Abstract and Keywords
Visceral pain is qualitatively distinct from other pain types; it is poorly localized, difficult to quantify, and accompanied by marked autonomic changes. Acute visceral pain may be an indication of a medical emergency requiring urgent surgical or clinical intervention. However, chronic visceral pain, which contributes significantly to lifelong morbidity, occurs most frequently in the absence of any distinct pathology making it difficult to treat. This chapter reviews our current understanding of how visceral pain is detected in the periphery, and processed within the spinal cord and central nervous system. We focus on recent work that has identified pro-nociceptive changes in the bowel of patients with chronic visceral pain and discuss how these findings could lead to the development of novel viscero-specific analgesics. Finally, we consider how the microbiota can act locally to shape the detection of pain in the periphery and centrally to modulate our perception of visceral pain.
Visceral pain arising from the internal organs of the body is one of the most common types of pain experienced (Gebhart & Bielefeldt, 2016). The presence of visceral pain can be an indication of significant underlying organic pathology that may be life threatening and require urgent clinical treatment (e.g., during myocardial infarction, pancreatitis, or ischemia of the bowel). Additionally, blockage of ducts or tubes in response to kidney stones or gallstones gives rise to intense visceral pain that may also require surgical intervention. In these conditions, the pain normally resolves following treatment of the underlying pathology and may be effectively managed by acute treatment with opioid-based painkillers. By contrast, chronic visceral pain most frequently occurs in patients with no clear underlying pathology, leading to the diagnosis of a functional pain syndrome, such as noncardiac chest pain, functional dyspepsia, irritable bowel syndrome (IBS), and interstitial cystitis (Gebhart & Bielefeldt, 2016).
Functional pain syndromes are common (Table 1); IBS, for example, has a global prevalence of between 10% and 15% and is a cause of significant lifelong disease morbidity (Lovell & Ford, 2012). The absence of treatable pathology makes the clinical management of functional pain syndromes difficult. Additionally, commonly prescribed painkillers lack efficacy for the treatment of visceral pain or are contraindicated due to the presence of gut-specific side effects, such as the constipation produced by opioids. As a consequence, functional visceral pain syndromes are associated with high socioeconomic costs (Ford, Lacy, & Talley, 2017), and a significant unmet clinical need exists for effective treatments of functional visceral pain. Recent advances in our understanding of the pathophysiology that contributes to symptom presentation in functional bowel disorders may provide a basis for future rational drug design and address this unmet need. For these reasons, this review focuses on the pathways and mechanisms of visceral pain processing in the context of functional pain experienced by the significant proportion of the population who suffer from IBS.
Table 1 Organic versus Functional Pain Syndromes
Painful bladder syndrome
Bladder pain syndrome
Pain related to bladder filling accompanied by other symptoms in the absence of urinary tract infection and other obvious pathologies
Lack of objective markers
Difficult to establish
Douglas-Moore and Goddard (2017)
Irritable bowel syndrome
Abdominal pain and altered bowel habits in the absence of infection or other obvious pathologies
Lovell and Ford (2012)
Noncardiac chest pain
Cardiac syndrome X
Sensitive heart syndrome
Angina pectoris–like pain in the absence of cardiac ischemia
No global clinical definition
~25% of patients with chest pain
Sensory Innervation of the Viscera
The sensory innervation of the viscera differs from that of somatic structures, which are innervated by afferent sensory nerve fibers (commonly referred to as afferents) that project via spinal nerves to the dorsal horn of the spinal cord and have cell bodies located in dorsal root ganglia (DRG). Instead, most visceral organs receive dual sensory innervation from afferent fibers that travel along with sympathetic and parasympathetic efferent fibers in nerves that form part of the autonomic nervous system (ANS) (Berthoud, Blackshaw, Brookes, & Grundy, 2004). This led historically to the classification of sensory nerves, which innervate the viscera as sympathetic or parasympathetic afferent fibers. This nomenclature has now been superseded, and parasympathetic afferents are instead described by reference to the nerve in which they travel (e.g., vagal or pelvic afferents). Sympathetic afferents are now described as spinal afferents in reference to their site of central termination within the dorsal horn of the spinal cord. Pelvic afferents are also spinal afferents, so to avoid confusion in organs receiving innervation from both pelvic and sympathetic spinal afferents, it is common practice to name both types of afferents after the nerves in which they project. For example, the colorectal region of the gut is innervated by lumbar splanchnic spinal afferents and pelvic spinal afferents.
Visceral pain is a feature of transmission within the spinal afferent signaling pathways (pelvic and sympathetic spinal afferents), as evidenced by studies on patients with transection of the spinal cord or loss of spinal afferent innervation due to nerve ablation or trauma (Ray & Neill, 1947; Sun et al., 1995). This is consistent with the central projection of spinal afferent input from the viscera via ascending pathways strongly associated with the perception of visceral pain (e.g., spinothalamic, dorsal column, and spinoparabrachial tracts) (Al-Chaer, Lawand, Westlund, & Willis, 1996b; Bernard, Huang, & Besson, 1994; Milne, Foreman, Giesler, & Willis, 1981).
