1. Why Are Visceral Sensations Important To The Survival Of An Animal?
Mol Interv. Writer manuscript; bachelor in PMC 2009 Aug 26.
Published in last edited class equally:
PMCID: PMC2732716
NIHMSID: NIHMS131017
Inside data – The unique features of visceral awareness
Abstract
Near of what is written and believed about pain and nociceptors originates from studies of the "somatic" (non-visceral) sensory system. As a issue, the unique features of visceral pain are often overlooked. In the dispensary, the direction of visceral hurting is typically poor, and drugs that are used with some efficacy to treat somatic pain frequently present unwanted furnishings on the viscera. For these reasons, a meliorate agreement of visceral sensory neurons—particularly visceral nociceptors—is required. This review provides testify of functional, morphological, and biochemical differences between visceral and non-visceral afferents, with a focus on potential nociceptive roles, and too considers some of the potential mechanisms of visceral mechanosensation.
Introduction
The bulk of what is known about pain and nociceptors originates from studies of "somatic" structures (i.due east., non-visceral components of the body, principally skin). All the same, the most common pain produced by disease (and the most difficult to manage) is that originating from the internal organs (i.e., visceral pain), and the characteristics of visceral innervation differ significantly from other tissues. Visceral pain may consequence from direct inflammation of a visceral organ (e.g., inflammatory bowel illness, pancreatitis, appendicitis), occlusion of bile or urine flow (e.yard., kidney stones), or from functional visceral disorders [e.g., irritable bowel syndrome (IBS)]. Add to this list angina, painful bladder syndrome (interstitial cystitis), gastroesophageal reflux disease, endometriosis, and dyspepsia, and the widespread impact of visceral disease becomes articulate. Nigh basic and clinical pain inquiry has focused on somatic (principally cutaneous) tissue, which has significantly influenced strategies for pain direction. As a result, the unique features of visceral pain and innervation have remained underappreciated, and thus visceral pain management is typically poor. Moreover, visceral nociceptors are intrinsically unlike from cutaneous and most other not-visceral nociceptors. We provide here a review of the visceral sensory system and highlight some of the features that distinguish it from not-visceral systems. The visceral system encompasses a large number of organs, from the optics (technically, the brain is besides a visceral organ) down to the genitourinary organs, and so this review volition focus on our laboratory's electric current principal area of experimental expertise: the lower gastrointestinal tract (principally colon) and bladder.
The Visceral Sensory System
The principal extrinsic afferent nerves innervating visceral organs are anatomically associated with sympathetic and parasympathetic nerves and are accordingly named (due east.chiliad., pelvic nerve afferent), although they are not office of these efferent, autonomic, pathways. Most extrinsic visceral afferent neurons have prison cell bodies in dorsal root ganglia (DRG) and stop in the spinal cord (spinal afferents); visceral afferent fibers in the vagus nervus, with cell bodies in the nodose and side by side jugular ganglia, stop in the brainstem nucleus tractus solitarius. There are two features that are unique to the visceral sensory innervation: 1) most organs also take an intrinsic innervation (e.g., the enteric nervous system of the alimentary canal) and 2) each organ is innervated by 2 unlike extrinsic nerves (east.m., the distal colon and urinary float are innervated by the pelvic and splanchnic fretfulness). Although there are likely important functional interactions between the intrinsic and extrinsic visceral innervations, their anatomical human relationship and means of intercommunication are largely unknown. Figure i summarizes the visceral sensory innervation, using the gut as an example.
