Histamine antagonism and post-inflammatory visceral hypersensitivity
M.M. Wouters1
1 Translational Research Center for Gastrointestinal Disorders, University Hospital Leuven, KU Leuven,
Leuven, Belgium
Correspondence address:
Mira M. Wouters, PhD
Translational Research Center for Gastrointestinal Disorders (TARGID)
Center of Neuro-immune interaction and Mucosal Immunology
KU Leuven, University Hospital of Leuven
Herestraat 49
3000 Leuven, Belgium
email: mira.wouters@med.kuleuven.be
Tel +(32)16330837
Fax +(32)16330723
Key words: Visceral hypersensitivity, mast cell, histamine receptor 4
Word count: 960
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Abdominal pain is one of the most difficult to treat symptoms in patients suffering from irritable bowel
syndrome (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 ulcerative colitis (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 post-infectious (PI-)IBS. Colonic biopsies of PI-IBS patients 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 IBS patients indeed contains more mast cell mediators such as serotonin,
histamine, and proteases, that are able to activate visceral afferent nerve fibres (2). Moreover,
abdominal pain in IBS patients 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 synthesized 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 microbiota. Four histamine receptors have been identified, all of which are G
protein-coupled 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-fibers, although recent studies demonstrate that histamine can also trigger neurogenic
inflammation (4) 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 paw (5) and inhibits both thermal and mechanical
hyperalgesia following nerve injury (6). Moreover, recent data support a role for H4Rs in inflammationinduced hyperalgesia: the selective H4R antagonist JNJ7777120 potently reversed both acute and
chronic inflammatory pain following intraplantar carrageenan and complete Freund's adjuvant injection
(7) and in carrageen induced pleurisy (8). In addition, JNJ7777120 significantly reduced hyperalgesia in
neuropathic pain models of spinal and sciatic nerve ligation(7;9).
In this issue of Gut, Deiteren et al. elegantly demonstrate that also in the intestine, H1R and H4R play a
key role in aberrant pain perception following intestinal inflammation (10). The authors induced distal
colitis in rats by intrarectal instillation of 2,4,6-trinitrobenzenesulfonic acid (TNBS). 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 post-colitis rats compared to control rats.
In addition, the spontaneous histamine release was threefold increased in specimens obtained from
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post-colitis rats, indicating that mast cells and in particular histamine may play a key role in postinflammatory visceral hypersensitivity. This was further underscored by a dose-dependent reduction of
pain responses evoked by colonic distention after treatment with the H1R antagonist levocetirizine.
These findings are in line with previous studies supporting a role of H1R in visceral hypersensitivity in IBS
patients 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 ketotifen (12) and ebastin (13) in IBS patients. Most interestingly, Deiteren et al. present
evidence that H4R may also be involved in visceral hypersensitivity. The selective H4R antagonist
JNJ7777120 dose-dependently normalized the visceromotor response to colorectal distension, an effect
that was potentiated when combined with a H1R antagonist.
The results reported by Deiteren et al. are of extreme interest because they indicate an unexpected role
for H4R antagonism in aberrant post-inflammatory pain perception. The role of H4Rs in visceral
nociception may bear great potential for the treatment of post-inflammatory 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 stabilizer 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 post-inflammatory hypersensitivity and if 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 evaluating the role of H4R in abdominal pain in IBS and IBD in remission, including clinical
studies investigating the effect of H4R antagonists.
Reference List
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Ref Type: Abstract
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