Downloaded from http://gut.bmj.com/ on November 14, 2014 - Published by group.bmj.com
Gut Online First, published on April 4, 2014 as 10.1136/gutjnl-2014-306894 Commentary
Histamine antagonism and postinflammatory visceral hypersensitivity M M Wouters Abdominal pain is one of the most difficult to treat symptoms in patients suffering from IBS. Recent evidence shows that abnormal perception of visceral stimuli, or visceral hypersensitivity, represents an important underlying mechanism. Of interest, similar mechanisms may be involved in abdominal pain reported by UC and Crohn’s disease patients in remission. Although the underlying mechanisms are not fully understood, it becomes increasingly clear that intestinal inflammation may provide an initial stimulus for a persistent state of visceral hypersensitivity. Most insight in the role of inflammation in chronic abdominal pain comes from studies evaluating patients with postinfectious (PI)-IBS. Colonic biopsies of patients with PI-IBS reveal no signs of overt inflammation but show persistent minor increases in epithelial T lymphocytes and mast cells,1 suggesting that long-term inflammatory changes may be responsible for colonic hypersensitivity. To date, mast cells are considered to play a key role in this process. Supernatant of mucosal biopsies of visceral hypersensitive patients with IBS indeed contains more mast cell mediators such as serotonin, histamine and proteases, which are able to activate visceral afferent nerve fibres.2 Moreover, abdominal pain in patients with IBS was reported to be correlated with the number of activated mast cells in proximity of colonic nerves, further suggesting that mediators released by mast cells may play an important role in abdominal pain.3 One of the potential candidate mast cell mediators involved is histamine. Histamine is synthesised in all human tissues, but is particularly abundant in skin, lung and gastrointestinal tract. Mast cells are a prominent source of histamine, although histamine is to a lesser extent also secreted by basophils, histaminergic neurons and
Correspondence to Dr Mira M Wouters, Translational Research Center for Gastrointestinal Disorders (TARGID), Center of Neuro-immune interaction and Mucosal Immunology, KU Leuven, University Hospital of Leuven, Herestraat 49, Leuven 3000, Belgium; mira. [email protected]
microbiota. Four histamine receptors have been identified, all of which are G proteincoupled receptors, that are designated H1 through H4. In the skin, histamine is mainly released from mast cells in response to crosslinking of IgE molecules expressed on the cell membrane by allergens. Once released, it induces itch by excitation of a subset of afferent, histamine-sensitive unmyelinated C-fibres, although recent studies demonstrate that histamine can also trigger neurogenic inflammation4 and pain. At least in the skin, multiple HRs seem to be involved in these processes. Blockade of H1R and H2R by pyrilamine and ranitidine respectively reduces pain induced by subcutaneous injection of formaline in the paw5 and inhibits both thermal and mechanical hyperalgesia following nerve injury.6 Moreover, recent data support a role for H4Rs in inflammation-induced hyperalgesia: the selective H4R antagonist JNJ7777120 potently reversed both acute and chronic inflammatory pain following intraplantar carrageenan and complete Freund’s adjuvant injection7 and in carrageen-induced pleurisy.8 In addition, JNJ7777120 significantly reduced hyperalgesia in neuropathic pain models of spinal and sciatic nerve ligation.7 9 Deiteren et al10 elegantly demonstrate that also in the intestine, H1R and H4R play a key role in aberrant pain perception following intestinal inflammation. The authors induced distal colitis in rats by intrarectal instillation of 2,4,6-trinitrobenzenesulfonic acid. After resolution of colitis, confirmed by endoscopic healing and regression of the inflammatory infiltrate (T cells and MPO activity), the animals showed increased pain responses, assessed by the visceromotor response, to colorectal distention, indicating the presence of postinflammatory visceral hypersensitivity. Intriguingly, mast cell numbers were significantly increased in the colon of postcolitis rats compared with control rats. In addition, the spontaneous histamine release was threefold increased in specimens obtained from postcolitis rats, indicating that mast cells and, in particular, histamine may play a key role in