Functional neuroanatomy of the visceral sensory organization
The gut is depicted here as an example of the sensory innervation of the visceral organization. Vagal afferent neurons, which do not innervate the urinary float or the distal gut, have cell bodies in the nodose ganglia (NG) bilaterally and travel alongside parasympathetic efferent pathways to organs in the thoracic and abdominal cavities. Once in the gut wall, vagal afferent fibers innervate neurons in the myenteric or submucosal plexus (1000/SP), circular and longitudinal muscle layers, and the mucosa. Pelvic afferent neurons also travel aslope parasympathetic efferent pathways, but their jail cell bodies are in dorsal root ganglia (DRG). Other spinal nerves (east.g., greater splanchnic) travel aslope sympathetic efferent pathways, have cell bodies in DRG, and pass through prevertebral ganglia (e.1000., the celiac ganglion, CG). Intestinofugal afferents (purple) synapse onto efferent sympathetic neurons in prevertebral ganglia, such every bit the inferior mesenteric ganglion (IMG) and have their cell bodies in G/SP. Afferent fibers of the intrinsic (or enteric) nervous system, termed intrinsic primary afferent neurons (IPANs), synapse onto intestinofugal fibers, either directly, or via interneurons (i). Rectospinal fibers (blue) have cell bodies in the myenteric plexus or musculus layers, with axons terminating in the spinal cord (CNS). Notation that non all these nerves and fibers will terminate in the same areas of the gut, and inputs to the spinal cord may traverse a number of different levels; this figure has been simplified for clarity.
Visceral Afferents are Anatomically Dissimilar from Non-Visceral Afferents
A key difference between visceral and non-visceral sensory neurons is the degree to which their peripheral terminals are specialized. For example, cutaneous afferents can have one of many different sensory endings to transduce stimuli into electric energy (e.g., Merkel cells, Ruffini endings, Pacinian corpuscles), whereas only two types of specialized ending take been reported in visceral afferents: intraganglionic laminar endings (IGLEs) and intramuscular arrays (IMAs). Both types have limited distributions (e.g., almost sphincters), are specific to muscular vagal or pelvic innervation, and are less intricate than their non-visceral counterparts [for review, see (ane, 2)]. IGLEs and IMAs announced to be low-threshold mechanoreceptors and are therefore less likely to be involved in detecting noxious events. Most spinal visceral afferents are believed to have primitive, unencapsulated endings (similar non-visceral nociceptors), with no specialized structure and 1 or a few punctate receptive fields.
Visceral Afferents Transmit Unique Sensations
Visceral and non-visceral afferents encode unlike types of information: the conscious experiences generated by the visceral sensory organisation are not initiated by not-visceral afferents. For example, the sensation of nausea does non arise from the skin, and vice versa, one cannot observe cutting of the gut [for review, see (three, 4)]. Conscious sensations arising from the viscera, in improver to pain, include organ filling, bloating and distension, dyspnea, and nausea, whereas non-visceral afferent activity gives rise to sensations such every bit touch, compression, estrus, cutting, beat out, and vibration. Both sensory systems can discover chemical stimuli.
The Visceral Nociceptor Divers
Nociceptors were originally defined as receptors that reply to noxious stimuli, peculiarly those that harm or threaten to impairment peel. Thus, they were defined in a functional context. As our agreement of nociceptors has increased, however, attempts to redefine the nociceptor have generated much debate and fiddling agreement. Furthermore, a "baneful stimulus" is semantically distinct from a "painful stimulus," a concept that has evolved from the descriptions of "nocicipient" cutaneous receptors by Sherrington at the kickoff of the twentieth century (five).
"Hurting" is a psychological state, defined by the International Association for the Written report of Pain (IASP) every bit "an unpleasant sensory and emotional feel associated with bodily or potential tissue damage, or described in terms of such damage" (6). This concept, and the distinction between nociception and pain, has been appreciated for some time, as the post-obit quotation from 1900 shows (7):
The stimuli which evoke pain may exist characterised as 'excessive.' It might near be asserted that 'excess' is that quality of a stimulus in virtue of which it becomes 'acceptable' for the sense of pain. 'Excessive' in this application connotes 'harmful,' or 'to be avoided,' due east.yard. by muscular activeness for resistance or escape. The 'backlog' of the stimulus may lie in its intensity, or in its extensity (spatial or temporal).
