Editorial
Copyright ©2011 Baishideng Publishing Group Co., Limited. All rights reserved.
World J Gastroenterol. Oct 14, 2011; 17(38): 4251-4257
Published online Oct 14, 2011. doi: 10.3748/wjg.v17.i38.4251
Systematic review of modulators of benzodiazepine receptors in irritable bowel syndrome: Is there hope?
Pooneh Salari, Mohammad Abdollahi
Pooneh Salari, Medical Ethics and History of Medicine Research Center, and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran 1417614411, Iran
Mohammad Abdollahi, Faculty of Pharmacy, and Pharmaceutical Sciences Research Center, and Endocrinology and Metabolism Research Institute, Tehran University of Medical Sciences, Tehran 1417614411, Iran
Author contributions: Salari P collected the data and drafted the manuscript; Abdollahi M conceived the study, reviewed the data, and edited the manuscript.
Correspondence to: Mohammad Abdollahi, Professor, Faculty of Pharmacy, and Pharmaceutical Sciences Research Center, and Endocrinology and Metabolism Research Institute, Tehran University of Medical Sciences, Tehran 1417614411, Iran. mohammad.abdollahi@utoronto.ca
Telephone: +98-21-66959104 Fax: +98-21-66959104
Received: February 23, 2011
Revised: May 20, 2011
Accepted: May 27, 2011
Published online: October 14, 2011

Abstract

Several drugs are used in the treatment of irritable bowel syndrome (IBS) but all have side effects and variable efficacy. Considering the role of the gut-brain axis, immune, neural, and endocrine pathways in the pathogenesis of IBS and possible beneficial effects of benzodiazepines (BZD) in this axis, the present systematic review focuses on the efficacy of BZD receptor modulators in human IBS. For the years 1966 to February 2011, all literature was searched for any articles on the use of BZD receptor modulators and IBS. After thorough evaluation and omission of duplicate data, 10 out of 69 articles were included. BZD receptor modulators can be helpful, especially in the diarrhea-dominant form of IBS, by affecting the inflammatory, neural, and psychologic pathways, however, controversies still exist. Recently, a new BZD receptor modulator, dextofisopam was synthesized and studied in human subjects, but the studies are limited to phase IIb clinical trials. None of the existing trials considered the neuroimmunomodulatory effect of BZDs in IBS, but bearing in mind the concentration-dependent effect of BZDs on cytokines and cell proliferation, future studies using pharmacodynamic and pharmacokinetic approaches are highly recommended.

Key Words: Benzodiazepines, Benzodiazepine receptor modulators, Dextofisopam, Irritable bowel syndrome, Systematic review



PRESENT KNOWLEDGE ON IRRITABLE BOWEL SYNDROME

Irritable bowel syndrome (IBS) is well-defined as a functional abdominal disorder categorized by intestinal pain or distress, and changes in bowel habits without recognizable malefactor[1]. The symptoms are either constant or intermittent and vary from diarrhea or constipation, hypersecretion of colonic mucus, flatulence, to the sensation of weakness or depression[2]. The pathophysiology of IBS is in some ways multifaceted, yet no consistent biomarker, anatomic, or biochemical alteration has been found[3]. Several pathophysiologic paths have been deliberated for elucidation leading symptoms such as motor and sensory dysfunction, neuroimmune mechanisms, dysregulation of mucus secretion, emotions, colonic motility, enteric nervous system, changes in intraluminal situation and visceral feeling[4]. Gut motility turbulence creates different bowel behaviors and IBS subtypes, according to these outlines they are presented as IBS-D (diarrhea-predominant), IBS-C (constipation-predominant) and IBS-M (mixed)[5].

Earlier, the role of parasympathetic and hormonal provocations in motor activity of some portions of the gut was demonstrated[2]. The most important observation is well-thought-out visceral hypersensitivity as a substantial element in combination with fluctuations in gastrointestinal (GI) motility and secretory activity[6]. Recent epidemiological findings further underline the central and peripheral disease activators or exacerbations as psychosomatic contributions[7-9] and gastroenteric infections[10]. In addition, the brain-gut axis endorses the strong relationship between the brain and the gut via neural, immune and endocrine paths which is affected by neuroimmunological or neuroendocrinological stressors[11,12]. A summary of the pathophysiological mechanisms involved in IBS are presented in Table 1.

Table 1 A summary of the pathophysiological mechanisms of irritable bowel syndrome.
MechanismDescription
Visceral hypersensitivity↓ Threshold of visceral perception, hyperalgesia; ↑ Viscerosomatic referral areas
Modulation of CNSAltered activation in reaction to rectosigmoid stimuli; fail to inhibit pain perception; activation of pain facilitatory pathways
StressChanges in visceral perception and neuro-endocrine responses to stressor
Infection↑ Incidence after bacterial, viral, parasitic infections
InflammationIncreased inflammatory cytokines; decreased anti-inflammatory cytokines
SerotoninInfluencing gut motility, sensation and secretion; altered serotonin signaling in IBS
Genetic factorsFamilial clustering

Contemporary treatment approaches depend on patients’ signs and symptoms as well as comorbid conditions. Other than lifestyle and dietary changes, psychotherapy and psychopharmacological treatment, prokinetics (dopamine antagonists, 5-HT3 antagonists and/or 5-HT4 agonists), antispasmodics, sedatives and tranquilizers, antibiotics[13], probiotics[14], fecal bulking agents and complementary and alternative therapies are now considered as symptomatic treatment[2,15]. Prokinetics and antispasmodics[16] are usually used in IBS-C type, while patients with IBS-D benefit from opioid agonists, anticholinergics, and 5-HT3 antagonists. Treatment options are summarized in Table 2.