By contrast, vagal afferents terminate within the nucleus tractus solitarius (NTS) (Figure 1), located in the dorsal brainstem (Berthoud & Neuhuber, 2000). The NTS is a key site for the integration of autonomic reflex function within the central nervous system, receiving afferent input from other key sensory components of the ANS, such as the baroreceptors and peripheral chemoreceptors (Dampney, Polson, Potts, Hirooka, & Horiuchi, 2003). Although vagal afferents are not nociceptors as the information they process does not give rise to the perception of pain and hence they do not signal nociception, vagal afferent endings are sensitive to many of the same noxious chemical mediators as spinal afferent nociceptors (e.g., serotonin [5-HT], adenosine triphosphate [ATP], prostaglandins, or capsaicin; Mazzone & Undem, 2016). Consequently, the simultaneous activation of vagal afferents by painful stimuli provides a mechanistic explanation for some of the marked autonomic responses that accompany visceral pain. In particular, the activation of gastrointestinal (GI) vagal afferents during visceral pain will produce sensations of nausea and trigger vomiting due to their termination within the area postrema, the vomiting center within the brainstem (Andrews & Sanger, 2002; Rudd, Nalivaiko, Matsuki, Wan, & Andrews, 2015).
Within the colorectal region most commonly associated with pain in IBS, the majority of afferent input in rodents is derived from unmyelinated C-fibers (Brierley, Jones, Xu, Gebhart, & Blackshaw, 2005), and our preliminary studies indicated this is also true for the human colon. In contrast to somatic C-fiber populations that can be divided into peptidergic fibers that are positive for calcitonin gene–related peptide (CGRP) and nonpeptidergic fibers positive for isolectin B4 (IB4), the majority of IB4-positive DRG neurons that innervate the colorectum are also CGRP positive, so the classification of visceral afferents by molecular markers is not functionally useful at present (Hockley, Winchester, & Bulmer, 2016; Robinson, McNaughton, Evans, & Hicks, 2004).
Instead, a functional characterization of visceral afferent populations has developed based on differences in their mechanosensitivity. A consistent finding of these studies is the observation of two distinct visceral afferent populations based on their threshold of sensitivity to mechanical stimuli. For example, in tubular preparations of the gut, one population of fibers with a higher threshold to mechanical stimuli can be identified that displays sensitivity to a range of noxious and algogenic chemical stimulus, such as bradykinin or ATP, leading to their classification as putative polymodal nociceptors (Blackshaw, Brookes, Grundy, & Schemann, 2007; Bulmer & Grundy, 2011; Gebhart & Bielefeldt, 2016). The second population is sensitive at lower thresholds of mechanical stimulation and displays a saturated stimulus response function at levels of stimuli that give rise to pain in humans (Feng, La, Schwartz, & Gebhart, 2012; Gebhart & Bielefeldt, 2016). This population of afferent fibers is most likely not nociceptors; instead, these fibers are thought to be important in the relay of physiological, as opposed to pathophysiological, information from the bowel (e.g., filling of the gut).
Additionally, two further putative nociceptor populations can be identified by their responsiveness to noxious chemical stimuli. One population displays the classical features of “silent nociceptors,” initially insensitive to mechanical stimuli and subsequently gaining sensitivity in the presence of noxious inflammatory or algogenic stimuli. The second population does not exhibit mechanosensitivity in the presence or absence of inflammatory stimuli, so it remains only sensitive to chemical stimuli (Brierley et al., 2005; Feng & Gebhart, 2011).
Importantly, evidence for the presence of all four of these different visceral afferent populations (three that display nociceptor function and one nonnociceptor population) have been found in electrophysiological recordings of human colonic afferent fiber activity (McGuire et al., 2017). Furthermore, the threshold of mechanical stimulus required to elicit pain in humans during colorectal distension is comparable to the threshold required to activate putative polymodal nociceptors in visceral afferent recordings from the human appendix and colorectal afferents in rodent studies highlighting the translatability of physiological studies of nociception in rodent and human tissue with pain perception to the same stimulus in humans in vivo (Kuiken, Lindeboom, Tytgat, & Boeckxstaens, 2005; Peiris et al., 2011).
Despite this progress, our understanding of the major afferent pathways responsible for the processing of pathophysiological pain is still unclear. For example, we do not currently understand the extent to which the different putative nociceptor populations (polymodal, silent, chemosensitive) contribute to pain signaling in human disease states such as IBS. Additionally, the relative contribution of different anatomical spinal afferent fiber subtypes (splanchnic vs. pelvic) to visceral pain in IBS is also unknown. The advent of next-generation RNA sequencing technologies that enable whole transcriptome profiling at the single-cell level may finally facilitate the identification of distinct molecular markers for these different visceral afferent populations. This in turn will enable the relative contribution of each afferent fiber population to nociception to be studied using a combination of population-selective silencing approaches, such as conjugation of marker genes to diphtheria toxin A or inhibitory DREADDs (designer receptors exclusively activated by designer drugs), and population-selective activation approaches, such as light activation of channel rhodopsins or excitatory DREADDs (Whissell, Tohyama, & Martin, 2016). Furthermore, the development of in vitro visceral afferent recordings from surgically resected human tissue means these findings can be translated quickly to humans (McGuire et al., 2017; Ng, Brookes, Montes-Adrian, Mahns, & Gladman, 2016).
