Basic and Clinical Aspects of Gastrointestinal Pain HPA Axis Bladder Vagus Nerve
Basic and Clinical Aspects of Gastrointestinal Pain HPA Axis Bladder Vagus Nerve
Basic and Clinical Aspects of Gastrointestinal Pain HPA Axis Bladder Vagus Nerve
www.elsevier.com/locate/pain
Review
Neurogastroenterology Group, Centres for Academic Surgery, Barts and the London NHS Trust and the Homerton, University NHS Foundation Trust,
3rd Floor Alexandra Wing, Royal London Hospital, London E1 1BB, UK
Gastroenterology, Wingate Institute of Neurogastroenterology, Barts and the London, Queen Marys School of Medicine and Dentistry, Whitechapel, London, UK
a r t i c l e
i n f o
Article history:
Received 31 July 2008
Received in revised form 29 September 2008
Accepted 3 December 2008
Keywords:
Visceral pain
Gastrointestinal pain
Nociception
Visceral hypersensitivity
Sensitisation
a b s t r a c t
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.
2008 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.
0304-3959/$34.00 2008 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.pain.2008.12.011
192
2.2. GI nociceptors
In respect of extrinsic afferents, the division of the autonomic
nervous system into sympathetic and parasympathetic divisions
is a misnomer that only accurately refers to efferent functions
[27]. Rather, the most useful broad anatomical and functional division is into that of vagal and spinal visceral afferent bres [95,104].
The latter may be further divided into splanchnic and pelvic afferents, with these following the paths of sympathetic and parasympathetic nerves, respectively. Vagal and spinal nerves have endings
in all layers of the gut wall (Fig. 1), which, unlike some somatic
sensory nerve endings, lack dened anatomical specication such
as encapsulation. Axons are in the most part unmyelinated (C bres) with a minority having thin myelination (Ad bres). It is generally held that vagal afferents have a much lesser role in
nociception than spinal afferents [58], however, the vagus may
have some role in pathophysiologic conditions [95]. The reader is
reminded that much of the following description relates to experimental animals.
193
Fig. 1. Schematic representation of nerve endings in the gut wall. Endings are located in all gut layers, however, based on current evidence, those indicated are most likely to
play a role in nociception with others, particularly those arising from vagal and pelvic nerves (intraganglionic laminar endings and intramuscular arrays) having no currently
proven role.
in which application of an acute aversive stimulus provides temporary relief of chronic and recurrent pain [245]. Recent studies suggest that some patients with chronic abdominal pain demonstrate
abnormal perceptual responses and brain activation patterns to
rectal pain when it is associated with concomitant heterotopic
stimulation using ice water immersion of the foot, which is known
to activate this system [255,256]. In a feline model of visceral pain,
such neurons can also rene ascending information to assist in injury localisation [88].
194
Fig. 2. (a) Schematic representation of the viscerotropic distribution of spinal afferent bre innervation of the GI tract on the basis of retrograde tracer studies in experimental
animals. The bars represent DRGs labelled with tracer from each organ with peak distributions (dark shade) and ranges (white) shown for each. Key: E, oesophagus. Note:
although human studies suggest (like the bladder) a rectal afferent innervation to L5S4, the anatomical lack of distinction of this organ from the colon in small mammals
means that direct tracer data are unavailable. Adapted from Beyak et al. [24]. (b) Main central connections for GI pain pathways. Key: pACC, perigenual anterior cingulated
cortex; MCC, mid-cingulate cortex. For clarity, spinomesencephalic and spinohypothalamic pathways have been omitted (reproduced with permission from Matthews and
Aziz. Postgrad Med J 2005).
195
196
Table 1
Experimental methods used in determining molecular mechanisms of visceral nociception.
Studies on isolated (cultured) cells (in vitro) (Ca2+ imaging, patch clamping and intracellular recordings)
Electrophysiologic studies of afferent nerve bres sensitisation
Studies of provoked rodent pseudo-affective behaviours and visceromotor responses following chemical or microbial-induced luminal inammation and
Modulation of these responses by pharmacologic blockade (selective antagonists)/gene knock-out or knock-down using siRNA)
Tissue (protein and RNA) expression studies of molecular targets (following sacrice: gut, DRG, nodose, spinal cord)
Studies of protein expression in full-thickness GI tissues from patients with proven inammatory pain conditions, e.g. inammatory bowel disease
Studies of human healthy volunteers exposed to intraluminal inammatory stimuli with subsequent specic pharmacologic manipulation
197
Fig. 3. Molecular basis of peripheral visceral nociceptive signalling before (1 and 2) and after (35) sensitisation. The main as yet proven steps in this process are
schematically demonstrated (see text for details).
in intrinsic neurons or small nerve endings (by limitation of availability of human DRG or spinal cord tissues), experimental studies
support these observations. Considering gastroesophageal reux
disease as an example (a condition in which PS has been clearly
demonstrated [127]), and increased TRPV1 correlated with
198
sensitivity [30,161], TRPV1 is upregulated in response to acid exposure in DRG and nodose in a rat chronic reux model [16] with
TRPV1 antagonists ameliorating ulceration in the model [270].
