation in rats. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2013; 2013:931283. [PMID: 23762171 PMCID: PMC3671227 DOI: 10.1155/2013/931283] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/22/2013] [Revised: 04/18/2013] [Accepted: 04/23/2013] [Indexed: 02/02/2023]
Abstract
Objective. To explore the area and sensitization variance of acupoint when internal organs are under pathological condition. To observe quantity-effect variance of subnucleus reticularis dorsalis (SRD) to electroacupuncture under both physiological and pathological conditions. To explain medulla oblongata mechanism of acupoint sensitization. Method. Mustard oil was imported into colon and rectum of 20 male SD rats in order to observe its influence on acupoint sensitization. SRD neuron activity was recorded. Visceral nociceptive stimulus was generated by colorectal distension (CRD). Quantity-effect variance of neuron activity to electroacupuncture to “Zusanli-Shangjuxu” area both before and after CRD was observed. Paired t-test is used for cross-group comparison; P < 0.05 is deemed as of statistical differences. Result. Visceral inflammation could facilitate SRD neuron activity to acupoint stimulation. Visceral nociceptive afference could enhance neuron activity to acupoint acupuncture. Wide dynamic range (WDR) neuron activity caused by electroacupuncture increased when visceral nociception increased. Conclusion. The size and function of the acupoints comply with the functionality of the internal organs. The sensitive degree of acupoints changed according to malfunction of internal organs.
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Szczesniak MM, Fuentealba SE, Zhang T, Cook IJ. Modulation of esophageal afferent pathways by 5-HT3 receptor inhibition. Neurogastroenterol Motil 2013; 25:383-8, e293. [PMID: 23360084 DOI: 10.1111/nmo.12074] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
BACKGROUND The study aims were to investigate whether neural pathways involving 5-HT3 receptors mediate: (i) distension-induced upper esophageal sphincter (UES) relaxation reflex, (ii) esophageal sensitivity to acid and electrical stimuli, and (iii) viserosomatic sensitization following acid exposure. METHODS In Study I, in a double-blind crossover trial (n = 9) esophageal sensory and pain thresholds to electrical stimulation were measured in the esophagus, midsternum, and the foot, before subjects were randomized to receive either Ondansetron (8 mg i.v.) or NaCl (0.9% w/v). HCl (0.15 mol L(-1)) was then infused into distal esophagus and electrical thresholds were reassessed. Following electrical sensory threshold testing, subjects received a second esophageal infusion of HCl to evaluate esophageal sensitivity to acid. In Study II (N = 10), frequencies of distension-induced UES relaxation responses were scored before and after treatment with Ondansetron and NaCl in a double-blind crossover trial. KEY RESULTS In Study I, ondansetron had no effect on esophageal sensitivity to HCl or acid-induced sensitization. However, blockade of 5-HT3 receptors did reduce midsternum somatic pain thresholds. Sixty minutes after esophageal acid exposure, pain thresholds were significantly lower in the ondansetron arm (mean Δ-1.36 ± 0.4 mA) when compared with NaCl (mean Δ-0.14 ± 0.58 mA) (P < 0.05). In Study II, 5-HT3 receptor blockade had no significant effect on UES relaxation reflex. CONCLUSIONS & INFERENCES This study does not support the hypothesis that in health, 5-HT3 receptors play a significant role in esophago-UES distention-induced relaxation reflex and esophageal sensitivity to acid or electrical stimulation. It does provide new evidence for involvement of 5-HT3 receptors in viscerosomatic sensitization.
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Affiliation(s)
- M M Szczesniak
- Department of Gastroenterology, St George Hospital, University of New South Wales, Sydney, NSW, Australia.
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Abstract
The primary role of the esophagus is to propel swallowed food or fluid into the stomach and to prevent or clear gastroesophageal reflux. This function is achieved by an organized pattern that involves a sensory pathway, neural reflexes, and a motor response that includes esophageal tone, peristalsis, and shortening. The motor function of the esophagus is controlled by highly complex voluntary and involuntary mechanisms. There are three different functional areas in the esophagus: the upper esophageal sphincter, the esophageal body, and the LES. This article focused on anatomy and physiology of the esophageal body.
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Affiliation(s)
- E Yazaki
- Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
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Meng QW, Xu SC. Advances in research of esophageal visceral hypersensitivity. Shijie Huaren Xiaohua Zazhi 2012; 20:568-573. [DOI: 10.11569/wcjd.v20.i7.568] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Gastroesophageal reflux disease (GERD) is a common disorder that is often associated with unpleasant symptoms requiring utilization of health care resource. Both animal and clinical studies suggest that a variety of receptors on afferent nerves sensitized upon exposure to acid increase afferent input to the spinal cord dorsal horn neurons and lead to a reduction in threshold of these neurons together with an increase in their receptive field. This increased sensitivity of primary afferent nerves is described as peripheral sensitization, whereas the consequent increase in sensitivity of the spinal dorsal horn neurons is described as central sensitization. Once these mechanisms have been established, they can cause a long-term increase in sensitivity of tissues to previously innocuous stimuli. Furthermore, psychological stress and mechanical stimulation both have been shown to increase DIS and may therefore facilitate peripheral sensitization. Currently peripheral and central sensitizations are considered to be important mechanisms of esophageal pain hypersensitivity and occurrence of symptoms to even physiological amounts of acid. In these patients treatments aimed at reducing neuronal sensitivity may be effective. This article mainly focuses on the recent advances in research of esophageal visceral hypersensitivity.
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Brock C, Andresen T, Frøkjaer JB, Gale J, Olesen AE, Arendt-Nielsen L, Drewes AM. Central pain mechanisms following combined acid and capsaicin perfusion of the human oesophagus. Eur J Pain 2012; 14:273-81. [DOI: 10.1016/j.ejpain.2009.05.013] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2009] [Revised: 05/12/2009] [Accepted: 05/24/2009] [Indexed: 12/13/2022]
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The pain system in oesophageal disorders: mechanisms, clinical characteristics, and treatment. Gastroenterol Res Pract 2011; 2011:910420. [PMID: 21826137 PMCID: PMC3150142 DOI: 10.1155/2011/910420] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2011] [Accepted: 05/23/2011] [Indexed: 12/14/2022] Open
Abstract
Pain is common in gastroenterology. This review aims at giving an overview of pain mechanisms, clinical features, and treatment options in oesophageal disorders. The oesophagus has sensory receptors specific for different stimuli. Painful stimuli are encoded by nociceptors and communicated via afferent nerves to the central nervous system. The pain stimulus is further processed and modulated in specific pain centres in the brain, which may undergo plastic alterations. Hence, tissue inflammation and long-term exposure to pain can cause sensitisation and hypersensitivity. Oesophageal sensitivity can be evaluated ,for example, with the oesophageal multimodal probe. Treatment should target the cause of the patient's symptoms. In gastro-oesophageal reflux diseases, proton pump inhibitors are the primary treatment option, surgery being reserved for patients with severe disease resistant to drug therapy. Functional oesophageal disorders are treated with analgesics, antidepressants, and psychological therapy. Lifestyle changes are another option with less documentation.
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Chua YC, Aziz Q. Perception of gastro-oesophageal reflux. Best Pract Res Clin Gastroenterol 2010; 24:883-91. [PMID: 21126701 DOI: 10.1016/j.bpg.2010.10.003] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2010] [Accepted: 10/08/2010] [Indexed: 01/31/2023]
Abstract
Gastro-oesophageal reflux disease (GORD) is common and often associated with unpleasant symptoms requiring utilisation of health care resource. While in the majority of patients symptom resolution occurs with acid suppressant therapy, in a proportion this treatment is ineffective in resolving symptoms. This is particularly the case in patients with non-erosive reflux disease (NERD) and functional heartburn (FH). It is increasingly being recognised that the presence of acid in the oesophagus can cause dilated intercellular spaces (DIS) which increases the exposure of the sub-epithelial nerves to the acid. Experimental studies in both animals and humans suggest that a variety of receptors on afferent nerves can be sensitised upon exposure to acid so that there is increased afferent input to the spinal cord dorsal horn neurons which leads to a reduction in threshold of these neurons together with an increase in their receptive field. This increased sensitivity of primary afferent nerves is described as peripheral sensitisation, whereas the consequent increase in sensitivity of the spinal dorsal horn neurons is described as central sensitisation. Once these mechanisms have been established they can cause a long term increase in sensitivity of tissues to previously innocuous stimuli. Furthermore, psychological stress has been shown to increase DIS and may therefore facilitate peripheral sensitisation. Currently peripheral and central sensitisations are considered to be important mechanisms of oesophageal pain hypersensitivity and occurrence of symptoms to even physiological amounts of acid. In these patients treatments aimed at reducing neuronal sensitivity may be effective in the management.