Stimulus Transduction in Visceral Nociceptor
Over the past decade, significant progress has been made in our understanding of the molecular mechanisms responsible for the transduction of noxious stimuli by visceral afferents (Blackshaw 2014; Erickson et al., 2018). Key roles have been established for ion channels from the transient receptor potential (TRP) channel family and the acid-sensitive ion channel (ASIC) family as the major transducer channels for noxious external stimuli, such as temperature, pH, and mechanical stress (Basbaum, Bautista, Scherrer, & Julius, 2009). These channels give rise to generator potentials, which if sufficient in magnitude trigger action potential firing in nociceptors. In addition, the activation of P2X2/3 receptors in response to distension-mediated ATP release from the epithelium of hollow organs in the viscera has also been shown to be an important mechanism of visceral mechanotransduction (Burnstock, 2017; Shinoda, La, Bielefeldt, & Gebhart, 2010). Perhaps unsurprisingly, the same channel (TRPV4) has been shown to transduce mechanical stimuli in both epithelial cells and visceral afferents, suggesting that a common therapeutic approach could be utilized to inhibit direct and indirectly mediated mechanical pain in the viscera (Grace, Bonvini, Belvisi, & McIntyre, 2017; Matsumoto et al., 2017). Additionally, distension-mediated ATP release had been shown to be significantly enhanced during inflammation, suggesting a key role for this pathway in the development of visceral hypersensitivity in disease states, and consistent with this role, mechanical hypersensitivity to colitis does not develop in mice lacking P2X2/3 (Burnstock, 2017; Shinoda et al., 2010). The mechanisms contributing to the enhanced release of ATP during inflammation have not been studied in detail, but release of ATP from immune cells recruited to the site of inflammation and enhanced sensitivity of the channels responsible for mechanotransduction in epithelial cells (e.g., TRPV4) by inflammatory mediators have been proposed.
The modulation of channel sensitivity by inflammatory mediators is well documented for the TRP family channels and, to a lesser degree, ASIC and P2X2/3 channels. This leads to increased inward currents; consequently, larger generator potentials are produced for a given level of stimulus, leading to an increased probability of action potential firing and a reduction in the magnitude of stimulus required to trigger action potential firing. The resultant increase in the sensitivity of sensory nerves to noxious stimuli and increase in the magnitude of response to a given noxious stimuli results in peripheral sensitization and increased pain signaling.
Due to the polymodal nature of visceral nociceptors, enhanced activity in a given transducer channel may also sensitize responses to other sensory modalities signaled by that nociceptor in addition to those signaled by that specific transducer channel. For example, sensitization of heat-sensitive TRPV1 channels by inflammatory mediators facilitates temperature-sensitive activation of TRPV1 at body temperature (Trevisani et al., 2002), leading to the depolarization of afferent endings, which in turn increases the sensitivity of visceral nociceptors to other modalities, such as noxious mechanical stimuli. As a consequence, inhibition of TRPV1 channel function attenuates responses to distension of the viscera during inflammation but does not alter visceral afferent mechanosensitivity in normal tissue (Phillis et al., 2009). Therapeutically, the modulation of TRPV1 channel function may therefore provide analgesic relief to visceral hyperalgesia in disease states without affecting the ability of normal bowel to elicit pain in response to noxious stimuli.
Mediators and Mechanisms of Visceral Nociception in Disease States
Visceral nociceptors are sensitive to a wide range of noxious mediators, ranging from “classical” mediators of inflammation and tissue damage such as 5-HT, histamine, bradykinin, substance P, ATP, adenosine, and prostaglandins in addition to cytokines and chemokines (tumor necrosis factor [TNF] alpha, interleukin [IL] 1beta, and IL-6) implicated in the immune responses to pathogens or disease, and most recently to novel lipid modulators of TRP channel function such as 5,6-epoxyeicosatrienoic acid (5,6-EET) (Cenac et al., 2015; Feng, Schwartz, & Gebhart, 2012; Hughes et al., 2012; Kirkup, Brundsen, & Grundy, 2001; Sadeghi et al., 2018). Therefore, there is a multitude of possible mediators of visceral pain in disease states. However, a compelling body of data predominantly built on studies using diseased human tissue obtained from the GI tract by endoscopic biopsy indicates that mast cell mediators such as histamine, 5-HT, and proteases are key effectors of visceral nociception in disease (Nasser, Boeckxstaens, Wouters, Schemann, & Vanner, 2014). These studies have repeatedly shown that supernatants generated using colonic biopsy tissue from patients with IBS and surgically resected colon or biopsies from patients with inflammatory bowel disease (IBD) stimulate visceral afferents (Cenac et al., 2007, 2015; Hockley et al., 2014).
Analysis of the mediator content in these supernatants has revealed elevated levels of histamine and 5-HT or increased proteolytic activity; consistent with this, pretreatment with the histamine H1 antagonist mepyramine, the 5-HT3 antagonist granisetron, or the serine protease inhibitor FUT-175 have been shown to inhibit IBS biopsy-mediated afferent activation (Barbara et al., 2007). These findings have changed our understanding of functional bowel disorders, and it is now accepted that persistent changes in afferent signaling contribute to the underlying pathophysiology of IBS (Drossman, 2016a, 2016b).
More detailed investigation into the phenotype of patients with IBS who display these pro-nociceptive changes in their bowel environment have shown that biopsy supernatants from patients with IBS who developed IBS after a bout of gastroenteritis (postinfectious patients with IBS) cause marked afferent activation, despite the gastroenteritis having resolved many years earlier (Balemans et al., 2017). Furthermore, biopsy supernatants from patients with IBS with hypersensitivity to colorectal distension robustly stimulate visceral afferents, while supernatants from patients with IBS normosensitive to bowel distension do not modulate visceral afferent activity (Buhner et al., 2014). Furthermore, histamine H1 receptor modulation of TRPV1 function was found to be an important mechanism of supernatant-mediated neuronal activation (Balemans et al., 2017; Wouters et al., 2016).