Table 2 Common therapeutic modalities.
Therapeutic approachMechanismExample of drugsTherapeutic issues
Cholinergic systemMuscarinic receptor antagonistsHyoscine, cimetropium, zamifenacin, solifenacinLimited value, limited side effects, no interaction
Serotonin system5-HT receptor antagonistsAlosetron, tegaserod, renzaprideSafe on cardiovascular system, anxiolytic, psychological side effects, adverse effects
Antidepressants (SSRIs, TCAs, SNRIs)Neurotransmitter reuptake inhibitorParoxetine, desipramine, venlafaxineLimited use, serious side effects, limited efficacy
Adrenergic agentsα, β3 adrenergic agentsClonidine, solabegronLimited use, side effects, limited efficacy
Corticoid systemCRF antagonistsΑ-Helical CRH9-41Limited use, under investigation
CholecystokininLoxiglumide, dexloxiglumideLimited use, under investigation
NeurotrophinsEnhance neuron survival and developmentNT3Expensive, under investigation, limited use
Sleeping processSleep regulatorMelatoninLimited use
BZD receptor modulatorsGabapentin, dextofisopam, pregabalinSide effects, limited use, under investigation
Guanylate cyclase-c agonistsActivates guanylate cyclase-c receptor in enterocytesLinaclotideLimited use, well toleration, minimal side effects, under investigation
Opioid systemModulating visceral nociceptionAsimadoline, naloxone, naltrexoneLimited central side effects, good efficacy
Neurokinin antagonistsAffect colonic motilityEzlopitant, nepadutantUnder investigation

Despite the wide range of medications and the high prevalence of the disease, to date no completely effective remedy is available. Therefore, investigations in this area should be continued. Pain relief is one of the challenges in the management of IBS as existing visceral analgesics have significant adverse effects and there is a balance to be struck between their usage and side effect profiles. Although various classes of drugs are used for visceral analgesia or other symptoms of IBS such as 5-HT3 antagonists[17], tricyclic antidepressants (TCAs)[18], selective serotonin reuptake inhibitors (SSRIs)[19,20], gabapentinoids, corticotrophin-releasing factor receptor-1 antagonists[21], β3 adrenoceptor agonists[21], somatostatin, and N-methyl d-aspartate receptor antagonists, melatonin[22], and sildenafil[23], there are hopes for new drug investigations. In accordance with this idea, the efficacy of benzodiazepines (BZD) receptor modulators is being determined in ongoing phase III clinical trials[24].

Bearing in mind the new advances in drug classes, and the special attention paid to new BZDs, we intend to study the promising advantageous effects of BZDs from diverse themes including neuroimmunology, anxiolytic, and visceral pain.

In the present review, the most relevant articles on the subject were searched using PubMed, Scopus, Web of Science, and Google Scholar databases up to February 2011. MeSH terms including irritable bowel syndrome, benzodiazepines, benzodiazepine receptor modulators, and gabamimetics were used as search terms. The search was limited to English articles only. All non-clinical and clinical studies were included. The search resulted in 69 papers on the role of benzodiazepines in IBS; of these, after thorough evaluation and the omission of duplicate or non-relevant articles, 10 papers were included and evaluated in detail.

FINDINGS
Visceral pain

Visceral sensitivity and abdominal pain are dual warning signs of IBS but are not present in all patients[25,26]. These patients show diminished visceral perceptual edges, augmented viscerosomatic referral area and larger sensory scores[26]. The regulation of sensory neurotransmission in the gut is indicative of a satisfactory goal in the treatment of IBS. Incidentally, sensory afferents from the intestine have been examined in preclinical and clinical models.

New approaches in brain imaging provided new understandings of the likeness between IBS symptoms and different non-gastrointestinal disorders which pointed to the reformed sense of visceral drive in the central nervous system (CNS) in IBS[27-29]. There is the possibility that the CNS fails to excite pain inhibitory pathways or activates pain facilitatory trails in patients with IBS[30]. As a consequence of the convenient connection between the brain and gut via neural, immune, and endocrine pathways (Figure 1), the involvement of the CNS in the pathophysiology of IBS is prominent[8,11,31-36]. Several parts of the CNS including cerebral regions, dorsal vagal nuclei, as well as the enteric nervous system contain γ-amino butyric acid (GABA) receptors[37,38]. Vagal fibers influence migrating motor complex activity via the enteric nervous system[38]. With the intention of reducing visceral hypersensitivity and the consequential pain, different pathological and pharmacological tactics have been used, for instance motility modulators (SSRIs), and special receptors or ion channels on visceral afferent pathways.

Figure 1
Figure 1 The brain-gut axis. BDZRs: Benzodiazepine receptors; GABARs: γ-aminobutyric acid receptors; 5-HT: 5-hydroxytryptamine; EP: Epinephrine; NEP: Norepinephrine; GABA: γ-aminobutyric acid; Ach: Acetylcholine; CCK: Cholecystokinin; IL-1: Interleukin-1; IL-6: Interleukin-6; TNF-α: Tumor necrosis factor-α; IFN-γ: Interferon-γ; IL-10: Interleukin-10; ENS: Enteric nervous system.

One of the newly targeted classes of drugs for the treatment of visceral pain, BZD receptor modulators, reduce sensitivity and ache perception. Consistent with the promising effects of these modulators, dextofisopam the R enantiomer of tofizopam was developed for the management of IBS-D[39].

BZDs interact with GABA receptors which exist in the CNS and influence the autonomic nervous system, dorsal vagal nuclei, and the enteric nervous system. Vagal fibers affect migrating motor complex movement by the enteric nervous system[40].