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Affiliation(s)
- Y C Chua
- Blizard Institute of Cell and Molecular Science, University of London, UK
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Qin C, Malykhina AP, Thompson AM, Farber JP, Foreman RD. Cross-organ sensitization of thoracic spinal neurons receiving noxious cardiac input in rats with gastroesophageal reflux. Am J Physiol Gastrointest Liver Physiol 2010; 298:G934-42. [PMID: 20378832 PMCID: PMC3774335 DOI: 10.1152/ajpgi.00312.2009] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Gastroesophageal reflux (GER) frequently triggers or worsens cardiac pain or symptoms in patients with coronary heart disease. This study aimed to determine whether GER enhances the activity of upper thoracic spinal neurons receiving noxious cardiac input. Gastric fundus and pyloric ligations as well as a longitudinal myelotomy at the gastroesophageal junction induced acute GER in pentobarbital-anesthetized, paralyzed, and ventilated male Sprague-Dawley rats. Manual manipulations of the stomach and lower esophagus were used as surgical controls in another group. At 4-9 h after GER surgery, extracellular potentials of single neurons were recorded from the T3 spinal segment. Intrapericardial bradykinin (IB) (10 microg/ml, 0.2 ml, 1 min) injections were used to activate cardiac nociceptors, and esophageal distensions were used to activate esophageal afferent fibers. Significantly more spinal neurons in the GER group responded to IB compared with the control group (69.1 vs. 38%, P < 0.01). The proportion of IB-responsive neurons in the superficial laminae of GER animals was significantly different from those in deeper layers (1/8 vs. 46/60, P < 0.01); no difference was found in control animals (7/25 vs. 20/46, P > 0.05). Excitatory responses of spinal neurons to IB in the GER group were greater than in the control group [32.4 +/- 3.5 impulses (imp)/s vs. 13.3 +/- 2.3 imp/s, P < 0.01]. Forty-five of 47 (95.7%) neurons responded to cardiac input and ED, which was higher than the control group (61.5%, P < 0.01). These results indicate that acute GER enhanced the excitatory responses of thoracic spinal neurons in deeper laminae of the dorsal horn to noxious cardiac stimulus.
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Affiliation(s)
- Chao Qin
- Department of Physiology, University of Oklahoma Health Sciences Center, P.O. Box 26901, Oklahoma City, OK 73190, USA.
| | - Anna P. Malykhina
- 2Department of Surgery, University of Pennsylvania School of Medicine, Glenolden, Pennsylvania
| | - Ann M. Thompson
- 3Department of Otorhinolaryngology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; and
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Brumovsky P, Gebhart G. Visceral organ cross-sensitization - an integrated perspective. Auton Neurosci 2010; 153:106-15. [PMID: 19679518 PMCID: PMC2818077 DOI: 10.1016/j.autneu.2009.07.006] [Citation(s) in RCA: 86] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2009] [Revised: 07/09/2009] [Accepted: 07/10/2009] [Indexed: 12/12/2022]
Abstract
Viscero-somatic referral and sensitization has been well documented clinically and widely investigated, whereas viscero-visceral referral and sensitization (termed cross-organ sensitization) has only recently received attention as important to visceral disease states. Because second order neurons in the CNS have been extensively shown to receive convergent input from different visceral organs, it has been assumed that cross-organ sensitization arises by the same convergence-projection mechanism as advanced for viscero-somatic referral and sensitization. However, increasing evidence also suggests participation of peripheral mechanisms to explain referral and sensitization. We briefly summarize behavioral, morphological and physiological support of and focus on potential mechanisms underlying cross-organ sensitization.
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Affiliation(s)
- P.R. Brumovsky
- Pittsburgh Center for Pain Research, Department of Anesthesiology, University of Pittsburgh, Pittsburgh, Pennsylvania
- Faculty of Biomedical Sciences, Austral University, Buenos Aires, Argentina
| | - G.F. Gebhart
- Pittsburgh Center for Pain Research, Department of Anesthesiology, University of Pittsburgh, Pittsburgh, Pennsylvania
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Banerjee B, Medda BK, Schmidt J, Zheng Y, Zhang Z, Shaker R, Sengupta JN. Altered expression of P2X3 in vagal and spinal afferents following esophagitis in rats. Histochem Cell Biol 2009; 132:585-97. [PMID: 19784665 DOI: 10.1007/s00418-009-0639-4] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/02/2009] [Indexed: 11/28/2022]
Abstract
Purinergic P2X(3) receptors are predominantly expressed in small diameter primary afferent neurons and activation of these receptors by adenosine triphosphate is reported to play an important role in nociceptive signaling. The objective of this study was to investigate the expression of P2X(3) receptors in spinal and vagal sensory neurons and esophageal tissues following esophagitis in rats. Two groups of rats were used including 7 days fundus-ligated (7D-ligated) esophagitis and sham-operated controls. Esophagitis was produced by ligating the fundus and partial obstruction of pylorus that initiated reflux of gastric contents. The sham-operated rats underwent midline incision without surgical manipulation of the stomach. Expressions of P2X(3) receptors in thoracic dorsal root ganglia (DRGs), nodose ganglia (NGs), and esophageal tissues were evaluated by RT-PCR, western blot and immunohistochemistry. Esophageal neurons were identified by retrograde transport of Fast Blue from the esophagus. There were no significant differences in P2X(3) mRNA expressions in DRGs (T1-T3) and NGs between 7D-ligated and sham-operated rats. However, there was an upregulation of P2X(3) mRNA in DRGs (T6-T12) and in the esophageal muscle. At protein level, P2X(3) exhibited significant upregulation both in DRGs and in NGs of rats having chronic esophagitis. Immunohistochemical analysis exhibited a significant increase in P2X(3) and TRPV1 co-expression in DRGs and NGs in 7D-ligated rats compared to sham-operated rats. The present findings suggest that chronic esophagitis results in upregulation of P2X(3) and its co-localization with TRPV1 receptor in vagal and spinal afferents. Changes in P2X(3) expression in vagal and spinal sensory neurons may contribute to esophageal hypersensitivity following acid reflux-induced esophagitis.
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Affiliation(s)
- Banani Banerjee
- Division of Gastroenterology and Hepatology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
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van den Elzen BDJ, Tytgat GNJ, Boeckxstaens GEE. Gastric hypersensitivity induced by oesophageal acid infusion in healthy volunteers. Neurogastroenterol Motil 2009; 21:160-9. [PMID: 18713312 DOI: 10.1111/j.1365-2982.2008.01172.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Distal oesophageal acid exposure has been shown to increase visceral sensitivity of the proximal oesophagus via central sensitization. Here we evaluated whether acidification of the distal oesophagus also affects the sensorimotor function of the proximal stomach. A gastric barostat study combined with a 30-min acid (HCl 0.15 mol L(-1)) or saline infusion in the distal oesophagus was performed in 18 healthy volunteers. Gastric and cutaneous sensitivity was assessed before and up to 2 h after the start of infusion. Directly after acid infusion, but not after saline, the threshold for discomfort decreased (-6.4 +/- 1.7 vs 0.4 +/- 0.4 mmHg; P = 0.028) and distension-induced symptoms increased significantly compared with the baseline (122 +/- 49% vs -3 +/- 9%). Cutaneous sensitivity remained unaffected by acid infusion. In contrast, when the infused liquid was aspirated 3 cm more distally, at the level of the lower oesophageal sphincter, the effect of acid infusion on gastric sensitivity was abolished and the increase in distension-induced symptoms was reduced (61 +/- 24%). Distal oesophageal acid infusion induces visceral hypersensitivity without affecting somatic sensitivity arguing against a similar mechanism of central sensitization as observed in non-cardiac chest pain. As reduction of the acid load to the stomach prevented this effect, our findings indicate that either gastric and/or duodenal acidification is involved. It should be emphasized though that aspiration from distal oesophagus may have attenuated the effect by reducing the acid-exposed area or by reducing the contact time.
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Affiliation(s)
- B D J van den Elzen
- Department of Gastroenterology and Hepatology, Academic Medical Centre, Amsterdam, The Netherlands
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Qin C, Ghorbani MLM, Wu M, Farber JP, Ma J, Foreman RD. Characterization of upper thoracic spinal neurons responding to esophageal distension in diabetic rats. Auton Neurosci 2009; 145:27-34. [PMID: 19027368 PMCID: PMC2658770 DOI: 10.1016/j.autneu.2008.10.015] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2008] [Accepted: 10/10/2008] [Indexed: 01/11/2023]
Abstract
The aim of this study was to examine spinal neuronal processing of innocuous and noxious mechanical inputs from the esophagus in diabetic rats. Streptozotocin (50 mg/kg, ip) was used to induce diabetes in 15 male Sprague-Dawley rats, and vehicle (10 mM citrate buffer) was injected into 15 rats as control. Four to eleven weeks after injections, extracellular potentials of single thoracic (T3) spinal neurons were recorded in pentobarbital anesthetized, paralyzed, and ventilated rats. Esophageal distensions (ED, 0.2, 0.4 ml, 20 s) were produced by water inflation of a latex balloon in the thoracic esophagus. Noxious ED (0.4 ml, 20 s) altered activity of 44% (55/126) and 38% (50/132) of spinal neurons in diabetic and control rats, respectively. The short-lasting excitatory responses to ED were encountered more frequently in diabetic rats (27/42 vs 15/41, P<0.05). Spinal neurons with low threshold for excitatory responses to ED were more frequently encountered in diabetic rats (33/42 vs 23/41, P<0.05). However, mean excitatory responses and duration of responses to noxious ED were significantly reduced for high-threshold neurons in diabetic rats (7.4+/-1.1 vs 13.9+/-3.3 imp/s; 19.0+/-2.3 vs 31.2+/-5.5 s; P<0.05). In addition, more large size somatic receptive fields were found for spinal neurons with esophageal input in diabetic rats than in control rats (28/42 vs 19/45, P<0.05). These results suggested that diabetes influenced response characteristics of thoracic spinal neurons receiving mechanical esophageal input, which might indicate an altered spinal visceroceptive processing underlying diabetic esophageal neuropathy.