Potential confusion arises from the IASP'southward definition (6) of a noxious stimulus as "one which is damaging to normal tissues," thereby excluding the potential for impairment that is considered under the definition of "pain". Thus, a nociceptor is a peripheral sensory receptor (considered colloquially to be the entire neuron, including its peripheral and fundamental terminals and soma) that signals bodily tissue impairment.
Ane problem with these definitions is demonstrated by the existence in visceral organs of low-threshold mechanosensory afferents (sometimes as well called "wide dynamic range") that proportionally encode organ distension from low, physiological (non-noxious), distending pressures through to pressures that are noxious (Figure 2A and B). Similarly, joint afferents and some cutaneous afferents also have low mechanical response thresholds and encode well into the noxious range; however, neither slowly nor rapidly adapting mechanosensitive afferents in peel encode into the noxious range, or sensitize (encounter beneath). The current definition thus appears to omit low-threshold visceral afferents from the classification of nociceptor, as no matter how prolonged a non-noxious stimulus may be, low-threshold mechanoreceptors volition not bespeak a noxious event until the stimulus intensity increases. Silent (or sleeping) nociceptors offer another complication. These neurons are unusual in that they are insensitive to all but the highest intensity of mechanical stimulation. However, inflammatory chemicals "awaken" these nociceptors and induce spontaneous activity and mechanosensitivity in the noxious range.
The viscera are innervated past depression- and loftier-threshold mechanoreceptors
Hollow viscera are exquisitely sensitive to distension, a phenomenon that tin can be observed experimentally by recording the electric activeness induced in pelvic nervus afferent fibers (mechanoreceptors) during distension of the visceral organ under written report. A) Low-threshold mechanoreceptors (blue) detect both non-noxious and baneful distension pressures, whereas high-threshold mechanoreceptors (green) only respond to noxious distention pressures. Information are recorded from distension of the rat bladder. B) Mechanoreceptors (of either the high- or low-threshold type) in the pelvic nerve can be sensitized by the add-on of irritants (e.k., xylenes) into the bladder. C) Mice defective the TRPV1 receptor show impaired visceral nociception. The visceromotor response (electric activity recorded in the abdominal musculature) produced during distension of the colon to a noxious pressure (e.g., 60 mmHg) is lower in mice that practice not accept functional TRPV1 receptors compared to wild-type controls. Even at the highest tested colonic distension pressure, TRPV1 knockout mice only testify a level of response equivalent to that of the wild-type mice at 30 mmHg, the pressure at which this stimulus is probable to be noxious (dashed red line). Panels A and B are adapted with permission from (64), and panel C is adapted with permission from (48).
Accordingly, we suggest that a visceral nociceptor (or indeed, a nociceptor in whatsoever tissue) is a sensory receptor that, when activated, can produce a reflex or response that is protective or adaptive (east.thou., withdrawal, guarding, vocalization); tin encode stimulus intensity in the noxious range; and can sensitize (i.e., give increased responses to noxious intensities of stimulation after insult or exposure to chemical mediators such as those produced during inflammation). Requirement for the latter two capabilities reveals that almost of the visceral sensory innervation is nociceptive in grapheme, especially during organ insult. Nearly (70-fourscore%) mechanosensitive visceral afferents have low thresholds for activation in the physiological range; the residual have high thresholds and are usually considered to represent the population of visceral nociceptors. Nevertheless, nearly low-threshold mechanosensitive visceral afferents encode into the noxious range and generally give greater responses than their loftier-threshold counterparts (Figure 2A). They besides sensitize after organ insult, giving increased responses to both innocuous and baneful intensities of stimulation. These findings fence for potential roles of both low- and loftier-threshold mechanoreceptive visceral afferents in visceral hurting conditions.
With an ever-increasing number of in vitro methods available to the pain researcher, the identification of nociceptors often relies on cellular characterization, such as size or biochemical markers, rather than functional definitions. For example, all modest-diameter, capsaicin-sensitive DRG neurons (that is, those that either limited the capsaicin receptor TRPV1 or answer to application of capsaicin) are sometimes considered as nociceptors. The reliability of biochemical targets, such equally TRPV1, to act as nociceptor markers is discussed below.