BZD receptors were identified in subcortical and hypothalamic regions and appear important in controlling autonomic function[41], such as motor and sensory activity of the gut[42]; nevertheless they do not exist in the gut[43]. Animal studies on the R-enantiomer of tofisopam (the non-sedating anxiolytic), dextofisopam, showed encouraging results in reducing colonic motility and visceral sensitivity with little effect beneath basal conditions[44]. Leventer et al[45] in a phase IIb study of dextofisopam for 12 wk in 140 patients with IBS observed overall symptom relief (primary end point) in 57% of patients as compared with placebo (43% of patients). Although dextofisopam improved stool consistency in men and women, the recurrence rate was only decreased in females. This occurred within one week. The most common side effects were headache and abdominal pain (in 12% of patients in comparison with 4% in the placebo group) which was comparable to placebo. No benefit on bloating, partial defecation, or hospital anxiety and depression scale scores was observed[45]. Interestingly, dextofisopam showed a slight influence on basal GI movement in animals, while after induction of hypermotility, it showed more efficacy[46].

There are a few studies on other BZDs in IBS patients. Castedal et al[40] showed a small effect of midazolam on small bowel motility using manometry, however, phase III related retroperistalsis did not work.

Other than the anxiolytic effect of BZDs, their effect on GABA may be constructive. Two antiepileptic drugs, gabapentin and pregabalin are effective in neuropathic pain. They equally affect GABA receptors in the CNS and increase their binding affinity for endogenous GABA ligand and elevate chloride ion efflux. In this regard, numerous studies assessed the beneficial influence of pregabalin and gabapentin on visceral pain.

Gabapentin, an amplifier of GABA transmission, prevents central neurotransmitter release by impeding α2-δ subunits of voltage-dependent calcium channels[47,48]. Gabapentin has favorable effects on neuropathic pain and hyperalgesia[49,50]. Lee et al[51] demonstrated the effect of gabapentin in reducing human experimental hyperalgesia. They randomized 40 IBS-D patients to receive gabapentin 300 mg/d and then 600 mg/d for 5 d. Gabapentin reduced rectal sensory thresholds by decreasing rectal sensitivity to expansion and improving rectal compliance.

Although the structure of pregabalin is related to GABA, it is inactive at GABA and BZD receptors. It strongly attaches to the α2-δ subunit of voltage-dependent calcium channels and reduces calcium arrival at nerve endings[52] and results in the release of excitatory neurotransmitters (noradrenaline, glutamate, substance P, and calcitonin gene-related peptide) decreasing their involvement in pain pathogenesis[53]. Accordingly, pregabalin reduces normal colonic pain responses and colonic hyperalgesia in a dose-dependent manner in animal studies[54,55]. In animal studies, pregabalin reduced viscerosomatic and autonomic responses caused by colorectal distension resulting in visceral pain relief[56]. In addition, the effect of GABAB receptors in visceral pain was confirmed[57]. In another preclinical study, pregabalin reduced both visceral allodynia and hyperalgesia with no change in basal sensitivity. Houghton et al[58] randomized 26 hypersensitive IBS patients to increasing doses of pregabalin for 3 wk or placebo. They reported significant increases in sensory thresholds from baseline for first defecation and pain, and rectal compliance. In IBS patients, pregabalin restored sensory thresholds to normal levels[58].

Neuroimmunology

Recent approaches to the pathophysiology of IBS have changed from spastic colitis to mucosal immune activation[59,60] and inflammation[61] which is supported by animal studies[62,63]. Generally, in 7%-30% of patients, there is a history of recent bacterial gastroenteritis[64]. Failure to reduce the inflammatory reaction to infection may increase cytokines or special inflammatory cells[65]. There is a discrepancy between pro-inflammatory and anti-inflammatory cytokines in IBS. The influence of the neuroimmune system in the pathogenesis can be elucidated by an augmented number of activated mast cells in the vicinity of colonic nerves, decreased interleukin-10/interleukin-12 (IL10/IL12) ratio and changes in local defense mechanisms in the sigmoid and colonic mucosa in IBS[65-67]. In fact, a number of investigators have proposed low-grade inflammation in IBS which is defined as infiltration of T lymphocytes, mast cells, and enteroendocrine cells into colonic mucosa with mast cells priority[68]. Excessive production of tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ), a trend toward excessive production of interleukin-6 (IL-6), and a defect in the production of interleukin-10 (IL-10) were reported in IBS[15,69]. In accordance with cellular infiltrations, increased levels of interleukin-1β (IL-1β), IL-6, INF-γ and TNF-α, and an abnormal ratio of IL-10/IL-12 in IBS patients were observed[68].

There is a counteraction between the endocrine, central and autonomic nervous and immune systems which is mediated by signal transduction, cytokines and mediators[70]. BZD receptors in both central and peripheral forms and their ligands create a regulatory network between anxiety and the immune system[71]. Central BZD receptors located in the CNS and their activation affects GABA binding to GABAA receptors which regulates chloride flux[72]. The peripheral receptors are located in peripheral tissues and are involved in cell proliferation, heme biosynthesis, cholesterol transport and immunomodulation[73]. Peripheral BZD receptors have been identified on immune cells such as macrophages, neutrophils, leukocytes, and lymphocytes and may have a crucial role in the relationship between the CNS, behavior and immunity[74-78]. Activation of cell growth and DNA synthesis requires nanomolar concentrations of BZDs, thus inhibition of cell proliferation is subject to micromolar concentrations of these compounds[79]. Of BZDs, diazepam and tofizopam bind to both types of receptors[80,81]. Kalashnikov et al[70] in an in vitro study confirmed the inhibitory effect of diazepam on cell proliferation at high doses, while tofizopam enhanced cell proliferation at low and moderate doses. In addition, they found dose-dependent suppression of TNF-α production with both diazepam and tofizopam and a wide range of effects of tofizopam on IL-2 production (enhancement to suppression), while diazepam suppressed IL-2 production[70].