postinflammatory visceral hypersensitivity. This was further underscored by a dosedependent reduction of pain responses evoked by colonic distention after treatment with the H1R antagonist levocetirizine. These findings are in line with previous studies supporting the role of H1R in visceral hypersensitivity in patients with IBS and an animal model of IBS.11 12 Two recent proof-of-principle clinical trials confirmed the clinical relevance of these findings showing improvement of abdominal pain and global relief by the H1R antagonists ketotifen12 and ebastin13 in patients with IBS. Most interestingly, Deiteren et al present evidence that H4R may also be involved in visceral hypersensitivity. The selective H4R antagonist JNJ7777120 dose-dependently normalised the visceromotor response to colorectal distension, an effect that was potentiated when combined with an H1R antagonist. The results reported by Deiteren et al are of extreme interest because they indicate an unexpected role for H4R antagonism in aberrant postinflammatory pain perception. The role of H4Rs in visceral nociception may bear great potential for the treatment of postinflammatory hypersensitivity, although the underlying mechanism needs further study. In the colon, H4Rs are expressed on mast cells and immune cells (T cells and dendritic cells) but not on sensory neurons, indicating an indirect effect of H4R antagonism on neuronal sensitivity. Even at the highest dose used by the authors, JNJ7777120 did not act as a mast cell stabiliser, indicating that H4Rs probably do not play a role in mast cell degranulation.14 More studies are required to evaluate to what extent pro-inflammatory cytokines and mast cell mediators such as histamine contribute to inflammation and subsequent neuronal sensitivity in models of postinflammatory hypersensitivity and whether these immune parameters are modulated by H4R and H1R. One point of concern may perhaps be the high doses of JNJ7777120 used, implying that interaction with other receptors, including H1R, may have to be considered. Nevertheless, H4R has become a promising target for immuno-inflammatory diseases, such as allergic rhinitis, asthma or dermal allergies. Several proof-of-concept clinical trials are completed with H4R antagonists in asthma, allergic rhinitis and itch.15 As these agents are already available for human use, the data presented by Deiteren et al beg for further studies
Wouters MM.Article Gut Monthauthor 2014 Vol (or 0 No their 0 1 Copyright employer) 2014. Produced by BMJ Publishing Group Ltd (& BSG) under licence.
Downloaded from http://gut.bmj.com/ on November 14, 2014 - Published by group.bmj.com
Commentary evaluating the role of H4R in abdominal pain in IBS and IBD in remission, including clinical studies investigating the effect of H4R antagonists. Competing interests None. Provenance and peer review Commissioned; internally peer reviewed. To cite Wouters MM. Gut Published Online First: [ please include Day Month Year] doi:10.1136/gutjnl2014-306894
2
3
4
5
Received 14 March 2014 Accepted 17 March 2014 6
▸ http://dx.doi.org/10.1136/gutjnl-2013-305870
7
Gut 2014;0:1–2. doi:10.1136/gutjnl-2014-306894
REFERENCES 1
2
Ohman L, Simren M. Pathogenesis of IBS: role of inflammation, immunity and neuroimmune interactions. Nat Rev Gastroenterol Hepatol 2010;7:163–73.
8
Buhner S, Li Q, Berger T, et al. Submucous rather than myenteric neurons are activated by mucosal biopsy supernatants from irritable bowel syndrome patients. Neurogastroenterol Motil 2012;24:1134–e572. Barbara G, Stanghellini V, De GR, et al. Activated mast cells in proximity to colonic nerves correlate with abdominal pain in irritable bowel syndrome. Gastroenterology 2004;126:693–702. Rosa AC, Fantozzi R. The role of histamine in neurogenic inflammation. Br J Pharmacol 2013;170:38–45. Mobarakeh JI, Torkaman-Boutorabi A, Rahimi AA, et al. Interaction of histamine and calcitonin gene-related peptide in the formalin induced pain perception in rats. Biomed Res 2011;32:195–201. Zuo Y, Perkins NM, Tracey DJ, et al. Inflammation and hyperalgesia induced by nerve injury in the rat: a key role of mast cells. Pain 2003;105:467–79. Hsieh GC, Chandran P, Salyers AK, et al. H4 receptor antagonism exhibits anti-nociceptive effects in inflammatory and neuropathic pain models in rats. Pharmacol Biochem Behav 2010;95:41–50. Pini A, Somma T, Formicola G, et al. Effects of a selective Histamine H4R antagonist on inflammation in a model of carrageenan-induced pleurisy in the rat. Curr Pharm Des 2014;20:1338–44.