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Affiliation(s)
- Chao Qin
- Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73190, USA.
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Basic and clinical aspects of gastrointestinal pain. Pain 2009; 141:191-209. [PMID: 19155134 DOI: 10.1016/j.pain.2008.12.011] [Citation(s) in RCA: 110] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2008] [Revised: 09/29/2008] [Accepted: 12/03/2008] [Indexed: 12/12/2022]
Abstract
The gastrointestinal (GI) tract is a system of organs within multicellular animals which facilitates the ingestion, digestion, and absorption of food with subsequent defecation of waste. A complex arrangement of nerves and ancillary cells contributes to the sensorimotor apparatus required to subserve such essential functions that are with the exception of the extreme upper and lower ends of the GI tract normally subconscious. However, it also has the potential to provide conscious awareness of injury. Although this function can be protective, when dysregulated, particularly on a chronic basis, the same system can lead to considerable morbidity. The anatomical and molecular basis of gastrointestinal nociception, conditions associated with chronic unexplained visceral pain, and developments in treatment are presented in this review.
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Banerjee B, Medda BK, Zheng Y, Miller H, Miranda A, Sengupta JN, Shaker R. Alterations in N-methyl-D-aspartate receptor subunits in primary sensory neurons following acid-induced esophagitis in cats. Am J Physiol Gastrointest Liver Physiol 2009; 296:G66-77. [PMID: 18974310 PMCID: PMC2636931 DOI: 10.1152/ajpgi.90419.2008] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
The excitatory amino acid glutamate plays an important role in the development of neuronal sensitization and the ionotropic N-methyl-d-aspartate receptor (NMDAR) is one of the major receptors involved. The objective of this study was to use a cat model of gastroesophageal reflux disease (GERD) to investigate the expression of the NR1 and NR2A subunits of NMDAR in the vagal and spinal afferent fibers innervating the esophagus. Two groups of cats (Acid-7D and PBS-7D) received 0.1 N HCl (pH 1.2) or 0.1 M PBS (pH 7.4) infusion in the esophagus (1 ml/min for 30 min/day for 7 days), respectively. NR1 splice variants (both NH(2) and COOH terminals) and NR2A in the thoracic dorsal root ganglia (DRGs), nodose ganglia (NGs), and esophagus were evaluated by RT-PCR, Western blot, and immunohistochemistry. Acid produced marked inflammation and a significant increase in eosinophil peroxidase and myeloperoxidase contents compared with PBS-infused esophagus. The NR1-4 splice variant gene exhibited a significant upregulation in DRGs and esophagus after acid infusion. In DRGs, NGs, and esophagus, acid infusion resulted in significant upregulation of NR1 and downregulation of NR2A subunit gene expression. A significant increase in NR1 polypeptide expression was observed in DRGs and NGs from Acid-7D compared with control. In conclusion, long-term acid infusion in the cat esophagus resulted in ulcerative esophagitis and differential expressions of NR1 and NR2A subunits. It is possible that these changes may in part contribute to esophageal hypersensitivity observed in reflux esophagitis.
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Affiliation(s)
- Banani Banerjee
- Division of Gastroenterology and Hepatology and Division of Pediatric Gastroenterology, Hepatology and Nutrition, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Bidyut K. Medda
- Division of Gastroenterology and Hepatology and Division of Pediatric Gastroenterology, Hepatology and Nutrition, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Yue Zheng
- Division of Gastroenterology and Hepatology and Division of Pediatric Gastroenterology, Hepatology and Nutrition, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Heather Miller
- Division of Gastroenterology and Hepatology and Division of Pediatric Gastroenterology, Hepatology and Nutrition, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Adrian Miranda
- Division of Gastroenterology and Hepatology and Division of Pediatric Gastroenterology, Hepatology and Nutrition, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Jyoti N. Sengupta
- Division of Gastroenterology and Hepatology and Division of Pediatric Gastroenterology, Hepatology and Nutrition, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Reza Shaker
- Division of Gastroenterology and Hepatology and Division of Pediatric Gastroenterology, Hepatology and Nutrition, Medical College of Wisconsin, Milwaukee, Wisconsin
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21
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Lipopolysaccharide-Induced Upregulation of Tumor Necrosis Factor-α (TNF-α) in Rat Spinal Cord. Inflammation 2008; 31:336-43. [DOI: 10.1007/s10753-008-9083-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
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22
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Shen A, Zhou D, Shen Q, Liu HO, Sun L, Liu Y, Chen J, Yang J, Ji Y, Cheng C. The Expression of Tumor Necrosis Factor-α (TNF-α) by the Intrathecal Injection of Lipopolysaccharide in the Rat Spinal Cord. Neurochem Res 2008; 34:333-41. [DOI: 10.1007/s11064-008-9780-z] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2008] [Accepted: 06/10/2008] [Indexed: 12/11/2022]
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Drewes AM, Gratkowski M, Sami SAK, Dimcevski G, Funch-Jensen P, Arendt-Nielsen L. Is the pain in chronic pancreatitis of neuropathic origin? Support from EEG studies during experimental pain. World J Gastroenterol 2008; 14:4020-7. [PMID: 18609686 PMCID: PMC2725341 DOI: 10.3748/wjg.14.4020] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To prove the hypothesis that patients with chronic pancreatitis would show increased theta activity during painful visceral stimulation.
METHODS: Eight patients and 12 healthy controls underwent an experiment where the esophagus was electrically stimulated at the pain threshold using a nasal endoscope. The electroencephalogram (EEG) was recorded from 64 surface electrodes and “topographic matching pursuit” was used to extract the EEG information in the early brain activation after stimulation.
RESULTS: A major difference between controls and patients were seen in delta and theta bands, whereas there were only minor differences in other frequency bands. In the theta band, the patients showed higher activity than controls persisting throughout the 450 ms of analysis with synchronous brain activation between the channels. The main theta components oscillated with 4.4 Hz in the patients and 5.5 Hz in the controls. The energy in the delta (0.5-3.5 Hz) band was higher in the controls, whereas the patients only showed scattered activity in this band.
CONCLUSION: The differences in the theta band indicate that neuropathic pain mechanisms are involved in chronic pancreatitis. This has important implications for the understanding and treatment of pain in these patients, which should be directed against drugs with effects on neuropathic pain disorders.
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Qin C, Farber JP, Foreman RD. Intraesophageal chemicals enhance responsiveness of upper thoracic spinal neurons to mechanical stimulation of esophagus in rats. Am J Physiol Gastrointest Liver Physiol 2008; 294:G708-16. [PMID: 18187515 DOI: 10.1152/ajpgi.00477.2007] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Esophageal hypersensitivity is one of the most common causes of noncardiac chest pain in patients. In this study, we investigated whether exposure of the esophagus to acid and other chemical irritants affected activity of thoracic spinal neurons responding to esophageal distension (ED) in rats. Extracellular potentials of single thoracic (T3) spinal neurons were recorded in pentobarbital sodium-anesthetized, -paralyzed, and -ventilated male rats. ED (0.2 or 0.4 ml, 20 s) was produced by water inflation of a latex balloon placed orally into the middle thoracic region of the esophagus. The chemicals were administered via a tube that was passed through the stomach and placed in the thoracic esophagus. To irritate the esophagus, 0.2 ml of HCl (0.01 N), bradykinin (10 microg/ml), or capsaicin (10 microg/ml) were injected for 1-2 min. Only neurons excited by ED were included in this study. Results showed that intraesophageal instillation of HCl, bradykinin, and capsaicin increased activity in 3/20 (15%), 7/25 (28%), and 9/20 (45%) neurons but enhanced excitatory responses to ED in 9/17 (53%), 8/15 (53%), and 7/11 (64%) of the remaining spinal neurons, respectively. Furthermore, intraesophageal chemicals were more likely to enhance the responsiveness of low-threshold neurons than high-threshold neurons to the esophageal mechanical stimulus. Normal saline (pH 7.4, 0.2 ml) or vehicle instilled in the esophagus did not significantly affect activity or ED responses of neurons. We conclude that enhanced responses of thoracic spinal neurons to ED by the chemically challenged esophagus may provide a possible pathophysiological basis for visceral hypersensitivity in patients with gastroesophageal reflux and/or esophagitis.