Numerous comparable studies exist for colonic inammation
[68,173,261].
3.3. GI-specic sensitisation mechanisms
Of specic relevance to the gut is the additional presence of
intrinsic enteric sensory neurons as well as other specic cell types
such as enteroendocrine cells. It is eminently feasible that numerous (approximately 100 million intrinsic versus 100,000 extrinsic)
afferents that are well known to express both SP and CGRP [93],
whilst not directly being able to transmit conscious pain, can nevertheless participate by releasing these neuropeptides in response
to noxious stimuli (via expressed transducer channels outlined
above) and thus promote neurogenic inammation. It may thus
be that the above studies examining increases in intrinsic neuronal
expression of such molecules or indeed mucosal endings might be
observing an indirect but important part of the process of GI sensitisation. In addition to the release of biogenic amines from mast
cells, enteroendocrine cells are also (unlike nearly all neurons) distributed in the epithelium itself and have the capacity to directly
taste the lumen. These cells are closely apposed to nerves supplying in the lamina propria and are able to basolaterally release substances such as 5HT 98% of 5HT is in the GI tract [96], whose role
in PS as well as in motor dysfunction is well established experimentally and in human conditions characterised by visceral hypersensitivity (VH) (see below). Very recent data suggest that mucosal
epithelial cells may also participate in PS in certain contexts such
as acid exposure with effects also in part mediated by TRPV1 [150].
3.4. Central sensory signalling and sensitisation
The central terminals of nociceptors drive synaptic input to second-order neurons, transferring information about site, duration
and intensity of the noxious stimulus. In the somatic nervous system, it has been established that unlike low-threshold bres that
use glutamate as their sole transmitter, nociceptors use both this
and a variety of neuropeptides, e.g. SP and 5HT, and trophic factors,
e.g. BDNF, as transmitters and synaptic modulators [262]. There is
reasonable evidence that GI nociceptors have a similar molecular
identity with experimental studies demonstrating that NK [138],
NMDA [132,192], AMPA [192] and 5HT [96] receptors present on
the post-synaptic membrane have a role in visceral pain transmission. In terms of pre-synaptic release of transmitters in response to
incoming action potentials, there is evolving evidence in the somatic nervous system that voltage-gated calcium channels
(Cav2.2 and N-type) have a key role [262]. Such channels have
not to our knowledge been studied in GI afferents, although a subunit (alpha2delta) of Cav receptors is evolving as an area of therapeutic interest (below).
3.5. Central sensitisation
Repetitive ring of action potentials from the periphery (as occurs with PS) leads to amplied responses to both noxious (hyperalgesia) and innocuous (allodynia) stimuli [10]. Such facilitation is
triggered by greater pre-synaptic release of the above described
transmitters, which, acting at their respective receptors, lead
(much akin to PS) to increased intracellular calcium and calciumdependent activation of protein kinases A and C [123]. This in turn
leads to phosphorylation of N-methyl-D-aspartate (NMDA) receptors with a change in receptor kinetics that reduces their voltage-dependent magnesium block, thus increasing subsequent
responsiveness to glutamate [263]. Central sensitisation also has
effects on adjacent spinal neurons leading to recruitment of previously silent nociceptors and hypersensitivity in areas (somatic
and visceral) that are remote from the site of peripheral sensitisation (termed secondary hyperalgesia). In the GI tract, viscerosomatic convergence has been shown experimentally in a number
of gut regions and species, for instance, in the oesophagus of cats
following sensitisation with acid [94]. The role of NMDA receptors
in this process, like that in somatic pain transmission, has been
conrmed experimentally [17,132].
Similarly, in humans, secondary hyperalgesia (by testing of the
relevant dermatome) has been demonstrated in a number of conditions characterised by acute [228] and chronic abdominal pain
[40,174,241]. In addition, viscerovisceral: proximal oesophagus
and viscerosomatic: chest wall hyperalgesia has been demonstrated in a well-validated human volunteer model of distal
oesophageal acidication (Fig. 4) [215]. This secondary hyperalgesia was both prevented and reversed with prostaglandin PGE2
[216] and N-methyl-D-aspartate (NMDA) receptor antagonists
(ketamine) [258], suggesting that CS occurs by similar pathways
to the somatic nervous system.