Visceral Pain is Dissimilar from Non-Visceral Hurting
The ability to identify the source (spatial location) of cutaneous pain is fantabulous, and the power to identify that of joint and musculus pain is generally good; in contrast, visceral pain is diffuse in character and poorly localized. 2 factors contribute to this deviation. First, relative to not-visceral structures, the viscera are sparsely innervated. It is estimated that fewer than seven per centum of spinal afferents in the DRG project to the viscera [encounter (1,8,9,10)], and only a fraction of these convey input to the primal nervous system that will be perceived. This thin innervation is compensated for in the spinal cord, where visceral terminations arborize widely over several spinal segments and even to the contralateral spinal cord (xi). 2nd, spinal neurons that receive visceral input also receive convergent input from skin or deeper structures (including other viscera), producing referred pain. For example, cardiac pain (angina) is typically referred to the left arm and shoulder (simply skin, joint, or muscle pain is not referred from shoulder to eye). In addition, whereas hurting tin exist evoked from virtually all non-visceral structures, parenchymous viscera (east.thousand., liver and pancreas) exercise non give ascent to pain unless the organ is inflamed or the organ capsule is distorted, for case past a tumor. Finally, visceral pain is normally associated with greater emotional valence and exaggerated autonomic reflexes, although the former is a fundamental phenomenon not to be confused with nociception.
Distinguishing Visceral Nociceptors from Their Not-Visceral Counterparts
We discuss hither some of the differences between visceral and non-visceral nociceptors—with the caveat that the bulk of studies are done in the absence of a physiologically (functionally) defined nociceptor population.
Morphological Considerations
The most obvious parameter for distinguishing cell types is size. It is by and large accepted that DRG neurons are bimodally distributed in terms of soma size, resulting in the designation of "(large) light" or "small dark" neurons. The former take myelinated A-fibers and somata with dense neurofilament (typically detected using antibodies raised confronting neurofilament protein, such equally RT97 (12)); the latter have unmyelinated C-fibers and are significantly less dense. Generally, the somata of visceral afferents in DRG are larger than those considered to be non-visceral nociceptors (13, 14).
By and large, smaller-diameter neurons have myelinated Aδ- or unmyelinated C-cobweb processes, whereas myelinated Aα/β-fibers can be found on cells of nearly sizes. Up to eighty percent of visceral DRG somata can have C-fibers, whereas fewer than twoscore pct generally have Aδ-fibers (fifteen,16). An exception, even so, can be institute in the perianal mucosa, where the distribution is reversed: 23% C-fibers, 77% Aδ-fibers (xvi). Visceral Aβ-fibers are rarely encountered. In contrast, L4 DRG neurons with projections in the sciatic nerve (a not-visceral nerve that innervates skin and muscle) bear witness a bias towards Aα/β-fibers (≥ 69%), with few Aδ- (approximately 15%) or C- (7-17%) fibers (17, xviii). A similar design has been shown in guinea pig neurons that innervate the left hind limb and flank; the bias shifts to C-fibers in an identified nociceptive population of these afferents (19). In addition to nociceptive Aδ- and C-fibers, non-visceral nociceptors tin also have Aβ-fibers [for review, see (20)]. It is important to capeesh that studies such as these do non necessarily reflect the exact proportions of each type of cobweb nowadays; the data are subject to varying selection dynamics and other experimental parameters chosen by the investigator.
Visceral and non-visceral afferents also differ in their spinal cord terminations. Spinal visceral afferent fibers terminate in the superficial dorsal horn, lamina Five, and around the central canal, an area also referred to as lamina X (21, 22). In contrast, the last fields of cutaneous nociceptive afferent neurons are much smaller than those of visceral afferents and stop throughout the spinal dorsal horn (11, 23). Not-visceral nociceptors as well terminate in the superficial dorsal horn and lamina 5, and thus converge on some of the same second order spinal neurons as visceral afferents; this convergence may account for the perception of pain from referred visceral sensations. Furthermore, visceral C-fibers have significantly more extensive spinal terminations (more concluding regions in unlike laminae and at multiple levels of the spinal cord) than the "nest-like" terminations of not-visceral C-fibers that are found principally in laminae I and Two (11).