Psychotherapy

A history of psychiatric complaints or mental instabilities in patients is a key factor in IBS and some studies have indicated extensive occurrence of psychiatric disorders in IBS[82,83]. Similarly, the mental state of the patient affects bowel symptoms and may relieve symptoms[84]. The most dominant psychological features of IBS patients are hypochondriasis, depression, anxiety, obsession, and neuroticism[84]. Whitehead et al[85] demonstrated higher scores of psychopathology in IBS patients. High comorbidity exists between functional bowel and stress-related psychiatric disorders[86,87]. Stress precipitates or exacerbates IBS[88].

Since the possibility of comorbidity with mood disturbances such as depression and anxiety is high in IBS, almost all patients with IBS may benefit from TCAs or BZDs. These agents may also decrease pain perception.

Guidelines of the Britain Society of Gastroenterology and the American Gastroenterology Association endorse psychotherapeutic interventions for severe forms of IBS[89,90] to relieve psychological, visceral, and somatic symptoms. Overall benefit was found in IBS patients following psychological treatments in a meta-analysis[91]. In these conditions, combining psychotherapy with psychopharmacological treatment is effective[92]. Studies show that the two most common antidepressant and anxiolytic classes of drugs, TCAs and SSRIs, are effective in symptom relief[93]. Compared to TCAs, SSRIs have fewer side effects but do not improve bloating or visceral pain[93,94]. BZDs are used routinely in anxiety disorders but their efficacy in symptom relief of IBS is under debate[90].

Clouse et al[95] studied the effect of antidepressants in a retrospective study in 138 IBS patients. They evaluated patients’ response to a wide range of antidepressants such as TCA (amitriptyline, doxepin, etc.), trazodone, amoxapine, alprazolam and thioridazine at lower doses than used for affective disorders. They reported significant responses regardless of the presence or absence of psychiatric illness .

CONCLUSION

In the present work, all possible beneficial effects of BZD receptor modulators in IBS from the view points of visceral pain, psychopharmacologic effects, and neuroimmunologic properties were reviewed. It seems that these BZDs influence IBS symptoms via different mechanisms, and these mechanisms are under investigation. There are a small number of studies examining the effects of dextofisopam on patient’s symptoms, however, we are still waiting for the results of phase III trials. In addition, none of these trials have considered the neuroimmunomodulatory effect of BZDs in IBS. Moreover, bearing in mind the concentration-dependent effect of BZDs on cytokines and cell proliferation, future studies using pharmacodynamic and pharmacokinetic approaches are highly recommended.

ACKNOWLEDGMENTS

This paper is the outcome of an in-house non-financially supported study. The paper has been written upon invitation of Professor Mohammad Abdollahi by EiC of WJG.

Footnotes

Peer reviewer: Dr. Rene Lambert, Professor, International Agency for Research on Cancer, 150 Cours Albert Thomas, Lyon 69372 cedex 8, France