Consistent with these observations, clinical treatment of patients with IBS with the mast cell stabilizer ketotifen or the histamine H1 antagonist ebastine produced significant reduction in abdominal pain scores within a subgroup of patients with IBS who displayed hypersensitivity to colorectal distension (Klooker et al., 2010; Wouters et al., 2016). In contrast, no change in pain scores was observed in patients with IBS normosensitive to colorectal distension during treatment with either ketotifen or ebastine.
Parallel to these studies, a large body of work has identified a critical role for protease-activated receptors (PARs) as the main effectors of afferent activation in response to protease activity in IBS or IBD biopsy supernatants. Collectively these studies have shown that trypsin-3 is a major constituent of serine protease activity in biopsy supernatants, PAR-2 receptor activation is the principal mechanism of trypsin-/tryptase-mediated nociceptor stimulation, and PAR-4 receptor activation in response to cathepsin G inhibits afferent activation and visceral nociception (Annaházi et al., 2009; Augé, Balz-Hara, Steinhoff, Vergnolle, & Cenac 2009; Cenac et al., 2007; Rolland-Fourcade et al., 2017). In common with other G-protein–coupled receptors, the stimulatory effects of PAR-2 receptor activation on neuronal activity are a consequence of its downstream effector coupling to ion channels. In particular, enhanced calcium flux in the TRP family ion channel subtypes TRPV1, TRPV4, and TRPA1 has been demonstrated following PAR-2 activation, with TRPV4 in particular being critical for PAR-2–mediated activation of visceral nociceptors (Amadesi et al., 2004; Brierley et al., 2008, 2009; Cenac et al., 2008).
TRPV4 function can also be modulated by histamine and 5-HT, so a central role for TRPV4 as a major effector of visceral nociception in response to pro-nociceptive changes in the bowel of patients with IBS and IBD has emerged from these experimental studies (Cenac et al., 2010). Furthermore, compelling evidence in support of TRPV4 as a critical mechanism of visceral nociception in IBS has been provided by studies showing elevated levels of the TRPV4 agonist 5,6-EET in IBS patient biopsies, which correlate significantly with the abdominal pain scores in the patients with IBS from whom the biopsies were taken (Cenac et al., 2015). Confirmation of TRPV4 signaling in human visceral nociceptors has come recently from electrophysiological studies in surgically resected human bowel; these studies demonstrated reduced activation of human visceral afferents to mechanical stimulation in the presence of the TRPV4 inhibitor HC-06704 (McGuire et al., 2017), so the initiation of clinical trials for TRPV4 antagonists in patients with IBS is eagerly awaited.
Sensitization of Visceral Nociceptors by Voltage-Gated Channels
Voltage-gated ion channels are the determinants of action potential electrogenesis in sensory neurons; accordingly, they are ultimately responsible for the activation and sensitization of visceral nociceptors by noxious or inflammatory mediators. In particular, proteases and other prototypic inflammatory mediators such as bradykinin have been shown to inhibit activity of voltage-gated potassium channels from the KV7 (Kcnq) family and to enhance the persistent sodium current generated by the voltage-gated sodium channel subtype NaV1.9 (Hockley et al., 2014; Linley et al., 2008; Maingret et al., 2008; Peiris et al., 2016). Both channels have low-voltage activation thresholds, close to the resting membrane potential of sensory neurons, so modulation of activity in KV7 or NaV1.9 channels is thought to be particularly important in the sensitization of visceral nociceptors by inflammatory mediators. Additionally, enhanced NaV1.9 activity is critical for the direct activation of visceral afferents by inflammatory mediators, including pro-nociceptive mediators released from the bowel of patients with gastrointestinal disease (Hockley et al., 2014). This effect is consistent with the presence of episodic abdominal pain in patients with gain-of-function mutations in NaV1.9, and validation of this phenomenon in human visceral afferent recording is now a priority (Erickson et al., 2018; Hockley et al., 2016; Huang et al., 2017).
Changes in the function of other voltage-gated potassium and sodium channels are also altered during visceral hypersensitivity. In particular, A-type (voltage-gated) and K-type (delayed rectifier) potassium currents are reduced in sensory neurons following incubation of DRGs in supernatants derived from patients with IBD, and the tetrodotoxin-resistant currents formed by the NaV1.8 voltage-gated sodium channel subtype is enhanced by incubation in IBD biopsy supernatants (Ibeakanma & Vanner, 2010). Additionally, the initiation of action potential firing in visceral afferents appears to be dependent on the activation of the NaV1.6 as opposed to the NaV1.7 voltage-gated sodium channel subtype (in contrast to somatic afferents) (Feng, Zhu, La, Wills, & Gebhart, 2015; Hockley et al., 2017), and a novel mechanosensory role for the NaV1.1 subtype has recently been demonstrated in visceral nociceptors (Osteen et al., 2016).
Targeting Peripheral Sensitization to Treat Visceral Pain
The presence of peripheral sensitization in patients with organic and functional visceral pain syndromes has significant implications for clinical treatment. These findings indicate that peripherally restricted drugs that inhibit visceral nociceptor signaling (and therefore are free of central side effects) would be effective analgesics across a broad range of visceral disorders. Evidence in support of this hypothesis was provided by the approval of linaclotide, a guanylate cyclase C agonist for the treatment of IBS-C (IBS with constipation).