Balanced against these pro-nociceptive inuences are the braking effects of endogenous opioids acting on mu and delta opioid
receptors, GABA acting on GABAB receptors and endogenous cannibinoids acting on CB1 2 receptors. In the peripheral somatic NS,
these receptors are upregulated in response to central sensitisation
[122]. Although this remains to be proven in the GI tract, there is
sufcient experimental and clinical evidence to suggest that these
receptors have similar roles in visceral pain modulation [200].
3.6. Summary box
GI nociception is dependent on many of the peripheral and central molecular mechanisms observed in somatic nociception.
Both peripheral sensitisation and central sensitisation have been
demonstrated as mechanisms in visceral pain.
The roles of several transducer cation channels, e.g. TRPs and
ASICs, are receiving particular attention because of their proven
activation by chemical agents that are in some cases specic to
the gut.
199
Fig. 5. Highly schematic representation of effector pathways from higher cortical centres in response to external stressors. Following activation of cortical and subcortical
regions, such as the medial prefrontal cortex, subregions of the anterior cingulate cortex, insula and the hypothalamus release increased quantities of corticotropin-releasing
hormone (CRH) inducing the release of adrenocorticotropin (ACTH) from the anterior pituitary. This in turn stimulates the release of glucocorticoids from cells in the zona
fasciculata and reticularis of the adrenal glands. In response to ANS activation, cells of the adrenal medulla produce catecholamines such as adrenaline and noradrenaline, and
both effector arms have potential to modulate enteric neuronal and gut immunocyte activity.
200
descending modulation, projecting to the amygdala and periaqueductal grey (PAG) of the mid-brain [10]. The PAG controls nociceptive transmission by means of connections through neurons
in the rostral ventromedial medulla and the dorsolateral pontine
tegmentum. These two regions project through the spinal cord dorsolateral funiculus and selectively target the dorsal horn laminae
that accommodate nociceptive relay neurons. This circuit can
therefore selectively modulate nociceptive transmission by its anatomical proximity to primary afferent nociceptor terminals and
dorsal horn neurons that respond to noxious stimulation. Stimulation of these sites inhibits responses of spinal neurons to noxious
stimuli. In the lower brainstem, the noradrenergic locus cereleus,
serotenergic raphe nuclei and the rostrolateral ventral medulla receive inputs from the amygdala and PAG, and in turn project to the
dorsal horn of the spinal cord where incoming transmission can
thence be gated [10]. While much of this information has been
translated from somatic pain studies [199], a limited number of
studies in experimental animals [57,97,172,178,271] and some human data [89] conrm that stimulating such areas can have analgesic effects by modulating visceral input.
4.2. The autonomic nervous system (ANS)
The ANS is a core part of the emotional motor system [113,165]
and is a hierarchically controlled, bidirectional, bodybrain interface that integrates afferent bodily inputs and central motor outputs for homeostatic-emotional processes [119]. This is
particularly so for the viscera where, in addition to extrinsic nerves,
the ENS has been considered by some to be a further effector of the
ANS [24,118]. Animal studies suggest that differences in visceral
and somatic ANS pain response are largely mediated via defence
systems in which the roles of hypothalamus and PAG are best characterised. In particular, differential activation of either the ventrolateral or lateral PAG, arising in response to pain from deep/
visceral or supercial structures, respectively, results in variation
of patterned ANS defence responses and behaviours in animals
(freeze versus ght-ight, respectively) [13]. Sympathetically mediated mechanisms are implicated in several chronic pain syndromes
[102,221], and animal and human data support a vagally mediated
inhibition of visceral nociceptive sensory inputs [75,198]. In this
way, the ANS has the potential to modulate visceral sensory perception. Iovino et al. determined the effect of increasing sympathetic
(and reducing parasympathetic) activity on the perception of intestinal stimulation. These autonomic modulations were induced
using lower body negative pressure which induces venous pooling
in the lower extremities [116]. Using brief distending stimuli in the
intestine, the effect of lower body negative pressure on sympathetically mediated intestinal relaxation and on vagally mediated gastric
relaxation was measured by corresponding barostats. The effect of
lower body negative pressure on perception of duodenal distension
was also compared to that on the perception of somatic stimulation.
It was found that lower body negative pressure signicantly heightened perception of intestinal distension without modifying perception of somatic stimuli. Also, the reex responses to duodenal
distension signicantly increased both in the stomach and in the
intestine. These ndings support the reported nociceptive and
anti-nociceptive actions of sympathetic and parasympathetic
efferent systems, respectively.
The mechanism by which sympathetic and parasympathetic
nervous systems modulate pain is unknown. The pro-nociceptive
action of the sympathetic nervous system may relate to the release
of catecholamines and/or prostaglandins from sympathetic nerve
terminals in close proximity to the terminals of damaged primary
afferent nerves. This in turn may result in the direct activation of
afferent bres that have developed (or upregulated) a-adrenergic
receptors [118].
201
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