S- Editor Tian L L- Editor Webster JR E- Editor Xiong L

References
1.  Cremonini F, Talley NJ. Irritable bowel syndrome: epidemiology, natural history, health care seeking and emerging risk factors. Gastroenterol Clin North Am. 2005;34:189-204.  [PubMed]  [DOI]
2.  Ritchie JA, Truelove SC. Treatment of irritable bowel syndrome with lorazepam, hyoscine butylbromide, and ispaghula husk. Br Med J. 1979;1:376-378.  [PubMed]  [DOI]
3.  Mayer EA, Collins SM. Evolving pathophysiologic models of functional gastrointestinal disorders. Gastroenterology. 2002;122:2032-2048.  [PubMed]  [DOI]
4.  Schwetz I, Bradesi S, Mayer EA. Current insights into the pathophysiology of irritable bowel syndrome. Curr Gastroenterol Rep. 2003;5:331-336.  [PubMed]  [DOI]
5.  Camilleri M, McKinzie S, Busciglio I, Low PA, Sweetser S, Burton D, Baxter K, Ryks M, Zinsmeister AR. Prospective study of motor, sensory, psychologic, and autonomic functions in patients with irritable bowel syndrome. Clin Gastroenterol Hepatol. 2008;6:772-781.  [PubMed]  [DOI]
6.  Mayer EA, Gebhart GF. Basic and clinical aspects of visceral hyperalgesia. Gastroenterology. 1994;107:271-293.  [PubMed]  [DOI]
7.  Bennett EJ, Tennant CC, Piesse C, Badcock CA, Kellow JE. Level of chronic life stress predicts clinical outcome in irritable bowel syndrome. Gut. 1998;43:256-261.  [PubMed]  [DOI]
8.  Collins SM. A case for an immunological basis for irritable bowel syndrome. Gastroenterology. 2002;122:2078-2080.  [PubMed]  [DOI]
9.  Gwee KA, Graham JC, McKendrick MW, Collins SM, Marshall JS, Walters SJ, Read NW. Psychometric scores and persistence of irritable bowel after infectious diarrhoea. Lancet. 1996;347:150-153.  [PubMed]  [DOI]
10.  Gwee KA, Leong YL, Graham C, McKendrick MW, Collins SM, Walters SJ, Underwood JE, Read NW. The role of psychological and biological factors in postinfective gut dysfunction. Gut. 1999;44:400-406.  [PubMed]  [DOI]
11.  Jones MP, Dilley JB, Drossman D, Crowell MD. Brain-gut connections in functional GI disorders: anatomic and physiologic relationships. Neurogastroenterol Motil. 2006;18:91-103.  [PubMed]  [DOI]
12.  Shanahan F. Brain-gut axis and mucosal immunity: a perspective on mucosal psychoneuroimmunology. Semin Gastrointest Dis. 1999;10:8-13.  [PubMed]  [DOI]
13.  Rezaie A, Nikfar S, Abdollahi M. The place of antibiotics in management of irritable bowel syndrome: a systematic review and meta-analysis. Arch Med Sci. 2010;6,1:49-55.  [PubMed]  [DOI]
14.  Nikfar S, Rahimi R, Rahimi F, Derakhshani S, Abdollahi M. Efficacy of probiotics in irritable bowel syndrome: a meta-analysis of randomized, controlled trials. Dis Colon Rectum. 2008;51:1775-1780.  [PubMed]  [DOI]
15.  Salari P, Abdollahi M. Current opinion in the pharmaceutical management of irritable and inflammatory bowel diseases: role of ATP. Recent Pat Endocr Metab Immune Drug Discov. 2009;3:69-75.  [PubMed]  [DOI]
16.  Darvish-Damavandi M, Nikfar S, Abdollahi M. A systematic review of efficacy and tolerability of mebeverine in irritable bowel syndrome. World J Gastroenterol. 2010;16:547-553.  [PubMed]  [DOI]
17.  Rahimi R, Nikfar S, Abdollahi M. Efficacy and tolerability of alosetron for the treatment of irritable bowel syndrome in women and men: a meta-analysis of eight randomized, placebo-controlled, 12-week trials. Clin Ther. 2008;30:884-901.  [PubMed]  [DOI]
18.  Rahimi R, Nikfar S, Rezaie A, Abdollahi M. Efficacy of tricyclic antidepressants in irritable bowel syndrome: a meta-analysis. World J Gastroenterol. 2009;15:1548-1553.  [PubMed]  [DOI]
19.  Rahimi R, Nikfar S, Abdollahi M. Selective serotonin reuptake inhibitors for the management of irritable bowel syndrome: a meta-analysis of randomized controlled trials. Arch Med Sci. 2008;4:71-76.  [PubMed]  [DOI]
20.  Talley NJ. Newer antidepressants in irritable bowel syndrome: what is the evidence? Arch Med Sci. 2008;4:77-78.  [PubMed]  [DOI]
21.  Ghaith O, El-Halabi M, Hashash JG, Sharara AI. Investigational agents for the irritable bowel syndrome. Expert Opin Investig Drugs. 2010;19:1161-1178.  [PubMed]  [DOI]
22.  Mozaffari S, Rahimi R, Abdollahi M. Implications of melatonin therapy in irritable bowel syndrome: a systematic review. Curr Pharm Des. 2010;16:3646-3655.  [PubMed]  [DOI]
23.  Zamani MJ, Sharifzadeh M, Rezaie A, Mashayekhi F, Abdollahi M. Effects of sildenafil on rat irritable bowel syndrome. Therapy. 2005;2:237-242.  [PubMed]  [DOI]
24.  Bulmer DCE, Coelho AM, Winchester WJ. Approaches to the treatment of visceral pain. Drug Discovery Today: therapeutic strategies. 2007;4:171-176.  [PubMed]  [DOI]
25.  Mertz H, Naliboff B, Munakata J, Niazi N, Mayer EA. Altered rectal perception is a biological marker of patients with irritable bowel syndrome. Gastroenterology. 1995;109:40-52.  [PubMed]  [DOI]
26.  Delvaux M. Role of visceral sensitivity in the pathophysiology of irritable bowel syndrome. Gut. 2002;51 Suppl 1:i67-i71.  [PubMed]  [DOI]