Linaclotide was developed as a pro-secretory agent for the treatment of constipation due to its stimulatory effects on the CFTR (cystic fibrosis transmembrane conductance regulator) transporter following guanylate cyclase–mediated increase in cyclic guanosine monophosphate (cGMP) levels (Hannig et al., 2014). In addition, and somewhat unexpectedly, linaclotide demonstrated analgesic activity in animal models of visceral hypersensitivity, an effect that has been consistently reproduced across several clinical trials in patients with IBS-C (Hannig et al., 2014). Elegant laboratory work has demonstrated that linaclotide inhibits visceral nociceptors through its release of cGMP, and clinical studies using a colonic release formulation of linaclotide have confirmed the presence of analgesic activity in the absence of a marked secretory effect, thereby demonstrating that the analgesic effect is not a consequence of relieving the constipation (Castro et al., 2013).
The inhibitory effect of linaclotide on visceral afferent activity is greater in tissue from animals with visceral hypersensitivity. This phenomenon is also observed for a range of inhibitory mediators, such as the kappa opioid receptor agonist asimadoline (Hughes et al., 2014), the gamma-aminobutyric B (GABAB) receptor agonists baclofen and α-conotoxin Vc1.1 (Castro et al., 2018), and activation of the oxytocin receptor by selenoether oxytocin analogues (Araujo et al., 2014). Further investigation has revealed that this effect is mediated via increased receptor expression; so, although there is a net sensitization of visceral nociceptor activity in sensitized states, this occurs in the presence of a compensatory change in inhibitory receptor expression and coupling to voltage-gated calcium channels. Therapeutically, the upregulation of inhibitory receptors offers an attractive opportunity for the development of analgesics that can target sensitized nociceptors (Brierley, 2016). It may therefore be possible to treat abdominal pain arising from visceral hypersensitivity in chronic functional pain disorders while preserving acute visceral nociception to potentially life-threatening conditions such as ischemia of the bowel.
Central Processing of Visceral Pain
In addition to peripheral sensitization, central changes in pain processing have been described in patients with functional and organic visceral pain. These changes occur in response to sustained peripheral input, altered descending regulation of pain processing, and changes in the central processing and perception of pain. Therapeutically, the modulation of central pain processing is a successful approach to the treatment of visceral pain with centrally acting drugs such as tricyclic antidepressants and gabapentin showing efficacy for the treatment of chronic visceral pain (Camilleri & Boeckxstaens, 2017). Furthermore, the presence of maladaptive stress responses and the high comorbidity of anxiety and depression in patients with functional visceral pain disorders has prompted the common use of psychotherapy and encouraged research into the processing of visceral pain in higher centers of the brain (Cashman, Martin, Dhillon, & Puli, 2016).
Processing of Visceral Afferent Input in the Spinal Cord
The sensory innervation of a given visceral organ typically accounts for less than 10% of the total number of afferent fibers present within a spinal nerve (see Giamberardino, 1999, for a review). Although the total visceral afferent innervation is much greater than that represented at a single spinal level, as the visceral projecting neurons for a particular target organ are located in DRGs across a broad range of spinal levels (Figure 2). For example, injection of tracer dye into the descending colon has been shown to label DRGs over T7–L3 spinal levels, with the highest concentration of labeled neurons occurring over a more discrete range of spinal levels (e.g., L1–L2).
In addition, visceral afferents exhibit large and diffuse arborization of their central terminals within the spinal cord. These extend rostrocaudally for several spinal segments, covering mediolateral and dorsoventral areas of the dorsal horn, and within the same segment, the central endings of visceral afferents branch profusely and can be found through lamina I, V (Cervero & Connell, 1984; Sugiura et al., 1993). As a consequence of this broad distribution of a relatively sparse population of sensory nerve fibers, the perception of visceral pain is typically diffuse and poorly localized. However, due to their extensive arborizations, the influence of visceral afferents on dorsal horn neurons is extensive (e.g., up to 75%), or neurons recorded electrophysiologically in the dorsal horn are reported to receive visceral inputs.
These features result in a large and typically bilateral representation of visceral pain over the thorax or abdomen and give rise to the phenomenon of referred pain due to the convergence of visceral and somatic afferent input on dorsal horn neurons (viscero–somatic neurons). It has been suggested that referred pain may arise due to the presence of primary afferent neurons ending in visceral organs and somatic structures, and although evidence for so-called dichotomizing afferents can be found, these are sparse (less than ~ 1% of the total somatic structures). Instead, it is most likely that the central perception of ascending input from dorsal horn neurons with viscero–somatic input is interpreted as coming from the somatic dermatomes innervated by the somatic input to viscero–somatic neurons despite these neurons being activated by their visceral afferent input.
Several electrophysiological studies in vivo described the presence of such viscero–somatic neurons along cervical, thoracic, lumbar, and sacral segments and in different species from mice to nonhuman primates in response to the stimulation of a range of visceral organs or structures, such as the gallbladder, colon, esophagus, heart, and ureter (Cervero, 1983; Euchner-Wamser, Sengupta, Gebhart, & Meller, 1993; Garrison, Chandler, & Foreman, 1992; Laird, Roza, & Cervero, 1996). These neurons are mainly located in lamina I and V, with lamina II lacking substantive direct visceral afferent input. The convergence of visceral and somatic afferent input can be found in both interneurons and projection neurons, and the somatic input arises from nociceptors (e.g., high-threshold cutaneous afferents or Class 3 afferents) and afferents that respond across a wide dynamic range of mechanical thresholds (e.g., both low- and high-threshold afferents or Class 2 afferents) (Handwerker, Iggo, & Zimmermann, 1975), thereby providing an explanation for why only unpleasant sensations are perceived from the viscera as opposed to sensations of light touch.