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Affiliation(s)
- Chao Qin
- Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73190, USA.
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25
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Qin C, Foreman RD, Farber JP. Inhalation of a pulmonary irritant modulates activity of lumbosacral spinal neurons receiving colonic input in rats. Am J Physiol Regul Integr Comp Physiol 2007; 293:R2052-8. [PMID: 17761515 DOI: 10.1152/ajpregu.00154.2007] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The purpose of the present study was to determine whether an intraspinal nociceptive pathway from the lungs modulated activity of spinal neurons that also received afferent input from the colon. Extracellular potentials of single lumbosacral (L6-S2) spinal neurons were recorded in pentobarbital-anesthetized, paralyzed, and ventilated male rats. The lower airways and lungs were irritated by injecting ammonia vapor over a 30% NH(4)OH solution into the inspiratory line of the ventilator (0.5 ml, 20 s). Graded colorectal distension (CRD; 20-60 mmHg, 20 s) was produced by air inflation of a balloon. Inhaled ammonia (IA) altered activity of 31/51 (61%) lumbosacral spinal neurons responding to noxious CRD (60 mmHg, 20 s). In contrast, IA changed activity of 3/30 (10%) spinal neurons with somatic fields that did not respond to colorectal inputs. IA decreased activity of 16/31 (52%) spinal neurons and increased activity of the other 15 neurons with colorectal input. Multiple patterns of viscerovisceral convergent spinal neurons with excitatory and inhibitory responses to CRD and IA were observed; 87% (27/31) of the viscerovisceral convergent neurons also responded to innocuous and/or noxious stimuli of somatic fields. Bilateral cervical vagotomy abolished responses to IA in 2/8 tested neurons, indicating that the remaining 6 neurons had input originating from sympathetic afferent fibers. Rostral C1 spinal transection did not abolish inhibitory responses to IA in 4/4 neurons, but L2 transection eliminated inhibitory responses to IA in 3/3 neurons. These results indicated that irritation of the lower airways modulated activity of lumbosacral spinal neurons with colorectal input. It might contribute to intraspinal cross talk between the colon and lungs.
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Affiliation(s)
- Chao Qin
- Dept. of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73190, USA.
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26
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Banerjee B, Medda BK, Lazarova Z, Bansal N, Shaker R, Sengupta JN. Effect of reflux-induced inflammation on transient receptor potential vanilloid one (TRPV1) expression in primary sensory neurons innervating the oesophagus of rats. Neurogastroenterol Motil 2007; 19:681-91. [PMID: 17640184 DOI: 10.1111/j.1365-2982.2007.00947.x] [Citation(s) in RCA: 50] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
A possible mechanism of oesophageal hypersensitivity is the acid-induced activation of transient receptor potential vanilloid receptor 1 (TRPV1) in the primary sensory neurons. We investigated TRPV1 expression and its colocalization with substance P (SP) and isolectin B4 (IB4)-positive cells in the thoracic dorsal root ganglia (DRGs) and nodose ganglia (NGs) of rats with reflux-induced oesophagitis (RO). RO was developed by fundus ligation and partial obstruction of the pylorus of Sprague-Dawley rats. Four groups of rats were used; fundus ligated acute (RO 48 h), chronic 7 days (RO 7D), RO 7D + omeprazole (7D + Omz, 40 mg kg(-1), i.p.) and sham-operated controls. Immunohistochemical analysis of TRPV1, SP and IB4 expression were carried out in spinal cord (SC), DRGs and NGs. RO rats exhibited significant inflammation and increase in TRPV1-ir and SP-ir expressions in the SC, DRGs and NGs. The maximum colocalization of TRPV1 and SP was observed in RO 7D rats, but Omz prevented inflammation and over expression of TRPV1 and SP. TRPV1-ir significantly increased in IB4-positive cells in DRGs and SC, but not in the NGs. Results document that acid-induced oesophagitis increases TRPV1 expression in both SP- and IB4-positive sensory neurons. The over expression of TRPV1 may contribute to oesophageal hypersensitivity observed in gastro-oesophageal reflux disease (GORD).
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Affiliation(s)
- B Banerjee
- Division of Gastroenterology and Hepatology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
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27
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Willert RP, Delaney C, Kelly K, Sharma A, Aziz Q, Hobson AR. Exploring the neurophysiological basis of chest wall allodynia induced by experimental oesophageal acidification - evidence of central sensitization. Neurogastroenterol Motil 2007; 19:270-8. [PMID: 17391243 DOI: 10.1111/j.1365-2982.2006.00890.x] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
In somatic models of central sensitisation (CS) allodynia develops following changes to somatic A-beta fibres, allowing these afferents which normally only process innocuous sensations to encode pain. The aim of this study was to determine whether somatic allodynia induced by visceral sensitisation occurs via N-Methyl-D-Aspartate (NMDA) receptor mediated changes to the neurophysiological characteristics of somatic A-beta fibres. Twelve healthy subjects had oesophageal, chest wall and foot pain thresholds (PT) to electrical stimulation measured, and chest wall evoked potentials (CEP) recorded before and 30 minutes after distal oesophageal acidification on 2 separate visits. Intravenous ketamine (an NMDA receptor antagonist) or saline was given 30 minutes post acid with repeated oesophageal and chest wall PT measurements and CEP recordings. Distal oesophageal acidification reduced PT to electrical stimulation on the anterior chest wall (37 +/- 10 mA v 29 +/- 7 mA p = 0.01) and proximal oesophagus (46 +/- 10 mA v 33 +/- 11 mA p = 0.001) but not the foot (37 +/- 25 mA v 39 +/- 23 mA p = 0.12). The induction of chest wall somatic allodynia was accompanied by a reduction in the latency of the P1 (36 +/- 3 ms to 30 +/- 4 ms p = 0.016) and P2 (87 +/- 7 ms to v 76 +/- 7 ms p = 0.049) components of the CEP. NMDA receptor antagonism reversed both visceral and somatic pain hypersensitivity but did not affect CEP latencies. These data provide objective neurophysiological evidence that CS contributes to the development of somatic allodynia following visceral sensitisation.
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Affiliation(s)
- R P Willert
- GI Sciences Department, University of Manchester, Hope Hospital, Salford, Lancs, UK
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28
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Nazif O, Teichman JMH, Gebhart GF. Neural Upregulation in Interstitial Cystitis. Urology 2007; 69:24-33. [PMID: 17462476 DOI: 10.1016/j.urology.2006.08.1108] [Citation(s) in RCA: 120] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2005] [Revised: 06/27/2006] [Accepted: 08/24/2006] [Indexed: 01/12/2023]
Abstract
Interstitial cystitis (IC) is a syndrome of bladder hypersensitivity with symptoms of urgency, frequency, and chronic pelvic pain. Although no consensus has been reached on the underlying cause of IC, several pathophysiologic mechanisms, including epithelial dysfunction, mast cell activation, and neurogenic inflammation, have been proposed. Despite multiple different causes of urinary cystitis, the bladder's response to cystitis is limited and typical. Animal experiments have shown upregulation of proteinase-activated receptors, tryptase, beta-nerve growth factor, inducible nitric oxide synthase, nuclear transcription factor-kappaB, c-Fos, phosphodiesterase 1C, cyclic adenosine monophosphate (cAMP)-dependent protein kinase, and proenkephalin B. After the noxious stimulus has abated, downregulation of genes appears to follow. Distention of the bladder results in the release of adenosine triphosphate (ATP) from urothelial cells, which activates purinergic P2X3 receptors. Activation by ATP of P2X3-expressing afferents is a fundamental signaling factor in bladder sensation and appears to play a role in bladder reflexes. Fos proteins present in spinal cord neurons have been shown to be upregulated in animals that have undergone cyclophosphamide-induced chemical cystitis. These and other findings suggest that neural upregulation occurs both peripherally and centrally in subjects with chronic cystitis. It is unclear whether neural mechanisms and inflammation are the cause of IC or the result of other initiating events. Neural upregulation is known to play a role in the chronicity of pain, urgency, and frequency and represents an exciting area of research that may lead to additional treatments and a better understanding of IC.