27.  Naliboff BD, Derbyshire SW, Munakata J, Berman S, Mandelkern M, Chang L, Mayer EA. Cerebral activation in patients with irritable bowel syndrome and control subjects during rectosigmoid stimulation. Psychosom Med. 2001;63:365-375.  [PubMed]  [DOI]
28.  Mertz H, Morgan V, Tanner G, Pickens D, Price R, Shyr Y, Kessler R. Regional cerebral activation in irritable bowel syndrome and control subjects with painful and nonpainful rectal distention. Gastroenterology. 2000;118:842-848.  [PubMed]  [DOI]
29.  Bonaz B, Baciu M, Papillon E, Bost R, Gueddah N, Le Bas JF, Fournet J, Segebarth C. Central processing of rectal pain in patients with irritable bowel syndrome: an fMRI study. Am J Gastroenterol. 2002;97:654-661.  [PubMed]  [DOI]
30.  Mayer EA, Berman S, Suyenobu B, Labus J, Mandelkern MA, Naliboff BD, Chang L. Differences in brain responses to visceral pain between patients with irritable bowel syndrome and ulcerative colitis. Pain. 2005;115:398-409.  [PubMed]  [DOI]
31.  Spiller RC. Role of nerves in enteric infection. Gut. 2002;51:759-762.  [PubMed]  [DOI]
32.  Barbara G, De Giorgio R, Stanghellini V, Cremon C, Corinaldesi R. A role for inflammation in irritable bowel syndrome? Gut. 2002;51 Suppl 1:i41-i44.  [PubMed]  [DOI]
33.  Mayer EA, Naliboff BD, Chang L, Coutinho SV. V. Stress and irritable bowel syndrome. Am J Physiol Gastrointest Liver Physiol. 2001;280:G519-G524.  [PubMed]  [DOI]
34.  Mertz H. Role of the brain and sensory pathways in gastrointestinal sensory disorders in humans. Gut. 2002;51 Suppl 1:i29-i33.  [PubMed]  [DOI]
35.  Shanahan F. Brain-gut axis and mucosal immunity: a perspective on mucosal psychoneuroimmunology. Semin Gastrointest Dis. 1999;10:8-13.  [PubMed]  [DOI]
36.  Sudo N, Chida Y, Aiba Y, Sonoda J, Oyama N, Yu XN, Kubo C, Koga Y. Postnatal microbial colonization programs the hypothalamic-pituitary-adrenal system for stress response in mice. J Physiol. 2004;558:263-275.  [PubMed]  [DOI]
37.  Greenwood-Meerveld B, Barron KW. Tonic GABA (A) receptor-mediated neurotransmission in the dorsal vagal complex regulates intestinal motility in rats. Eur J Pharmacol. 1998;346:197-202.  [PubMed]  [DOI]
38.  Gentilini G, Franchi-Micheli S, Pantalone D, Cortesini C, Zilletti L. GABAB receptor-mediated mechanisms in human intestine in vitro. Eur J Pharmacol. 1992;217:9-14.  [PubMed]  [DOI]
39.  Grundmann O, Yoon SL, Moshiree B. Current developments for the diagnosis and treatment of irritable bowel syndrome. Curr Pharm Des. 2010;16:3638-3645.  [PubMed]  [DOI]
40.  Castedal M, Björnsson E, Abrahamsson H. Effects of midazolam on small bowel motility in humans. Aliment Pharmacol Ther. 2000;14:571-577.  [PubMed]  [DOI]
41.  Yamaguchi K, Suzuki K, Niho T, Shimora M, Ito C, Ohnishi H. Tofisopam, a new 2,3-benzodiazepine. Inhibition of changes induced by stress loading and hypothalamic stimulation. Can J Physiol Pharmacol. 1983;61:619-625.  [PubMed]  [DOI]
42.  Iovino P, Azpiroz F, Domingo E, Malagelada JR. The sympathetic nervous system modulates perception and reflex responses to gut distention in humans. Gastroenterology. 1995;108:680-686.  [PubMed]  [DOI]
43.  Horváth EJ, Horváth K, Hámori T, Fekete MI, Sólyom S, Palkovits M. Anxiolytic 2,3-benzodiazepines, their specific binding to the basal ganglia. Prog Neurobiol. 2000;60:309-342.  [PubMed]  [DOI]
44.  Leventer SM, Kucharik RF, Keogh JC, Karen R, Kimm BG, Naidong Y, Brian TS, Judi G, Jess A, Kevin LK. The potential of dextofisopam for treatment of irritable bowel syndrome and inflammatory bowel disease. Am J Gastroenterol. 2004;99:S279.  [PubMed]  [DOI]
45.  Leventer SM, Raudibaugh K, Frissora CL, Kassem N, Keogh JC, Phillips J, Mangel AW. Clinical trial: dextofisopam in the treatment of patients with diarrhoea-predominant or alternating irritable bowel syndrome. Aliment Pharmacol Ther. 2008;27:197-206.  [PubMed]  [DOI]
46.  Mangel AW, Fehnel SE. Design of treatment trials in irritable bowel syndrome: opioid agonists and atypical benzodiazepine antagonists. Neurogastroenterol Motil. 2008;20:1086-1093.  [PubMed]  [DOI]
47.  Petroff OA, Rothman DL, Behar KL, Lamoureux D, Mattson RH. The effect of gabapentin on brain gamma-aminobutyric acid in patients with epilepsy. Ann Neurol. 1996;39:95-99.  [PubMed]  [DOI]
48.  Shimoyama M, Shimoyama N, Hori Y. Gabapentin affects glutamatergic excitatory neurotransmission in the rat dorsal horn. Pain. 2000;85:405-414.  [PubMed]  [DOI]
49.  Rice AS, Maton S. Gabapentin in postherpetic neuralgia: a randomised, double blind, placebo controlled study. Pain. 2001;94:215-224.  [PubMed]  [DOI]
50.  Lu Y, Westlund KN. Gabapentin attenuates nociceptive behaviors in an acute arthritis model in rats. J Pharmacol Exp Ther. 1999;290:214-219.  [PubMed]  [DOI]