Biochemical Considerations
Calcitonin Gene–Related Peptide
The vast majority (typically, 70–ninety%) of visceral afferent prison cell bodies in the DRG stain positive with antibody for the calcitonin gene-related peptide (CGRP) (Table 1) (24-35). In dissimilarity, DRG cell bodies of the non-visceral sensory arrangement are far less likely to manifest positive immunostaining for CGRP. For instance, approximately four-fifths of mouse colonic DRG somata are positive for CGRP, compared to about one-fourth of cells in the whole DRG population (24), i-third to half of cutaneous afferents (25, 36, 37), and ane-fifth to one-third of muscle afferents (37). Information technology has also been noted that visceral neurons that are positive for CGRP show a more intense signal than practice positive not-visceral neurons (38).
Table 1
a Biochemical Differences between Visceral and Non-Visceral Spinal Afferents
| Biochemical marker | Visceral afferents | Percent positive | Non-visceral afferents | Percent positive | Reference(southward) |
|---|---|---|---|---|---|
| CGRP | mouse colon | 81% | rat ankle pare | 51% | (24, 25) |
| mouse colon | 79% | rat plantar pare | 41% | (34, 36 | |
| mouse colon | 63% | rat dorsal skin | 35% | (35, 37) | |
| rat colon | 88% | rat skin b | 51% | (35, 38) | |
| rat bladder | 60% | mouse skin b | 30% c | (26, 39) | |
| rat bladder | 52–63% | rat peel b | 20% | (27, twoscore) | |
| rat float | 69% | rat pare d | xix% | (25, 41) | |
| rat ureter and urethra | ninety% | rat trapezius muscle | 33% | (26, 37) | |
| rat kidney, ureter, or bladder | >90% | rat longissimus muscle | 22% | (26, 37) | |
| rat kidney | 93% | mouse muscle e | 39% | (xxx, 39) | |
| rat stomach | 47–88% | rat muscle f | 70% | (28, 38) | |
| mouse breadbasket | 69–95% | rat muscle f | thirty% | (28, xl) | |
| guinea pig stomach | 69–87% | (28) | |||
| rat tum | 36–84% | (33) | |||
| rat stomach | 74% | (29) | |||
| rat esophagus | 54–ninety% | (33) | |||
| dog testes | ~eighty% | (31) | |||
| lamb ileum | 57% | (32) | |||
| rat splanchnic due north. | 99% | (38) | |||
| rat splanchnic n. | 95% | (40) | |||
| rat splanchnic n. | 88% | (41) | |||
| trkA | rat bladder | 75% | rat ankle peel | 43% | (25) |
| rat pelvic n. | 90% | rat skin b | 48% | (43) | |
| rat muscle f | twenty% | (43) | |||
| rat skin/muscle g | 44% | (43) | |||
| IBiv bounden | mouse colon | 20% | rat ankle skin | 43% | (24, 25) |
| mouse colon | 14% | rat plantar pare | 20% | (34, 36) | |
| mouse colon | half dozen% | rat pare b | 37–42% h | (35, 44) | |
| rat colon | 12% | mouse skin b | 14% | (35, 39) | |
| rat bladder | 29% | rat muscle | 3% i | (25, 44) | |
| rat splanchnic n. | 1–3%h | (44) | |||
| rat splanchnic n. | four 5% i | (44) | |||
| TRPV1 | mouse colon | 82% | rat plantar skin | 35% | (24, 36) |
| mouse colon | 67% | rat pare j | 32% | (35, 45) | |
| mouse colon | 62% | mouse skin b | 28% c | (65, 39) | |
| rat colon | 83% | mouse muscle e | 39% | (35, 39) | |
| rat bladder | 69% | (45) | |||
| rat stomach | 71% | (46) |
Using techniques that label whole nerve bundles (Table 1 and Box 1), rather than just prison cell bodies in the DRG, 90 percent or more of visceral afferents are reactive to anti-CGRP immunostaining, compared to only nigh 20–fifty percent of skin and xxx–70 percent of musculus afferents (38-41). Approximately one-third of functionally identified non-visceral nociceptors in the guinea grunter are CGRP-positive (42), although proportions vary amidst tissues (e.g., hairy versus glabrous skin). If but C- and Aδ-fibers are considered, this value is just under half of nociceptive units. We are unaware of any visceral correlate to these experiments for comparison.