9
10
11
12
13
14
15
Smith FM, Haskelberg H, Tracey DJ, et al. Role of histamine H3 and H4 receptors in mechanical hyperalgesia following peripheral nerve injury. Neuroimmunomodulation 2007;14:317–25. Deiteren A, De Man JG, Ruyssers NE, et al. Histamine H4 and H1 receptors contribute to postinflammatory visceral hypersensitivity. Gut Published Online First: 21 Feb 2014. doi:10.1136/ gutjnl-2013-305870 Stanisor OI, van Diest SA, Yu Z, et al. Stress-induced visceral hypersensitivity in maternally separated rats can be reversed by peripherally restricted histamine1-receptor antagonists. PLoS ONE 2013;8:e66884. Klooker TK, Braak B, Koopman KE, et al. The mast cell stabiliser ketotifen decreases visceral hypersensitivity and improves intestinal symptoms in patients with irritable bowel syndrome. Gut 2010;59:1213–21. van Wanrooij SJ, Wouters MM, van Oudenhove L, et al. Effect of the H1-receptor antagonist ebastin on visceral perception and clinical symptoms in IBS. Gastroenterology 2013;144:S-160. Ref Type: Abstract Hofstra CL, Desai PJ, Thurmond RL, et al. Histamine H4 receptor mediates chemotaxis and calcium mobilization of mast cells. J Pharmacol Exp Ther 2003;305:1212–21. Salcedo C, Pontes C, Merlos M. Is the H4 receptor a new drug target for allergies and asthma? Front Biosci (Elite Ed) 2013;5:178–87.
Wouters MM. Gut Month 2014 Vol 0 No 0
Downloaded from http://gut.bmj.com/ on November 14, 2014 - Published by group.bmj.com
Histamine antagonism and postinflammatory visceral hypersensitivity M M Wouters Gut published online April 4, 2014
Updated information and services can be found at: http://gut.bmj.com/content/early/2014/04/04/gutjnl-2014-306894
These include:
References
This article cites 14 articles, 2 of which you can access for free at: http://gut.bmj.com/content/early/2014/04/04/gutjnl-2014-306894#BIBL
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To request permissions go to: http://group.bmj.com/group/rights-licensing/permissions To order reprints go to: http://journals.bmj.com/cgi/reprintform To subscribe to BMJ go to: http://group.bmj.com/subscribe/
Gut Online First, published on April 4, 2014 as 10.1136/gutjnl-2014-306894 Commentary
Histamine antagonism and postinflammatory visceral hypersensitivity M M Wouters Abdominal pain is one of the most difficult to treat symptoms in patients suffering from IBS. Recent evidence shows that abnormal perception of visceral stimuli, or visceral hypersensitivity, represents an important underlying mechanism. Of interest, similar mechanisms may be involved in abdominal pain reported by UC and Crohn’s disease patients in remission. Although the underlying mechanisms are not fully understood, it becomes increasingly clear that intestinal inflammation may provide an initial stimulus for a persistent state of visceral hypersensitivity. Most insight in the role of inflammation in chronic abdominal pain comes from studies evaluating patients with postinfectious (PI)-IBS. Colonic biopsies of patients with PI-IBS reveal no signs of overt inflammation but show persistent minor increases in epithelial T lymphocytes and mast cells,1 suggesting that long-term inflammatory changes may be responsible for colonic hypersensitivity. To date, mast cells are considered to play a key role in this process. Supernatant of mucosal biopsies of visceral hypersensitive patients with IBS indeed contains more mast cell mediators such as serotonin, histamine and proteases, which are able to activate visceral afferent nerve fibres.2 Moreover, abdominal pain in patients with IBS was reported to be correlated with the number of activated mast cells in proximity of colonic nerves, further suggesting that mediators released by mast cells may play an important role in abdominal pain.3 One of the potential candidate mast cell mediators involved is histamine. Histamine is synthesised in all human tissues, but is particularly abundant in skin, lung and gastrointestinal tract. Mast cells are a prominent source of histamine, although histamine is to a lesser extent also secreted by basophils, histaminergic neurons and
Correspondence to Dr Mira M Wouters, Translational Research Center for Gastrointestinal Disorders (TARGID), Center of Neuro-immune interaction and Mucosal Immunology, KU Leuven, University Hospital of Leuven, Herestraat 49, Leuven 3000, Belgium; mira. [email protected]