At the circuit level, recent in vitro studies have described the presence of viscero–somatic neurons with convergent monosynaptic inputs able to elicit suprathreshold responses in both projecting and local circuit neurons. On the other hand, polysynaptic inputs were usually found on viscero–somatic neurons with subthreshold responses (Luz et al., 2015). These polysynaptic circuits may be especially relevant during sensitization, allowing complex modulation of sensory input.
It is not uncommon for patients with visceral pain to have more than one internal organ affected. The crosstalk between internal organs is especially relevant during sensitization, producing complex clinical symptoms that can obscure the principle site of pathology. For example, women with IBS who also have dysmenorrhea display hypersensitivity to colorectal distension during menstruation and hypersensitivity at both somatic sites of referred pain for the uterus and colon as compared to patients with only IBS or dysmenorrhea (Giamberardino et al., 2010). These findings are attributed to the presence of viscero–visceral and viscero–somatic convergence on the same neurons within the dorsal horn. Consistent with these clinical observations, electrophysiological studies have demonstrated the presence of dorsal horn neurons that receive nociceptive inputs from the heart also receiving inputs from the esophagus, gallbladder, or stomach (Foreman, Garrett, & Blair, 2015).
A general feature of visceral pain is that the magnitude of pain experienced typically increases over time, making the initial insult difficult to identify. This change in pain intensity can be attributed to the development of disease pathology; however, hyperalgesia (an increase in the perception of pain attributed to a given painful stimulus) in response to changes in pain processing at peripheral and central sites is also an important contributing factor. Although the process underlying peripheral sensitization in visceral afferents has been well studied in recent years, the mechanisms by which central sensitization contributes to visceral hyperalgesia are still poorly understood.
Consistent with the presence of extensive viscero–visceral and viscero–somatic convergence in dorsal horn neurons, repetitive visceral stimulation not only increases the intensity and duration of pain experienced from the site of stimulation (primary hyperalgesia) but also enhances pain sensitivity in somatic sites of referral and other nonaffected areas (secondary hyperalgesia). For example, repetitive colonic distension in human volunteers increased the perception of pain in the colon and also the abdominal area over which referred pain was perceived (Ness, Metcalf, & Gebhart, 1990; Swarbrick, Hegarty, Bat, Williams, & Dawson, 1980).
This phenomenon occurs due to the sensitization of viscero–somatic neurons by ongoing visceral input, which enables neuronal activation in response to previously subthreshold somatic input or increases the response to suprathreshold somatic stimuli (Cervero, 2009; Cervero, Laird, & Pozo, 1992; Euchner-Wamser et al., 1993; Roza, Laird, & Cervero, 1998). As one would expect, this process is facilitated by peripheral inflammation, which increases afferent input to viscero–somatic dorsal horn neurons during disease states (Al-Chaer, Westlund, & Willis, 1997b; Garrison et al., 1992; McMahon, 1988). The changes, such as the increase in size of the somatic receptive field and excitability of viscero–somatic neurons following repetitive visceral stimuli, are still observed in spinalized animals (Cervero et al., 1992), demonstrating that spinal circuitry is sufficient for the development of referred hyperalgesia.
Furthermore, given the presence of viscero–somatic neurons that receive afferent input from different visceral organs, secondary hyperalgesia can also be observed in uninjured visceral organs as well as somatic sites of referred pain. For example, in experimental animals, esophageal inflammation increased the proportion of viscero–somatic neurons that responded to noxious stimulation of the heart, and in humans acidification of the distal esophagus sensitization elicited secondary hyperalgesia in the uninjured proximal esophagus and produced hyperalgesia at somatic sites of referred pain (Frøkjaer et al., 2005; Hobson, Khan, Sarkar, Furlong, & Aziz, 2004).
Supraspinal Processing of Visceral Pain
Most of our knowledge about human supraspinal processing of pain comes from neuroimaging studies. This work has led to the identification of several brain areas forming a network referred to as the “pain matrix.” This network consists of areas consistently activated by noxious stimuli, such as the suprasylvian opercular area, the mid- and posterior insula, and the mid–anterior cingulate cortex (ACC), in addition to a number of other regions whose contribution varied across different studies, such as the primary sensory cortex, anterior insula, prefrontal and posterior parietal cortices, amygdala, and hippocampus (reviewed in Garcia-Larrea, 2012a, 2012b; Garcia-Larrea & Peyron, 2013). Interestingly, despite the clear differences in the clinical manifestation of visceral pain compared to other pains, a similar neural network is observed in response to painful cutaneous or visceral stimuli. Furthermore, the pain matrix can also be activated by nonnociceptive stimuli, promoting debate between those who consider the pain matrix a direct measure of a pain experience and those who argue that most of those regions represent a nonspecific detection system to indicate what is important for the body.