Subpopulations of afferent neurons that deport the CGRP marker are known as "peptidergic. " Classically, peptidergic neurons are reported to express the nervus growth factor receptor trkA; in contrast, not-peptidergic neurons express Ret, the receptor for glial cell line–derived neurotrophic factor. It has been suggested that nonpeptidergic neurons likewise bind the Griffonia simplicifolia-dervied isolectin IB4 and express the purinergic P2X3 receptor. Immunoreactivity patterns for trkA correlate well with those for CGRP; for example, 75% of bladder and 43% of skin DRG somata express trkA (25), and in situ hybridization studies show trkA mRNA in xc percentage of visceral (pelvic nerve), 20% of muscle (gastrocnemius nervus), and 48% of cutaneous (saphenous nerve) afferents (43). Thus, a greater proportion of visceral DRG somata, relative to non-visceral DRG somata, contain CGRP and are, therefore, potential nociceptors. Any line of argument that maintains that visceral afferents are predominantly peptidergic, all the same, should be tempered by the caveat that a strict stardom between "peptidergic" and "nonpeptidergic" may not be completely suitable for this group of neurons.
Isolectin B4
Among DRG somata, cutaneous afferents are over 10 times more than likely to demark IB4 than are visceral afferents [40 percent vs 3 percentage; 72 hours after retrogradely labeling whole nerve trunks (44)]. Few muscle DRG somata (approximately 3%) bind this lectin (44). There are currently few studies detailing the binding of IBiv in afferents retrogradely labeled from specific organs, simply in the case of colon and bladder, the proportion of afferents that bind IBiv has been estimated at half-dozen to 30 percent (24, 25, 34, 35), whereas retrograde labeling from peel indicates that twenty to forty pct of cutaneous afferents bind IB4 (25,36). These data advise that visceral afferents are biased towards the peptidergic classification; however, it is worth noting that over ninety per centum of colonic DRG somata that bind IBfour (i.e., presumed to be "not-peptidergic") stain positive for CGRP (whereas but near xx percent of all IBfour-bounden DRG somata test positive for CGRP; David R. Robinson, PhD thesis, University of Cambridge, 2004). Too, although the functional significance is unknown, these IB4- and CGRP-positive neurons display lower-intensity IB4 staining than afferents that bind IB4 but are not CGRP-positive (24). In any outcome, these observations propose that the biochemical phenotype visceral afferents tin exist distinguished from that of non-visceral sensory neurons. This difference is reinforced by the finding that colonic afferents are far less probable to test positive for both the P2X3 receptor and IB4 binding, relative to the rate that both markers appear together in the general DRG population (24).
Transient Receptor Potential Vanilloid ane
The capsaicin receptor, TRPV1, is often regarded equally a marker for nociceptors. The majority of visceral DRG somata examination positive for TRPV1 (Table i) (24, 39, 45, 46). In contrast, cutaneous (36, 39,45) and muscle afferents (39) are far less likely to contain the receptor. The few studies that take functionally identified nociceptors report that just a very small number of cutaneous nociceptors contain TRPV1. For instance, one study showed only thirteen per centum of tested nociceptors (both C- and A-fiber afferents) innervating mouse skin were TRPV1-positive (47). In the colon, animals lacking the TRPV1 receptor are significantly less sensitive to colorectal distension (Figure 2C) than wild-type littermates (48). Although not specifically identified as nociceptors, approximately half of colonic serosal mechanoreceptors respond to capsaicin (49). In innervation of true cat viscera, all C-fibers and 38% of A-fibers are capsaicin-sensitive (fifty).