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Affiliation(s)
- Omar Nazif
- Division of Urology, University of British Columbia, Vancouver, British Columbia, Canada
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29
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Ma WL, Zhang WB, Xiong KH, Guo F. Visceral and orofacial somatic afferent fiber terminals converge onto the same neuron in paratrigeminal nucleus: An electron microscopic study in rats. Auton Neurosci 2007; 131:45-9. [PMID: 16962830 DOI: 10.1016/j.autneu.2006.06.006] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2006] [Revised: 06/17/2006] [Accepted: 06/26/2006] [Indexed: 01/02/2023]
Abstract
The paratrigeminal nucleus (Pa5) receives visceral sensory inputs through the vagus (X) and glossopharyngeal (IX) nerves and somatic sensory inputs through the trigeminal (V) nerve. In the present study, transganglionic transport of the WGA-HRP and Wallerian degeneration was used to identify whether two kinds of primary afferent fiber terminals converge onto a single neuron in the Pa5 at the utrastructural level. It was found that HRP-labeled and degenerated terminals originating from the IX and/or X nerves and infraorbital nerve formed asymmetrical synapses with unlabeled dendrites in the Pa5. Furthermore, approximately 7% (43/630) HRP-labeled and 31% (43/137) degenerated terminals formed synaptic connections with the same dendritic profiles simultaneously in the dorsal division of the Pa5. These results may provide a neuroanatomical substrate for integration of viscerosomatic sensory inputs associated with visceral and cardiovascular reflexes in the Pa5.
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Affiliation(s)
- Wen-Ling Ma
- Department of Anatomy and K K Leung Brain Research Centre, Fourth Military Medical University, Xi'an 710032, P R China.
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30
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Abstract
Visceral hypersensitivity (perception of gastrointestinal sensory events at a lower-than-normal threshold) is considered to be an important pathophysiological mechanism in the development of functional gastrointestinal disorders (FGIDs), such as irritable bowel syndrome, non-cardiac chest pain and functional dyspepsia. These disorders are associated with significant health care and socioeconomic costs due to factors such as repeated visits to consultants, hospitalizations and work absenteeism. Despite the presence of extensive evidence linking visceral hypersensitivity and FGIDs, the mechanism(s) underlying visceral hypersensitivity has not been fully elucidated. Suggested hypotheses include sensitization of afferent neurones, both at the level of the enteric and the (afferent) autonomic nervous system (peripheral sensitization), sensitization of spinal cord dorsal horn neurones (central sensitization) and psychosocial factors/psychiatric comorbidity influencing the processing of afferent signals at the level of the brain. Importantly, these hypotheses may be complementary rather than mutually exclusive. However, the degree to which each of these mechanisms contributes to the overall perception of visceral pain, and therefore the generation of symptoms, still remains unclear. This article discusses the mechanisms that may underlie visceral hypersensitivity, with reference to FGIDs. Understanding these mechanisms is essential in order to improve the diagnosis and treatment of patients with these disorders.
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Affiliation(s)
- P Anand
- Peripheral Neuropathy Unit, Department of Clinical Neuroscience, Imperial College London, London, UK
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31
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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; 12:2806-17. [PMID: 16718803 PMCID: PMC4087795 DOI: 10.3748/wjg.v12.i18.2806] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Methods related to experimental human pain research aim at activating different nociceptors, evoke pain from different organs and activate specific pathways and mechanisms. The different possibilities for using mechanical, electrical, thermal and chemical methods in visceral pain research are discussed with emphasis of combinations (e.g., the multimodal approach). The methods have been used widely in assessment of pain mechanisms in the esophagus and have contributed to our understanding of the symptoms reported in these patients. Hence abnormal activation and plastic changes of central pain pathways seem to play a major role in the symptoms in some patients with gastro-esophageal reflux disease and in patients with functional chest pain of esophageal origin. These findings may lead to an alternative approach for treatment in patients that does not respond to conventional medical or surgical therapy.
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Affiliation(s)
- Asbjørn Mohr Drewes
- Center for Visceral Biomechanics and Pain, Department of Medical Gastroenterology, Aalborg University Hospital, DK-9000 Aalborg, Denmark.
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32
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Sami SAK, Rössel 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; 140:269-79. [PMID: 16631315 DOI: 10.1016/j.neuroscience.2006.02.031] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2005] [Revised: 01/17/2006] [Accepted: 02/05/2006] [Indexed: 12/24/2022]
Abstract
Topographical organization in the neocortex shows experience-dependent plasticity. We hypothesized that experimental sensitization of the esophagus results in changes of the topographical distribution of the evoked potentials and the corresponding dipole source activities to painful stimulation. An endoscopic method was used to deliver 35 electrical stimuli at the pain threshold to a fixed area of the mucosa in 10 healthy volunteer men and women. The stimulations were repeated after 30 min (reproducibility experiment), and after 60 min following perfusion of 200 ml 0.1 N hydrochloric acid (sensitization experiment). During stimulation the electroencephalogram was recorded from 64 surface electrodes. The sensitization resulted in a decrease in the pain threshold (F=6.2; P=0.004). The topographic distribution of the evoked potentials showed reproducible negative (N1, N2) and positive (P1, P2) components. After acid perfusion a reduced latency and a change in localization was seen for the P1 subdivided into frontal and occipital components (F=29.5, P<0.001; F=53.7, P<0.001). Furthermore the sensitization resulted in a reduction of the latency for P2 (F=6.2, P=0.009). The source analysis showed consistent dipolar activity in the bilateral opercular-insular cortex before and after acid perfusion. For the anterior cingulate dipole there was a reduction in latency (P=0.03) and a posterior shift (P=0.0002) following acid perfusion. The findings indicate that short-term sensitization of the esophagus results in central neuroplastic changes involving the cingulate gyrus, which also showed pathological activation in functional diseases of the gut, thus reflecting the importance of this region in visceral pain and hyperalgesia.
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Affiliation(s)
- S A K Sami
- Center for Sensory-Motor Interactions, Department of Health Science and Technology, Aalborg University, Aalborg, Denmark
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33
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Yang M, Li ZS, Xu XR, Fang DC, Zou DW, Xu GM, Sun ZX, Tu ZX. Characterization of cortical potentials evoked by oesophageal balloon distention and acid perfusion in patients with functional heartburn. Neurogastroenterol Motil 2006; 18:292-9. [PMID: 16553584 DOI: 10.1111/j.1365-2982.2006.00761.x] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Oesophageal visceral hypersensitivity is thought to be important in generating symptoms in functional heartburn (FH). However, the neurophysiological mechanisms involved are poorly understood. The aim of this study was to compare the characteristics of oesophageal cortical evoked potentials (CEPs) induced by balloon distension and acid perfusion in FH and controls. We studied 21 FH patients and 12 healthy volunteers. Oesophageal mechanical stimulation was performed using the specially constructed mechanical pump. CEPs were recorded using the 10-20 international system of electroencephalogram recording. Oesophageal distention elicited recognizable, reproducible and muti-peak CEPs. CEP latencies for N1, P1 and N2 components were significantly shorter (P = 0.016, P = 0.003 and P = 0.031, respectively) in FH than in controls before perfusion. Acid perfusion significantly decreased the latencies of N1, P1 and N2 (P = 0.022, P = 0.007 and P = 0.041, respectively) and significantly increased the amplitude of P1-N2 components (P = 0.020) in FH patients, but not in controls. In conclusion, cortical evoked potential responses evoked by oesophageal distention and acid perfusion were greater in FH than in controls, suggesting that dysfunction of visceral neural pathways and/or alterations in cortical processing may produce and mediate oesophageal hypersensitivity in FH. These findings provide the evidence that central sensitization contributes to the development and maintenance of oesophageal hypersensitivity.
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Affiliation(s)
- M Yang
- Department of Gastroenterology, Changhai Hospital, Second Military Medical University, Shanghai, China
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34
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Lamb K, Zhong F, Gebhart GF, Bielefeldt K. Experimental colitis in mice and sensitization of converging visceral and somatic afferent pathways. Am J Physiol Gastrointest Liver Physiol 2006; 290:G451-7. [PMID: 16195421 DOI: 10.1152/ajpgi.00353.2005] [Citation(s) in RCA: 77] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Chronic pain syndromes affecting different organs often coexist. We hypothesized that sensitization of one afferent pathway may affect converging input from other areas of the body. We induced colitis in mice with 2,4,6-trinitrobenzenesulfonic acid (TNBS); control animals were treated with equal volumes of vehicle (50% ethanol) only. Visceromotor responses to graded colorectal distension, cystometrograms, and response thresholds to mechanical and thermal stimulation of both hind paws were determined on days 7 and 14. Inflammation of colon and bladder was assessed with validated histological markers and scores. TNBS caused significant colitis on day 7 that resolved by day 14; there was no evidence of bladder inflammation. There was a significant hypersensitivity to colorectal distension on day 7, which returned to normal on day 14. This was associated with bladder overactivity, as demonstrated by early onset of micturition and more frequent micturition on day 7 after TNBS administration. Colitis also significantly altered responses to mechanical and thermal stimulation of both hind paws on day 7 but not day 14. We conclude that cross talk between afferent visceral and somatic pathways may contribute to the coexistence of pain syndromes.