microbiota. Four histamine receptors have been identified, all of which are G proteincoupled receptors, that are designated H1 through H4. In the skin, histamine is mainly released from mast cells in response to crosslinking of IgE molecules expressed on the cell membrane by allergens. Once released, it induces itch by excitation of a subset of afferent, histamine-sensitive unmyelinated C-fibres, although recent studies demonstrate that histamine can also trigger neurogenic inflammation4 and pain. At least in the skin, multiple HRs seem to be involved in these processes. Blockade of H1R and H2R by pyrilamine and ranitidine respectively reduces pain induced by subcutaneous injection of formaline in the paw5 and inhibits both thermal and mechanical hyperalgesia following nerve injury.6 Moreover, recent data support a role for H4Rs in inflammation-induced hyperalgesia: the selective H4R antagonist JNJ7777120 potently reversed both acute and chronic inflammatory pain following intraplantar carrageenan and complete Freund’s adjuvant injection7 and in carrageen-induced pleurisy.8 In addition, JNJ7777120 significantly reduced hyperalgesia in neuropathic pain models of spinal and sciatic nerve ligation.7 9 Deiteren et al10 elegantly demonstrate that also in the intestine, H1R and H4R play a key role in aberrant pain perception following intestinal inflammation. The authors induced distal colitis in rats by intrarectal instillation of 2,4,6-trinitrobenzenesulfonic acid. After resolution of colitis, confirmed by endoscopic healing and regression of the inflammatory infiltrate (T cells and MPO activity), the animals showed increased pain responses, assessed by the visceromotor response, to colorectal distention, indicating the presence of postinflammatory visceral hypersensitivity. Intriguingly, mast cell numbers were significantly increased in the colon of postcolitis rats compared with control rats. In addition, the spontaneous histamine release was threefold increased in specimens obtained from postcolitis rats, indicating that mast cells and, in particular, histamine may play a key role in
postinflammatory visceral hypersensitivity. This was further underscored by a dosedependent reduction of pain responses evoked by colonic distention after treatment with the H1R antagonist levocetirizine. These findings are in line with previous studies supporting the role of H1R in visceral hypersensitivity in patients with IBS and an animal model of IBS.11 12 Two recent proof-of-principle clinical trials confirmed the clinical relevance of these findings showing improvement of abdominal pain and global relief by the H1R antagonists ketotifen12 and ebastin13 in patients with IBS. Most interestingly, Deiteren et al present evidence that H4R may also be involved in visceral hypersensitivity. The selective H4R antagonist JNJ7777120 dose-dependently normalised the visceromotor response to colorectal distension, an effect that was potentiated when combined with an H1R antagonist. The results reported by Deiteren et al are of extreme interest because they indicate an unexpected role for H4R antagonism in aberrant postinflammatory pain perception. The role of H4Rs in visceral nociception may bear great potential for the treatment of postinflammatory hypersensitivity, although the underlying mechanism needs further study. In the colon, H4Rs are expressed on mast cells and immune cells (T cells and dendritic cells) but not on sensory neurons, indicating an indirect effect of H4R antagonism on neuronal sensitivity. Even at the highest dose used by the authors, JNJ7777120 did not act as a mast cell stabiliser, indicating that H4Rs probably do not play a role in mast cell degranulation.14 More studies are required to evaluate to what extent pro-inflammatory cytokines and mast cell mediators such as histamine contribute to inflammation and subsequent neuronal sensitivity in models of postinflammatory hypersensitivity and whether these immune parameters are modulated by H4R and H1R. One point of concern may perhaps be the high doses of JNJ7777120 used, implying that interaction with other receptors, including H1R, may have to be considered. Nevertheless, H4R has become a promising target for immuno-inflammatory diseases, such as allergic rhinitis, asthma or dermal allergies. Several proof-of-concept clinical trials are completed with H4R antagonists in asthma, allergic rhinitis and itch.15 As these agents are already available for human use, the data presented by Deiteren et al beg for further studies
Wouters MM.Article Gut Monthauthor 2014 Vol (or 0 No their 0 1 Copyright employer) 2014. Produced by BMJ Publishing Group Ltd (& BSG) under licence.