Within specific regions, microstimulation of the thalamus in patients has been shown to evoke direct visceral pain sensations (one patient reported a clear sensation of angina) and memories of past visceral pain episodes (Davis, Tasker, Kiss, Hutchison, & Dostrovsky, 1995; Lenz et al., 1994), consistent with the projection of viscero–somatic neurons to the lateral thalamus via the spinothalamic tract (Figure 3) (Ammons, 1988; Berkley, Benoist, Gautron, & Guilbaud, 1995; Berkley, Guilbaud, Benoist, & Gautron, 1993; Brüggemann, Shi, & Apkarian, 1994, 1998; Kawakita, Dostrovsky, Tang, & Chiang, 1993). These neurons receive monosynaptic inputs from dorsal horn neurons located in laminae I, V, and VII, which ascend via spinothalamic pathways that terminate in multiple nuclei, within the ventral posterior thalamic complex, the central lateral thalamus, the posterior suprageniculate complex, and the caudal mediodorsal nucleus. In addition, the thalamus receives indirect visceral inputs from the spinal cord via the postsynaptic dorsal columns, which terminate within the cuneate nucleus and nucleus gracilis before projecting to the thalamus (Al-Chaer, Lawand, Westlund, & Willis 1996a; Al-Chaer, Westlund, & Willis 1997a).
The cortical projection of visceral afferent input from the thalamus is poorly understood. Recent work has defined the precise targets of thalamic neurons to the cortex using transsynaptic viral transport following herpes viruses injected at the dorsal horn. These are first transported rostrally to infect thalamic projection neurons and from there on to different cortical areas. The majority of infected neurons were located in the posterior insular cortex (~40%), medial parietal operculum (~30%), and the motor sections of the midcingulate cortex (~24%). Barely 5% of the thalamic projections ended at the primary somatosensory cortex (Dum, Levinthal, & Strick, 2009). Consistent with the robust projection of input to the insular cortex, sensations of visceral pain can be evoked by focal electrical stimulation at the medium and anterior insula, rather than at the posterior area (which was the identified target from the thalamus). These were described as unpleasant constrictive sensations arising at the pharyngolaryngeal, retrosternal, or abdominal region and ranged from simple discomfort to a “a frightening sensation of strangulation” that in some cases were associated with anxiety. Anterior insula stimulation evoked autonomic-driven responses similar to those experienced during visceral pain episodes (nausea, salivation, facial blush, sweaty hands, among others). Stimulation in those same areas was able to evoke unpleasant gustatory and olfactory sensations, and even a proportion of the evoked auditory sensations was described as unpleasant (Mazzola, Isnard, Peyron, & Mauguière, 2011; Mazzola, Mauguière, & Isnard, 2017).
In addition, noxious distension of the esophagus in human volunteers has been shown to preferentially activate the ACC (Coen et al., 2009; Strigo, Duncan, Boivin, & Bushnell, 2003). These data were supported by findings from animal studies that have shown that neurons located in the ACC display enhanced spontaneous activity and exhibit larger responses on colorectal distension following induction of visceral hypersensitivity. In addition, the visceromotor response to colorectal distension was reduced by lesions of the ACC, suggesting a descending excitatory role of this area during inflammation (Cao et al., 2008; Gao, Wu, Owyang, & Li, 2006). The precise role of the ACC in encoding unpleasantness or pain intensity of somatic origin has only recently gained attention in animal studies, and recent behavioral experiments in animals combining withdrawal reflexes with anxiety tests are providing interesting data (Fuchs, Peng, Boyette-Davis, & Uhelski, 2014). Similar approaches should be conducted for studies in visceral pain.
Consistent with a dominant role for the limbic system in the regulation of visceral pain changes in the central nucleus of the amygdala (CeA), a component of the limbic system that is critical in the coordination of brainstem, pontine, and midbrain nuclei with cortical and subcortical regions. The amygdala is thought to be critical for the processing of emotional aspects of pain, and bilateral CeA stimulation by a progesterone implant induces marked visceral hypersensitivity (Tran & Greenwood-Van Meerveld, 2012). Interestingly, the circuitry between left and right amygdalae is not identical, and pain evoked in response to bladder distension increased when the right CeA was activated optogenetically or when the left CeA was optogenetically inactivated (Crock et al., 2012; Sadler et al., 2017). Consistent with this, during bladder inflammation, activation of the right CeA was found to increase abdominal sensitivity, while activation of the left CeA reversed the referred bladder pain (Sadler et al., 2017).
Descending Control of Visceral Pain
Pain experience is highly variable among different individuals, and the correlation between activation of the nociceptors and the sensory experience of pain is not direct. In particular, emotional states or attention level can have profound modulatory (excitation and inhibition) effects on pain perception (Heinricher, 2016). The circuits mediating these effects are still poorly understood, and several sites important for the production of endogenous analgesia have been identified in the brainstem; among these, the periaqueductal gray (PAG) and rostral ventromedial medulla (RVM) are the best studied areas. Further, pontine and medullary noradrenergic nuclei, including the locus coeruleus, are also relevant. Both the PAG and RVM receive direct input from the spinal dorsal horn and several supraspinal sites. The PAG projects to the RVM, which in turn projects profusely via the dorsolateral funiculus to superficial and deep laminae in the dorsal horn (Heinricher, 2016; Heinricher, Tavares, Leith, & Lumb, 2009; Martins & Tavares, 2017). Direct PAG stimulation can produce profound analgesia through the activation of indirect descending inhibitory projections to the spinal cord, including viscero–somatic neurons (Ness & Gebhart, 1987; Reynolds, 1969).