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Affiliation(s)
- Kenneth Lamb
- Department of Pharmacology, University of Iowa, Iowa City, Iowa, USA
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35
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Frøkjær 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. [PMID: 16297555 DOI: 10.1016/j.pain.2005.09.031] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2005] [Revised: 08/15/2005] [Accepted: 09/29/2005] [Indexed: 12/13/2022]
Abstract
Widespread visceral hypersensitivity and the overlap of symptom complexes observed in functional gastrointestinal disorders may be related to central sensitization and neuroplastic changes. A multimodal and multi-segmental model was developed to evaluate viscero-visceral hyperalgesia induced by experimental esophageal sensitization in healthy volunteers. Twelve healthy subjects were studied using a double-blinded, placebo-controlled design. The sensitivity to mechanical and heat stimulations was assessed in the proximal esophagus, duodenum and rectum before and after perfusion of the distal esophagus with acid or saline. A special-designed probe was used allowing cross-sectional ultrasound imaging during mechanical and heat stimulation of the esophagus and duodenum. Another probe was used for mechanical stimulation of the rectum. The referred somatic pain areas to gut pain stimulations were also assessed. Following acid perfusion 11 of 12 volunteers showed increased sensitivity to one or more stimulation modalities. An overall increased sensitivity to mechanical stretch in the three gut segments was seen (P=0.0001). Posthoc analysis showed that this was mainly due to increased sensitivity in the rectum (P<0.001). No changes were seen to thermal stimulations (all P-values>0.4). The somatic referred pain area to duodenal stimulations increased (P=0.04), while it was unaffected to esophageal and rectal stimulations (P>0.3). The present method demonstrated a new approach to assess multimodal sensitivity to experimental sensitization of the esophagus and related viscero-visceral hyperalgesia. Central mechanisms can explain the remote hyperalgesia to mechanical visceral stimulation and the increase in referred pain areas. The present method may be used to explore pathophysiology and pharmacological interventions in patients with visceral hypersensitivity.
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Affiliation(s)
- Jens Brøndum Frøkjær
- Center for Visceral Biomechanics and Pain, Aalborg Hospital, Denmark Department of Radiology, Aalborg Hospital, Denmark Pfizer Ltd, Sandwich, UK Department of Health Science and Technology, Center for Sensory-Motor Interaction, Aalborg University, Denmark
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Drewes AM, Reddy H, Staahl C, Pedersen J, Funch-Jensen P, Arendt-Nielsen L, Gregersen H. Sensory-motor responses to mechanical stimulation of the esophagus after sensitization with acid. World J Gastroenterol 2005; 11:4367-74. [PMID: 16038036 PMCID: PMC4434664 DOI: 10.3748/wjg.v11.i28.4367] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: Sensitization most likely plays an important role in chronic pain disorders, and such sensitization can be mimicked by experimental acid perfusion of the esophagus. The current study systematically investigated the sensory and motor responses of the esophagus to controlled mechanical stimuli before and after sensitization.
METHODS: Thirty healthy subjects were included. Distension of the distal esophagus with a balloon was performed before and after perfusion with 0.1 mol/L hydrochloric acid for 30 min. An impedance planimetry system was used to measure cross-sectional area, volume, pressure, and tension during the distensions. A new model allowed evaluation of the phasic contractions by the tension during contractions as a function of the initial muscle length before the contraction (comparable to the Frank-Starling law for the heart). Length-tension diagrams were used to evaluate the muscle tone before and after relaxation of the smooth muscle with butylscopolamine.
RESULTS: The sensitization resulted in allodynia and hyperalgesia to the distension volumes, and the degree of sensitization was related to the infused volume of acid. Furthermore, a nearly 50% increase in the evoked referred pain was seen after sensitization. The mechanical analysis demonstrated hyper-reactivity of the esophagus following acid perfusion, with an increased number and force of the phasic contractions, but the muscle tone did not change.
CONCLUSION: Acid perfusion of the esophagus sensitizes the sensory pathways and facilitates secondary contractions. The new model can be used to study abnormal sensory-motor mechanisms in visceral organs.
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Affiliation(s)
- Asbjørn-Mohr Drewes
- Center for Biomechanics and Pain, Department of Medical Gastroenterology, Aalborg Hospital, DK-9000 Aalborg, Denmark.
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Medda BK, Sengupta JN, Lang IM, Shaker R. Response properties of the brainstem neurons of the cat following intra-esophageal acid–pepsin infusion. Neuroscience 2005; 135:1285-94. [PMID: 16165290 DOI: 10.1016/j.neuroscience.2005.07.016] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2005] [Revised: 06/24/2005] [Accepted: 07/01/2005] [Indexed: 11/16/2022]
Abstract
Studies in humans have documented that acute acid infusion into the esophagus leads to decrease in threshold for sensations to mechanical distension of the esophagus. It is not known whether acid infusion leads to sensitization of brainstem neurons receiving synaptic input from vagal afferent fibers innervating the esophagus. The aim of this study was to investigate the correlation of responses of vagal afferents and brainstem neurons after acute infusion of acid (0.1 N HCl)+pepsin (1 mg/ml) into the esophagus of cats. The vagal afferent fibers (n=20) exhibited pressure-dependent increase in firing to graded esophageal distension (5-80 mm Hg). Infusion of acid+pepsin into the esophagus produced a significant increase in ongoing resting firing of five of 16 fibers (31%) tested. However, their responses to graded esophageal distension did not change when tested 30 min after infusion. Pepsin infusion did not change the resting firing and response to esophageal distension (n=4). Twenty-one brainstem neurons were recorded that responded in an intensity-dependent manner to graded esophageal distension. Responses of 12 excited neurons were tested after intra-esophageal acid+pepsin infusion. Neurons exhibited a decrease in threshold for response to esophageal distension and increase in firing after acid+pepsin infusion. The sensitization of response after intra-esophageal acid remained unaffected after cervical (C1-C2) spinal transection (n=3). Results indicate that the esophageal distension-sensitive neurons in the brainstem exhibit sensitization of response to esophageal distension after acute acid+pepsin exposure. The sensitization of brainstem neurons is possibly initiated by increased spontaneous firing of the vagal afferent fibers to acid+pepsin, but not to sensitized response of vagal distension-sensitive afferent fibers to esophageal distension. Results also indicate that spinal pathway does not contribute to sensitization of brainstem neurons.
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Affiliation(s)
- B K Medda
- MCW Dysphagia Institute and Division of Gastroenterology and Hepatology, Medical College of Wisconsin, 9200 West Wisconsin Avenue, Milwaukee, WI 53226, USA
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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; 110:393-9. [PMID: 15275791 DOI: 10.1016/j.pain.2004.04.022] [Citation(s) in RCA: 36] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2003] [Revised: 03/13/2004] [Accepted: 04/12/2004] [Indexed: 12/24/2022]
Abstract
The aim of the present study was to investigate the effect of thermal stimulation of the oesophagus before and after sensitisation with acid. In 17 healthy subjects a stimulation bag was used to re-circulate water at 5 and 60 degrees C for up to 90 s in the lower part of the oesophagus. The area under the temperature curve was used to assess the caloric load. The thermal stimuli were repeated after perfusion of the oesophagus with acid. The evoked pain intensity and referred pain areas (at the pain threshold) were assessed. At baseline the subjects were able to tolerate less caloric load (42%) for the heat compared to the cold stimuli (P = 0.007). The heat stimuli resulted in an increased referred pain area as compared with the cold stimuli (P = 0.03). Following acid perfusion there was a selective sensitisation to the heat pain stimuli as only 36% of the initial caloric load was tolerated (P = 0.012) whereas the sensation to the cold stimuli was unchanged. After acid perfusion, the referred pain area to the heat pain stimulation increased 49% (P = 0.04) but was not changed to cold stimulation (P = 0.82). After sensitisation the words used to describe the sensations to heat pain stimuli shifted from a warmth quality towards a more burning quality in most subjects. This multi-modal sensory testing study showed that acid sensitises the oesophagus to heat but not to cold pain. This may account for the modality-specific symptoms and hypersensitivity reported in patients suffering from, e.g. gastro-oesophageal reflux disease.
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Affiliation(s)
- Jan Pedersen
- Center for Visceral Biomechanics and Pain, Department of Gastroenterology, Aalborg University Hospital, DK-9000 Aalborg, Denmark
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Abstract
Originally, sensory testing of the esophagus included the acid perfusion test and the edrophonium test, which were developed to assess patients with non-cardiac chest pain. In the last 2 decades interest in functional esophageal disorders has increased and thus further understanding of the underlying mechanisms of esophageal pain required development of new sensory testing techniques. Balloon distension using a computerized electronic device, electrical stimulation and impedance planimetry have generated important information about esophageal sensory thresholds for pain in different disease states. Intraluminal ultrasonography has been used to determine the physiologic changes of the muscle wall of the esophagus during perception of typical esophageal symptoms. Central evaluation of patients undergoing esophageal stimulation has recently been introduced to assess cerebral activation in different esophageal disorders. However, many studies using esophageal sensory testing are afflicted with significant design flaws, making interpretation of the results very difficult. This is primarily due to lack of recognition of factors that can modulate esophageal sensation.