Downloaded from http://gut.bmj.com/ on November 14, 2014 - Published by group.bmj.com
Commentary evaluating the role of H4R in abdominal pain in IBS and IBD in remission, including clinical studies investigating the effect of H4R antagonists. Competing interests None. Provenance and peer review Commissioned; internally peer reviewed. To cite Wouters MM. Gut Published Online First: [ please include Day Month Year] doi:10.1136/gutjnl2014-306894
2
3
4
5
Received 14 March 2014 Accepted 17 March 2014 6
▸ http://dx.doi.org/10.1136/gutjnl-2013-305870
7
Gut 2014;0:1–2. doi:10.1136/gutjnl-2014-306894
REFERENCES 1
2
Ohman L, Simren M. Pathogenesis of IBS: role of inflammation, immunity and neuroimmune interactions. Nat Rev Gastroenterol Hepatol 2010;7:163–73.
8
Buhner S, Li Q, Berger T, et al. Submucous rather than myenteric neurons are activated by mucosal biopsy supernatants from irritable bowel syndrome patients. Neurogastroenterol Motil 2012;24:1134–e572. Barbara G, Stanghellini V, De GR, et al. Activated mast cells in proximity to colonic nerves correlate with abdominal pain in irritable bowel syndrome. Gastroenterology 2004;126:693–702. Rosa AC, Fantozzi R. The role of histamine in neurogenic inflammation. Br J Pharmacol 2013;170:38–45. Mobarakeh JI, Torkaman-Boutorabi A, Rahimi AA, et al. Interaction of histamine and calcitonin gene-related peptide in the formalin induced pain perception in rats. Biomed Res 2011;32:195–201. Zuo Y, Perkins NM, Tracey DJ, et al. Inflammation and hyperalgesia induced by nerve injury in the rat: a key role of mast cells. Pain 2003;105:467–79. Hsieh GC, Chandran P, Salyers AK, et al. H4 receptor antagonism exhibits anti-nociceptive effects in inflammatory and neuropathic pain models in rats. Pharmacol Biochem Behav 2010;95:41–50. Pini A, Somma T, Formicola G, et al. Effects of a selective Histamine H4R antagonist on inflammation in a model of carrageenan-induced pleurisy in the rat. Curr Pharm Des 2014;20:1338–44.
9
10
11
12
13
14
15
Smith FM, Haskelberg H, Tracey DJ, et al. Role of histamine H3 and H4 receptors in mechanical hyperalgesia following peripheral nerve injury. Neuroimmunomodulation 2007;14:317–25. Deiteren A, De Man JG, Ruyssers NE, et al. Histamine H4 and H1 receptors contribute to postinflammatory visceral hypersensitivity. Gut Published Online First: 21 Feb 2014. doi:10.1136/ gutjnl-2013-305870 Stanisor OI, van Diest SA, Yu Z, et al. Stress-induced visceral hypersensitivity in maternally separated rats can be reversed by peripherally restricted histamine1-receptor antagonists. PLoS ONE 2013;8:e66884. Klooker TK, Braak B, Koopman KE, et al. The mast cell stabiliser ketotifen decreases visceral hypersensitivity and improves intestinal symptoms in patients with irritable bowel syndrome. Gut 2010;59:1213–21. van Wanrooij SJ, Wouters MM, van Oudenhove L, et al. Effect of the H1-receptor antagonist ebastin on visceral perception and clinical symptoms in IBS. Gastroenterology 2013;144:S-160. Ref Type: Abstract Hofstra CL, Desai PJ, Thurmond RL, et al. Histamine H4 receptor mediates chemotaxis and calcium mobilization of mast cells. J Pharmacol Exp Ther 2003;305:1212–21. Salcedo C, Pontes C, Merlos M. Is the H4 receptor a new drug target for allergies and asthma? Front Biosci (Elite Ed) 2013;5:178–87.
Wouters MM. Gut Month 2014 Vol 0 No 0
Downloaded from http://gut.bmj.com/ on November 14, 2014 - Published by group.bmj.com
Histamine antagonism and postinflammatory visceral hypersensitivity M M Wouters Gut published online April 4, 2014
Updated information and services can be found at: http://gut.bmj.com/content/early/2014/04/04/gutjnl-2014-306894
These include:
References
This article cites 14 articles, 2 of which you can access for free at: http://gut.bmj.com/content/early/2014/04/04/gutjnl-2014-306894#BIBL
Email alerting service
Receive free email alerts when new articles cite this article. Sign up in the box at the top right corner of the online article.
Notes
To request permissions go to: http://group.bmj.com/group/rights-licensing/permissions To order reprints go to: http://journals.bmj.com/cgi/reprintform To subscribe to BMJ go to: http://group.bmj.com/subscribe/