On the other hand, the RVM contains a network of neurons involved in nociceptive processing, including visceral pain. In particular, neurons in the RVM can be divided functionally into ON and OFF cells. The first increase their firing just prior to the initiation of the nociceptive reflex, while reduced firing takes place at the OFF cells (Fields, Bry, Hentall, & Zorman, 1983; Fields, Malick, & Burstein, 1995). In the context of pain, OFF cell activation is sufficient for analgesia, while the ON cells have a pronociceptive role in the context of pain.
It is noteworthy that direct electrical stimulation of RVM can reduce or enhance visceromotor responses evoked by bladder or colorectal distension (Randich, Mebane, DeBerry, & Ness, 2008; Zhuo & Gebhart, 2002), highlighting the opposing roles of these different subpopulations of cells in visceral pain processing. In addition, regulation of these cells by sensitizing stimuli (e.g., colonic administration of capsaicin) enhances function in ON-like cells and reduces responses in OFF-like cells, thereby facilitating visceral pain (Sanoja, Tortorici, Fernandez, Price, & Cervero, 2010).
The PAG–RVM circuits are also involved in the regulation of physiological parameters and coordinated behaviors, including heart rate, body temperature, defense, or maternal behaviors, highlighting their role at the interface of discriminatory and affective components of pain processing (Heinricher, 2016).
Role of the Microbiota in Visceral Pain
Recent data implicate the gut microbiota in the regulation of visceral pain processing at both peripheral and central sites. The gut microbiota includes all microbial organisms residing in the GI tract, of which bacteria have been the most studied to date. There is growing evidence that its manipulation by pro-, pre-, or even antibiotics can provide effective relief from abdominal pain. Intriguingly, this interaction between the microbiota and visceral pain is not just restricted to the periphery, and the concept of a microbiota–gut–brain axis has been developed as a framework to understand the overarching role of the microbiota in visceral pain perception (Figure 4).
With regard to IBS, a consistent finding from analysis of fecal samples from patients with IBS is a shift in the diversity of bacteria species present in the bowel away from probiotic lactobacilli and bifidobacteria strains toward more pathogenic gram-negative species, such as enterobacteria and bacteroides (Camilleri & Boeckxstaens, 2017; Enck et al., 2016; Hadizadeh et al., 2018; Pokusaeva et al., 2016); the degree to which these changes occur has been associated with the frequency, duration, and intensity of abdominal pain in the general population (Hadizadeh et al., 2018).
To address this apparent imbalance, therapeutic approaches such as treatment with probiotic strains of bacteria or fecal transplantation have been attempted in order to restore normal gut microbiota. Evidence in support of a positive effect of either approach is accumulating; in particular, recent clinical trial data show a positive effect of fecal microbiota transplantation against symptoms of abdominal pain in patients with IBS (Hadizadeh et al., 2018; Halkjær, Boolsen, Günther, Christensen, & Petersen, 2017), and several clinical trials support the beneficial effects of probiotic intake in IBS (Harper, Naghibi, & Garcha, 2018).
The efficacy of probiotics has been attributed to a number of mechanisms, with the modulation of pro-analgesic endogenous opioid and endocannabinoid signaling in particular being identified as key to the analgesic effects of probiotics (Rousseaux et al., 2007). Most recently, investigation into the production of serpins (endogenous antiproteases) by the microbiota and probiotics has provided a compelling mechanism by which probiotics may modify the protease-driven sensitization of visceral afferents observed in IBS and IBD (Sessewein et al., 2017). The production of GABA and GABA metabolites by the microbiota and probiotics (Pokusaeva et al., 2016) has been shown to influence peripheral and central sites to regulate pain processing and comorbid symptoms of anxiety and depression. In particular, enhanced GABAergic activity in the amygdala in response to elevated circulating levels of microbiota-derived GABA and its metabolites is thought to be key. In the periphery, elevated levels of microbiota-derived GABA have been shown to desensitize visceral afferents through the activation of GABAA channels on sensory afferents (see Cowan et al., 2018, for a recent review).
In contrast to these beneficial effects, pathogenic bacteria also play a role in mediating visceral pain through the activation of pattern recognition receptors (e.g., TLR4) by their bacterial cell wall component lipopolysaccharide (LPS). This can trigger inflammation due to the antidromic release of neuropeptides (such as CGRP and substance P) from the afferent terminals or cytokines such as IL-1beta or TNFalpha from immune cells such as mast cells (Coelho et al., 2000). Additionally, it has been observed that bacteria can directly signal to the nerve ending through the release of bacterial products such as N-formyl peptides, which stimulate formyl peptide receptors found on sensory nerves, and the release of the pore-forming toxin alpha hemolysin, which is thought to stimulate afferent endings by directly inserting itself into the sensory nerve endings (Chiu et al., 2013).
Significant progress has been made in our understanding of the peripheral mechanisms driving visceral nociceptor activation in visceral pain. In particular, translational studies using patient tissue have revealed the presence of significant peripheral pathology in patients with functional visceral pain syndromes. By comparison to pathological causes of visceral pain, functional visceral pain syndromes are highly prevalent and difficult to treat, so these findings have great significance in terms of relieving the leading causes of lifelong visceral pain. Parallel to these studies, greater understanding of the role played by the microbiota in the central and peripheral processing of pain is emerging, and it is likely that therapies targeting the microbiota will provide future treatments of visceral pain. How visceral pain is processed within the spinal cord and central nervous system remains to be understood in detail, and it is hoped that the use of opto- and chemogenetic approaches to selectively stimulate or silence different sensory signaling pathways and neuronal populations may finally provide the toolkit needed to interrogate the central circuits responsible for processing visceral pain.
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