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Affiliation(s)
- Ronnie Fass
- Neuro-Enteric Clinical Research Group, Department of Medicine, Section of Gastroenterology, Southern Arizona VA Health Care System, Tucson, Arizona 85723, USA.
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Qin C, Chandler MJ, Foreman RD. Esophagocardiac convergence onto thoracic spinal neurons: comparison of cervical and thoracic esophagus. Brain Res 2004; 1008:193-7. [PMID: 15145756 DOI: 10.1016/j.brainres.2003.12.056] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/28/2003] [Indexed: 12/31/2022]
Abstract
The aim of this study was to characterize thoracic spinal neurons receiving convergent inputs from the esophagus, heart and somatic receptive fields. Extracellular potentials of single T3-T4 spinal neurons were recorded in pentobarbital anesthetized male rats. Thoracic and cervical esophageal distensions (TED, CED) were produced by water inflation of a latex balloon. A catheter was placed in the pericardial sac to administer bradykinin or a mixture of algogenic chemicals. 96/311 (31%) neurons responded to both TED and intrapericardial chemicals (IC) and 48/177 (27%) neurons responded to both CED and IC. Long-lasting excitatory responses were more frequently encountered (P<0.05) in esophagocardiac spinal neurons responding to TED (T-ECSNs, 62/91) than in neurons responding to CED (C-ECSNs, 23/47). Ninety-one percent of T-ECSNs and 98% of C-ECSNs had somatic fields on chest, axilla and upper back areas. Esophagocardiac convergence on thoracic spinal neurons provided a spinal mechanism that might mediate viscerovisceral nociception and reflexes.
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Affiliation(s)
- Chao Qin
- Department of Physiology, University of Oklahoma Health Sciences Center, P.O. Box 26901, Oklahoma City, OK 73190, USA.
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Willert RP, Woolf CJ, Hobson AR, Delaney C, Thompson DG, Aziz Q. The development and maintenance of human visceral pain hypersensitivity is dependent on the N-methyl-D-aspartate receptor. Gastroenterology 2004; 126:683-92. [PMID: 14988822 DOI: 10.1053/j.gastro.2003.11.047] [Citation(s) in RCA: 142] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
BACKGROUND & AIMS Visceral hypersensitivity is a common feature of functional gastrointestinal disorders. One speculated mechanism is an activity-dependent increase in spinal cord neuronal excitability (central sensitization), which is dependent on activation of the N-methyl-D-aspartate (NMDA) receptor. Our aims were to determine whether the development and maintenance of human visceral hypersensitivity is NMDA receptor mediated. METHODS Healthy subjects were studied using a randomized, double-blind, placebo-controlled, crossover design. Pain thresholds to electrical stimulation were determined both in the proximal esophagus and in the foot (control) before and after a 30-minute distal esophageal infusion of 0.15 mol/L HCl acid. Ketamine (NMDA receptor antagonist) or saline (vehicle) was given intravenously either prior to or following acid infusion, and pain thresholds were measured for the following 120 minutes. Protocol 1: In 6 subjects, the effect of ketamine in the esophagus was assessed without acid infusion. Protocol 2: In 14 subjects, ketamine was given prior to esophageal acid. Protocol 3: In 12 subjects, ketamine was given after esophageal acid. RESULTS Protocol 1: In the absence of esophageal acid, ketamine had no effect on either esophageal or foot pain thresholds (area-under-the-curve, [AUC] P = 0.36 esophagus, P = 0.34 foot, ANOVA) within 30 minutes of cessation of the infusion. Protocol 2: Acid-induced esophageal hypersensitivity was prevented by ketamine (AUC, P < 0.0001, ANOVA) without affecting foot pain thresholds (AUC, P = 0.06, ANOVA). Protocol 3: Ketamine delivered after acid reversed the induction of esophageal hypersensitivity induced by acid (AUC, P < 0.0001, ANOVA). CONCLUSIONS The induction and maintenance of acid-induced esophageal hypersensitivity is prevented and reversed by ketamine. This finding strongly indicates that central sensitization is a mechanism of visceral hypersensitivity.
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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 2004; 7:539-49. [PMID: 14575667 DOI: 10.1016/s1090-3801(03)00053-3] [Citation(s) in RCA: 87] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND AIMS 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. METHODS 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. RESULTS 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. CONCLUSIONS 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.
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Affiliation(s)
- Asbjørn Mohr Drewes
- Center for Visceral Biomechanics and Pain, Departments of Medical and Surgical Gastroenterology, Aalborg University Hospital, DK-9000 Aalborg, Denmark.
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Qin C, Chandler MJ, Jou CJ, Foreman RD. Responses and afferent pathways of C1-C2 spinal neurons to cervical and thoracic esophageal stimulation in rats. J Neurophysiol 2003; 91:2227-35. [PMID: 14695350 DOI: 10.1152/jn.00971.2003] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Because vagal and sympathetic inputs activate upper cervical spinal neurons, we hypothesized that stimulation of the esophagus would activate C(1)-C(2) neurons. This study examined responses of C(1)-C(2) spinal neurons to cervical and thoracic esophageal distension (CED, TED) and afferent pathways for CED and TED inputs to C(1)-C(2) spinal neurons. Extracellular potentials of single C(1)-C(2) spinal neurons were recorded in pentobarbital-anesthetized male rats. Graded CED or TED was produced by water inflation (0.1-0.5 ml) of a latex balloon. CED changed activity of 48/219 (22%) neurons; 34 were excited (E), 12 were inhibited (I), and 2 were E-I. CED elicited responses for 18/18 neurons tested after ipsilateral cervical vagotomy, for 12/14 neurons tested after bilateral vagotomy and for 9/11 neurons tested after bilateral vagotomy and C(6)-C(7) spinal cord transection. TED changed activity of 31/190 (16%) neurons (28E, 3 I). Ipsilateral cervical vagotomy abolished TED-evoked responses of 5/12 neurons. Bilateral vagotomy eliminated responses of 2/4 neurons tested, and C(6)-C(7) spinal transection plus bilateral vagotomy eliminated responses of 2/2 neurons. Thus inputs from CED to C(1)-C(2) neurons most likely entered upper cervical dorsal roots, whereas inputs from TED were dependent on vagal pathways and/or sympathetic afferent pathways that entered the thoracic dorsal roots. These results supported a concept that C(1)-C(2) spinal neurons play a role in integrating visceral information from cervical and thoracic esophagus.
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Affiliation(s)
- Chao Qin
- Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73190, USA.
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Qin C, Chandler MJ, Foreman RD. Afferent pathways and responses of T3–T4 spinal neurons to cervical and thoracic esophageal distensions in rats. Auton Neurosci 2003; 109:10-20. [PMID: 14638308 DOI: 10.1016/j.autneu.2003.08.005] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
The purposes of this study were to (1) compare responses of T(3)-T(4) spinal neurons to thoracic and cervical esophageal distension (TED, CED) and (2) determine afferent pathways for esophageal input to these neurons. Extracellular potentials of single superficial and deeper T(3)-T(4) neurons were recorded in pentobarbital anesthetized male rats. Graded TED or CED was produced by water inflation (0.1-0.5 ml) of a latex balloon. TED changed activity of 121/432 (28%) neurons (114 were excited); CED activated 69/269 (26%) neurons (56 were excited). Of 151 neurons that were tested for responses to both TED and CED, 40 (26%) neurons responded to both TED and CED. Mean duration of excitatory responses in convergent neurons to TED was significantly longer than the duration of responses to CED (31.4+/-2.8 vs. 25.4+/-1.0 s, n=34, P<0.05). A total of 105 out of 121 (87%) and 66 out of 69 (96%) neurons responsive to TED and CED had somatic fields. Spinal transection at rostral C(1) and at C(7)-C(8) indicated that excitatory responses to TED resulted from activation of afferent input that entered thoracic spinal segments; whereas, excitatory responses to CED resulted from afferent inputs entering cervical or thoracic spinal segments. These data showed that the upper thoracic spinal cord received sensory information from the esophagus through cervical and/or thoracic spinal visceral afferent pathways.
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Affiliation(s)
- Chao Qin
- Department of Physiology, University of Oklahoma Health Sciences Center, P.O. Box 26901, Oklahoma City, OK 73190, USA.