An illustration of both the complexity of the definition of the nociceptor and the role of TRPV1 can be found in a less commonly studied animal species. The African naked mole-rat, Heterocephalus glaber, expresses functional TRPV1 receptors, simply does not showroom pain behavior in response to capsaicin applied to the hind paw, unless substance P, which is absent in cutaneous C-fibers (51), is starting time administered every bit an intrathecal injection (52). This observation raises an interesting question: Are the afferent neurons that are plain capable of encoding a noxious stimulus to be considered nociceptors, even if such "nociception" depends on a pharmacological intervention?
Differences amidst Visceral Afferent Populations
Although visceral afferents can be distinguished from their non-visceral counterparts, they do non announced to form a homogeneous population (Table 1). Indeed, the colon and bladder are innervated by afferents associated with two different nerves: afferents that follow the splanchnic nerves and have cell bodies in thoracolumbar DRG, and afferents that follow the pelvic nerve and have cell bodies in lumbrosacral DRG. Studying the mechanosensitivity of single afferent fibers that innervate the colon reveals five unlike classes of mechanosensory primary afferent (53) (Figure 3). Two of these are expressed in specific afferent populations, with the remaining iii (i.e., serosal, muscular, and mucosal) plant in both the splanchnic and pelvic pathways. Mesenteric afferents, an afferent class that is not observed in the pelvic nerve, constitute half the splanchnic innervation of the colon. Similarly, muscular/mucosal afferents accept been reported in the pelvic, just not splanchnic, innervation and have been likened to a population of vagal afferents. This prompts the question of whether the pelvic nervus is fulfilling a "vagal-like" role in those more distal portions of the alimentary canal that the vagus nervus does non innervate. (Pelvic afferent terminals in the colon are predominantly found distal to those from the lumbar splanchnic nerve). Generally, pelvic afferents have lower mechanical thresholds for activation but reply more intensely to a given stimulus than do splanchnic afferents. Chemical differences are also credible betwixt these ii visceral afferent subpopulations. For case, significantly more splanchnic than pelvic afferents (66% versus 11%) respond to the direct application of bradykinin (BK), a chemical mediator released post-obit tissue injury, to the receptive ending (54). BK-responsive pelvic afferents (two of nineteen fibers tested) were mechanosensitive, whereas the BK-responsive splanchnic population included mechanically insensitive as well as mechanically sensitive afferents. If a purely serosal afferent population is studied (called because they are equally represented in both the pelvic and splanchnic nerves), more splanchnic than pelvic afferents respond to activation of either P2X or TRPV1 receptors (49), findings that are confirmed immunohistochemically (35, 49).
The colon is innervated by five different types of mechanosensory afferent
Five different types of afferent fiber take been reported in the colon: serosal, mesenteric, muscular, mucosal, and muscular/mucosal. Each has feature response criteria based on a protocol of probing, stretching, and stroking the colonic wall, and each has a different putative functional role. Most serosal afferents are mechanosensitive and, given that their thresholds for activation are college than would exist expected physiologically, are thought to signal curt, precipitous events (eastward.g., muscle wrinkle). Found only in the splanchnic afferent innervation, mesenteric afferents are predominantly found closely associated with blood vessels and probable betoken twisting of the colon wall and some changes in mesenteric blood pressure, with a potential role in inflammation. Muscular afferents, named for their termination in the round and longitudinal muscle layers of the gut, respond direct to circumferential stretch with a low threshold of activation (though tin lawmaking into the noxious range). Muscular afferents exhibit slightly different backdrop depending upon the nerve (splanchnic or pelvic) in which they are found, just generally are considered to contribute to sustained filling, bloating, or distending sensations. Mucosal afferents are stretch-insensitive (at to the lowest degree circular stretch-insensitive) and respond to fine probing and stoking of the mucosal membrane. This suggests a function in providing feedback from physiological stimuli such as the normal passing of fecal material through the gastrointestinal tract. Finally, muscular/mucosal afferents, and so named for their ability to detect both circular stretch and fine mucosal stroking, are a class of mechanoreceptor that, in mouse colon at least, are only found in the pelvic innervation. Presumably, these fibers provide a combination of the data that is transmitted from the muscular and mucosal fibers described above. For examples of the responses seen for each of these mechanosensitive fiber types, please see reference (53).