51.  Lee KJ, Kim JH, Cho SW. Gabapentin reduces rectal mechanosensitivity and increases rectal compliance in patients with diarrhoea-predominant irritable bowel syndrome. Aliment Pharmacol Ther. 2005;22:981-988.  [PubMed]  [DOI]
52.  Bian F, Li Z, Offord J, Davis MD, McCormick J, Taylor CP, Walker LC. Calcium channel alpha2-delta type 1 subunit is the major binding protein for pregabalin in neocortex, hippocampus, amygdala, and spinal cord: an ex vivo autoradiographic study in alpha2-delta type 1 genetically modified mice. Brain Res. 2006;1075:68-80.  [PubMed]  [DOI]
53.  Dooley DJ, Taylor CP, Donevan S, Feltner D. Ca2+ channel alpha2delta ligands: novel modulators of neurotransmission. Trends Pharmacol Sci. 2007;28:75-82.  [PubMed]  [DOI]
54.  Million M, Wang L, Adelson DW, Roman F, Diop L, Taché Y. Pregabalin decreases visceral pain and prevents spinal neuronal activation in rats. Gut. 2007;56:1482-1484.  [PubMed]  [DOI]
55.  Diop L, Raymond F, Fargeau H, Petoux F, Chovet M, Doherty AM. Pregabalin (CI-1008) inhibits the trinitrobenzene sulfonic acid-induced chronic colonic allodynia in the rat. J Pharmacol Exp Ther. 2002;302:1013-1022.  [PubMed]  [DOI]
56.  Ravnefjord A, Brusberg M, Larsson H, Lindström E, Martínez V. Effects of pregabalin on visceral pain responses and colonic compliance in rats. Br J Pharmacol. 2008;155:407-416.  [PubMed]  [DOI]
57.  Brusberg M, Ravnefjord A, Martinsson R, Larsson H, Martinez V, Lindström E. The GABA(B) receptor agonist, baclofen, and the positive allosteric modulator, CGP7930, inhibit visceral pain-related responses to colorectal distension in rats. Neuropharmacology. 2009;56:362-367.  [PubMed]  [DOI]
58.  Houghton LA, Fell C, Whorwell PJ, Jones I, Sudworth DP, Gale JD. Effect of a second-generation alpha2delta ligand (pregabalin) on visceral sensation in hypersensitive patients with irritable bowel syndrome. Gut. 2007;56:1218-1225.  [PubMed]  [DOI]
59.  Chadwick VS, Chen W, Shu D, Paulus B, Bethwaite P, Tie A, Wilson I. Activation of the mucosal immune system in irritable bowel syndrome. Gastroenterology. 2002;122:1778-1783.  [PubMed]  [DOI]
60.  Spiller RC, Jenkins D, Thornley JP, Hebden JM, Wright T, Skinner M, Neal KR. Increased rectal mucosal enteroendocrine cells, T lymphocytes, and increased gut permeability following acute Campylobacter enteritis and in post-dysenteric irritable bowel syndrome. Gut. 2000;47:804-811.  [PubMed]  [DOI]
61.  Törnblom H, Lindberg G, Nyberg B, Veress B. Full-thickness biopsy of the jejunum reveals inflammation and enteric neuropathy in irritable bowel syndrome. Gastroenterology. 2002;123:1972-1979.  [PubMed]  [DOI]
62.  Barbara G, De Giorgio R, Deng Y, Vallance B, Blennerhassett P, Collins SM. Role of immunologic factors and cyclooxygenase 2 in persistent postinfective enteric muscle dysfunction in mice. Gastroenterology. 2001;120:1729-1736.  [PubMed]  [DOI]
63.  De Giorgio R, Barbara G, Blennerhassett P, Wang L, Stanghellini V, Corinaldesi R, Collins SM, Tougas G. Intestinal inflammation and activation of sensory nerve pathways: a functional and morphological study in the nematode infected rat. Gut. 2001;49:822-827.  [PubMed]  [DOI]
64.  Neal KR, Hebden J, Spiller R. Prevalence of gastrointestinal symptoms six months after bacterial gastroenteritis and risk factors for development of the irritable bowel syndrome: postal survey of patients. BMJ. 1997;314:779-782.  [PubMed]  [DOI]
65.  Barbara G, Stanghellini V, De Giorgio R, Cremon C, Cottrell GS, Santini D, Pasquinelli G, Morselli-Labate AM, Grady EF, Bunnett NW. Activated mast cells in proximity to colonic nerves correlate with abdominal pain in irritable bowel syndrome. Gastroenterology. 2004;126:693-702.  [PubMed]  [DOI]
66.  O'Mahony L, McCarthy J, Kelly P, Hurley G, Luo F, Chen K, O'Sullivan GC, Kiely B, Collins JK, Shanahan F. Lactobacillus and bifidobacterium in irritable bowel syndrome: symptom responses and relationship to cytokine profiles. Gastroenterology. 2005;128:541-551.  [PubMed]  [DOI]
67.  Aerssens J, Camilleri M, Talloen W, Thielemans L, Göhlmann HW, Van Den Wyngaert I, Thielemans T, De Hoogt R, Andrews CN, Bharucha AE. Alterations in mucosal immunity identified in the colon of patients with irritable bowel syndrome. Clin Gastroenterol Hepatol. 2008;6:194-205.  [PubMed]  [DOI]
68.  Rodríguez-Fandiño O, Hernández-Ruiz J, Schmulson M. From cytokines to toll-like receptors and beyond - current knowledge and future research needs in irritable bowel syndrome. J Neurogastroenterol Motil. 2010;16:363-373.  [PubMed]  [DOI]
69.  O'Mahony SM, Marchesi JR, Scully P, Codling C, Ceolho AM, Quigley EM, Cryan JF, Dinan TG. Early life stress alters behavior, immunity, and microbiota in rats: implications for irritable bowel syndrome and psychiatric illnesses. Biol Psychiatry. 2009;65:263-267.  [PubMed]  [DOI]