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45
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46
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Jou CJ, Farber JP, Qin C, Foreman RD. Convergent pathways for cardiac- and esophageal-somatic motor reflexes in rats. Auton Neurosci 2003; 99:70-7. [PMID: 12241090 DOI: 10.1016/s1566-0702(02)00136-4] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
Chest pain of esophageal and cardiac origin is often difficult to distinguish due to similar sensations and localization. We have shown that spasm-like contractions of the spinotrapezius muscles evoked by noxious cardiac stimulation could potentially sensitize muscle afferent fibers and produce angina-like referred pain. In this study, we proposed that a similar type of spinotrapezius contraction evoked by esophageal stimulation could produce nociceptive responses with similar quality and localization as evoked by cardiac stimulation. An objective of this study was to show convergence of pathways to the spinotrapezius muscles by measuring electromyographic (EMG) activity between the cardiac- and esophageal-motor reflexes. We also investigated afferent pathways of esophageal-motor reflexes by disrupting or activating the left sympathetic chain and vagus nerves; these pathways form the afferent limbs of the cardiac-motor reflexes. Results showed that more than 95% of animals responding to noxious cardiac stimulation also responded to esophageal distension. Transection of the left sympathetic chain to reduce upper thoracic visceral afferent innervation significantly decreased cardiac-evoked EMG activity or total motor unit potentials (t-MUP). In contrast, however, the transection did not significantly decrease t-MUP evoked by esophageal distension. Bilateral vagotomy and vagal afferent stimulation increased and decreased the cardiac-evoked t-MUP, respectively. However, the same vagal manipulations did not influence t-MUP evoked by esophageal distension. This study demonstrated that the spinotrapezius muscle could be activated by noxious stimulation of two different visceral organs. The spinotrapezius muscle contractions evoked by esophageal distension are produced in part by activation of esophageal afferent fibers found in upper thoracic sympathetic nerves, but not by activation of the vagus nerves.
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Affiliation(s)
- C Jerry Jou
- Department of Physiology, University of Oklahoma Health Sciences Center, OK 73190, USA
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47
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Garrison DW, Foreman RD. Effects of Transcutaneous Electrical Nerve Stimulation (TENS) Electrode Placement on Spontaneous and Noxiously Evoked Dorsal Horn Cell Activity in the Cat. Neuromodulation 2003; 5:231-7. [DOI: 10.1046/j.1525-1403.2002.02036.x] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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Qin C, Chandler MJ, Foreman RD, Farber JP. Upper thoracic respiratory interneurons integrate noxious somatic and visceral information in rats. J Neurophysiol 2002; 88:2215-23. [PMID: 12424263 DOI: 10.1152/jn.00120.2002] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
The aim of this study was to determine if thoracic respiratory interneurons (TRINs) might receive peripheral noxious somatic and visceral inputs. Extracellular potentials of 78 respiration-related T(3) neurons, whose activity was driven by central respiratory output, were recorded from the intermediate zone in pentobarbital anesthetized, paralyzed, and ventilated male rats. These neurons were identified as interneurons by their locations and by the absence of antidromic activation from the cervical sympathetic trunk and cerebellum. Thoracic esophageal distension (ED) was produced by water inflation of a latex balloon (0.1-0.5 ml, 20 s). A catheter was placed in the pericardial sac to administer 0.2 ml bradykinin (10(-5) M) for noxious cardiac stimulation. Of 78 TRINs examined for ED, activity of 24 TRINs increased and activity of 8 TRINs decreased. Intrapericardial bradykinin increased activity in 26/65 TRINs tested and decreased activity in 5 TRINs. Seventy-four TRINs were tested for effects of brush, pressure, and pinch of the chest and upper back areas. No TRINs responded to brushing hair. Low-threshold responses to pressure were observed in 27 TRINs. Fourteen TRINs were wide dynamic range and 4 TRINs had high-threshold responses. Peripheral stimuli affected all types of TRINs, including inspiratory, expiratory, and biphasic neurons. Simultaneous phrenic recordings showed that effects of various somatic and visceral stimuli on TRINs were independent of central respiratory drive. Various somatovisceral and viscerovisceral patterns of input were observed in TRINs. The results suggested that TRINs participate in intraspinal processing and integration of nociceptive information from somatic fields and visceral organs.
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Affiliation(s)
- Chao Qin
- Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73190, USA
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Traub RJ, Zhai Q, Ji Y, Kovalenko M. NMDA receptor antagonists attenuate noxious and nonnoxious colorectal distention-induced Fos expression in the spinal cord and the visceromotor reflex. Neuroscience 2002; 113:205-11. [PMID: 12123698 DOI: 10.1016/s0306-4522(02)00170-7] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
In the present three-part study, the effects of intrathecally administered N-methyl-D-aspartate (NMDA) receptor antagonists on responses to noxious and innocuous colorectal distention (CRD) were examined. In the first part, a passive-avoidance paradigm was used to confirm that 80 mm Hg CRD is a noxious stimulus since it produced avoidance behavior. Acquisition of this behavior was blocked by the NMDA receptor antagonist D(-)-2-amino-5-phosphonopetanoic acid (APV, 60 nmol, intrathecal). In contrast, 20 mm Hg CRD is an innocuous stimulus since there was no difference in the behavior of these animals compared to nondistended controls. In the second part, the effects of the NMDA receptor antagonist dizocilpine maleate (MK-801, 0-100 nmol, intrathecal) on CRD-induced Fos expression in the lumbosacral spinal cord were examined. Noxious and innocuous CRD induced 98+/-4 and 50+/-2 Fos labeled cells per section per side of the spinal cord, respectively. MK-801 dose-dependently attenuated noxious CRD-induced Fos. Compared to saline, the peak attenuation was 55%. Innocuous CRD-induced Fos was attenuated by 36% following 100 nmol MK-801. In the third part, the effects of APV (0-240 nmol, intrathecal) on the visceromotor reflex were examined. APV dose-dependently attenuated the visceromotor reflex to graded intensities of CRD that went from the innocuous into the noxious range. In separate animals that only received innocuous stimulation, APV dose-dependently attenuated the visceromotor reflex. The magnitude of attenuation was similar for both stimulus paradigms. These data expand upon our previous dorsal horn neuronal recordings which showed that spinal NMDA receptors partially mediate the processing of both noxious and innocuous colorectal stimuli. They further underscore a difference from somatic tissue in the role of NMDA receptors in processing acute or transient visceral stimuli in the absence of tissue injury.
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Affiliation(s)
- R J Traub
- Department of Oral and Craniofacial Biological Sciences, Dental School, University of Maryland, 666 W. Baltimore Street, Baltimore, MD 21201, USA.
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Strigo IA, Bushnell CM, Boivin M, Duncan GH. Psychophysical analysis of visceral and cutaneous pain in human subjects. Pain 2002; 97:235-246. [PMID: 12044620 DOI: 10.1016/s0304-3959(02)00023-4] [Citation(s) in RCA: 60] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Clinical evidence suggests that cutaneous and visceral pain differ in sensory, affective, and motivational realms, yet there has been little comparative characterization of these types of pain. This study uses psychophysical measures to compare directly visceral and cutaneous pain and sensitivity. Healthy subjects (10 males, seven females, age 19-29) evaluated perceptions evoked by balloon distention of the distal esophagus and contact heat on the upper chest. Subjects gave continuous ratings of pain intensity using an on-line visual analog scale (VAS), reported maximum pain intensity and unpleasantness on printed VASs, chose phrases from the McGill Pain Questionnaire and Spielberger State-Trait Anxiety Inventory, and drew the area of perceived sensation. For esophageal distention, the threshold for pain intensity was higher than that observed for unpleasantness, whereas for contact heat, pain and unpleasantness thresholds did not differ for either phasic (10s) or tonic (36s) stimulus application. The relative unpleasantness, calculated as the difference between the unpleasantness and the intensity ratings, was higher during esophageal distention than during either phasic or tonic cutaneous heat; this difference in relative unpleasantness was seen at all intensities of esophageal stimulation. Subjects chose significantly more affective words and reported more anxiety during visceral pain than during phasic cutaneous heat pain. A similar tendency was observed when visceral pain was compared to tonic cutaneous heat pain. Subjects also chose a wider range of words to describe visceral than cutaneous pain. On-line VAS ratings revealed greater pain sensation after stimulus termination during visceral than during phasic cutaneous pain; likewise, a similar tendency was observed between visceral and tonic cutaneous pain. Finally, visceral pain led to a more spatially diffuse sensation and was referred to the entire chest and sometimes to the back. Our results show that visceral pain is more unpleasant, diffuse, and variable than cutaneous pain of similar intensity, independent of the duration of the presented stimuli. The data suggest the likelihood of both similarities and differences in the neural substrates underlying visceral and cutaneous pain.
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Affiliation(s)
- Irina A Strigo
- Department of Physiology McGill University, Montreal, Quebec, Canada, H3G 1Y6 Department of Anesthesia, Anesthesia Research Unit, Room 1225, McGill University, 3655 Promenade Sir William Osler, Montreal, Quebec, Canada, H3G 1Y6 Département de gastroenétrologie, Faculté de médecine, Université de Montréal, Montreal, Quebec, Canada, H3C 3J7 Département de stomatologie, Faculté de médecine dentaire, Université de Montréal, Montreal, Quebec, Canada, H3C 3J7 Centre de recherche en sciences neurologiques, Faculté de médecine dentaire, Université de Montréal, Montreal, Quebec, Canada, H3C 3J7
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