70.  Kalashnikov SV, Kalashnikova EA, Kokarovtseva SN. Immunomodulating effects of tofizopam (Grandaxin) and diazepam in vitro. Mediators Inflamm. 2002;11:53-59.  [PubMed]  [DOI]
71.  Savino W, Dardenne M. Immune-neuroendocrine interactions. Immunol Today. 1995;16:318-322.  [PubMed]  [DOI]
72.  Olsen RW, Tobin AJ. Molecular biology of GABAA receptors. FASEB J. 1990;4:1469-1480.  [PubMed]  [DOI]
73.  Zisterer DM, Williams DC. Peripheral-type benzodiazepine receptors. Gen Pharmacol. 1997;29:305-314.  [PubMed]  [DOI]
74.  Drugan RC. Are the nonmitochondrial peripheral benzodiazepine receptors on leukocytes a novel intermediary of brain, behavior, and immunity? Lab Invest. 1994;70:1-5.  [PubMed]  [DOI]
75.  Zavala F, Haumont J, Lenfant M. Interaction of benzodiazepines with mouse macrophages. Eur J Pharmacol. 1984;106:561-566.  [PubMed]  [DOI]
76.  Zavala F, Masson A, Brys L, de Baetselier P, Descamps-Latscha B. A monoclonal antibody against peripheral benzodiazepine receptor activities the human neutrophil NADPH-oxidase. Biochem Biophys Res Commun. 1991;176:1577-1583.  [PubMed]  [DOI]
77.  Cahard D, Canat X, Carayon P, Roque C, Casellas P, Le Fur G. Subcellular localization of peripheral benzodiazepine receptors on human leukocytes. Lab Invest. 1994;70:23-28.  [PubMed]  [DOI]
78.  Cahard D, Canat X, Carayon P, Roque C, Casellas P, Le Fur G. Subcellular localization of peripheral benzodiazepine receptors on human leukocytes. Lab Invest. 1994;70:23-28.  [PubMed]  [DOI]
79.  Ikezaki K, Black KL. Stimulation of cell growth and DNA synthesis by peripheral benzodiazepine. Cancer Lett. 1990;49:115-120.  [PubMed]  [DOI]
80.  Braestrup C, Squires RF. Specific benzodiazepine receptors in rat brain characterized by high-affinity (3H)diazepam binding. Proc Natl Acad Sci USA. 1977;74:3805-3809.  [PubMed]  [DOI]
81.  Petócz L. Pharmacologic effects of tofizopam (Grandaxin). Acta Pharm Hung. 1993;63:79-82.  [PubMed]  [DOI]
82.  Walker EA, Roy-Byrne PP, Katon WJ. Irritable bowel syndrome and psychiatric illness. Am J Psychiatry. 1990;147:565-572.  [PubMed]  [DOI]
83.  Ford AC, Talley NJ, Schoenfeld PS, Quigley EM, Moayyedi P. Efficacy of antidepressants and psychological therapies in irritable bowel syndrome: systematic review and meta-analysis. Gut. 2009;58:367-378.  [PubMed]  [DOI]
84.  Stockbrügger R, Coremans G, Creed F, Dapoigny M, Müller-Lissner SA, Pace F, Smout A, Whorwell PJ. Psychosocial background and intervention in the irritable bowel syndrome. Digestion. 1999;60:175-186.  [PubMed]  [DOI]
85.  Whitehead WE, Bosmajian L, Zonderman AB, Costa PT, Schuster MM. Symptoms of psychologic distress associated with irritable bowel syndrome. Comparison of community and medical clinic samples. Gastroenterology. 1988;95:709-714.  [PubMed]  [DOI]
86.  Dinan TG, Quigley EM, Ahmed SM, Scully P, O'Brien S, O'Mahony L, O'Mahony S, Shanahan F, Keeling PW. Hypothalamic-pituitary-gut axis dysregulation in irritable bowel syndrome: plasma cytokines as a potential biomarker? Gastroenterology. 2006;130:304-311.  [PubMed]  [DOI]
87.  Koloski NA, Talley NJ, Boyce PM. Predictors of health care seeking for irritable bowel syndrome and nonulcer dyspepsia: a critical review of the literature on symptom and psychosocial factors. Am J Gastroenterol. 2001;96:1340-1349.  [PubMed]  [DOI]
88.  Dinan TG. Stress: the shared common component in major mental illnesses. Eur Psychiatry. 2005;20 Suppl 3:S326-S328.  [PubMed]  [DOI]
89.  Jones J, Boorman J, Cann P, Forbes A, Gomborone J, Heaton K, Hungin P, Kumar D, Libby G, Spiller R. British Society of Gastroenterology guidelines for the management of the irritable bowel syndrome. Gut. 2000;47 Suppl 2:ii1-i19.  [PubMed]  [DOI]
90.  Drossman DA, Camilleri M, Mayer EA, Whitehead WE. AGA technical review on irritable bowel syndrome. Gastroenterology. 2002;123:2108-2131.  [PubMed]  [DOI]
91.  Lackner JM, Mesmer C, Morley S, Dowzer C, Hamilton S. Psychological treatments for irritable bowel syndrome: a systematic review and meta-analysis. J Consult Clin Psychol. 2004;72:1100-1113.  [PubMed]  [DOI]
92.  Jackson JL, O'Malley PG, Tomkins G, Balden E, Santoro J, Kroenke K. Treatment of functional gastrointestinal disorders with antidepressant medications: a meta-analysis. Am J Med. 2000;108:65-72.  [PubMed]  [DOI]
93.  Käll E, Lindström E, Martinez V. The serotonin reuptake inhibitor citalopram does not affect colonic sensitivity or compliance in rats. Eur J Pharmacol. 2007;570:203-211.  [PubMed]  [DOI]
94.  Tack J, Broekaert D, Fischler B, Van Oudenhove L, Gevers AM, Janssens J. A controlled crossover study of the selective serotonin reuptake inhibitor citalopram in irritable bowel syndrome. Gut. 2006;55:1095-1103.  [PubMed]  [DOI]
95.  Clouse RE, Lustman PJ, Geisman RA, Alpers DH. Antidepressant therapy in 138 patients with irritable bowel syndrome: a five-year clinical experience. Aliment Pharmacol Ther. 1994;8:409-416.  [PubMed]  [DOI]