Similar findings take been reported in the rat float, an organ that also receives dual innervation through the pelvic and splanchnic nerves. Whole-prison cell patch clamp electrophysiology of cultured retrograde labeled DRG neurons has revealed that almost all pelvic afferent cell bodies respond to the P2X agonist α,β-methyleneATP, whereas only half of the splanchnic afferents responded (55). Although practically all the neurons studied responded to capsaicin, those from pelvic DRG evoked a significantly greater current.
The peptide content of splanchnic and pelvic afferent jail cell bodies in the DRG, based on immunostaining for CGRP, has been reported to be similar. On the other manus, there appears to exist a difference in the non-peptidergic population, as more than pelvic than splanchnic afferent cell bodies bind IB4, although variations in the use of retrograde tracers and fluorophphres accept produced some inconsistencies in results (35, 56). Of the 2 IBiv-binding populations, splanchnic afferent cell bodies tend to bear witness lower intensity in staining than does the pelvic population (DR Robinson and GA Hicks, unpublished). A college proportion of IBiv-binding afferents has as well been reported in splanchnic, as compared to pelvic, afferents that innervate the rat bladder (55).
Visceral Mechanosensation
As anyone who has experienced "gas" or bloating can attest, the distension of the gut can be an unpleasant and sometimes intensely painful feel. As genetically modified mice have become more widely available, there has been increased involvement in the study of molecules that mediate visceral mechanosensation and hypersensitivity (Tabular array 2). These studies have implicated a number of dissimilar molecules, including ii members of the TRP family unit of receptors, TRPV1 and TRPV4, and the acid-sensing ion channels (ASICs).
Table two
Molecules that Mediate Mechanosensation and Hypersensitivity
| Molecule | Clarification | Effects in the colon | Reference(s) |
|---|---|---|---|
| 5-HT3 | Serotonin receptor | Antagonists attenuate glycerol-induced visceral nociception and foreclose restraint stress–induced colonic hypersensitivity. | (66, 67) |
| ASIC3 | Acrid-sensing ion channel | Knockout mice evidence reduced mechanosensitivity. | (48, 62) |
| Na51.8 | Voltage-gated Na+ aqueduct | Knockout mice prove reduced response to intracolonic capsaicin or intracolonic mustard oil. | (68) |
| P2X | Purinergic P2X receptors | ATP is released from the colonic mucosa by colorectal distension, and pelvic nervus afferents are activated past α,β-methyleneATP; visceral hypersensitivity is reversed by specific P2Xone, P2X3, and P2Xii/three antagonists. | (69, lxx) |
| PAR | Protease-activated receptors | Luminal awarding of PAR2-activating peptide causes visceral hypersensitivity. | (71) |
| TRPV1 | TRPb-vanilloid i receptor | Knockout mice show reduced mechanosensitivity. | (48) |
| TRPV4 | TRPb-vanilloid 4 receptor | Knockout mice show attenuated mechanosensitivity and reduced response to colorectal amplification; a selective agonist increases response to colorectal distension. | (56, 60) |
Equally indicated above, five different types of afferent fiber have been reported in the colon, each of which is responsive to different forms of mechanical stimulation and has its own putative functional role. An overview of these, forth with the differences seen between the splanchnic and pelvic innervation of the colon, tin exist found in Figure 3.
TRPV1 knockout mice show a significant reduction in their behavioral (visceromotor) response to colorectal distension besides as in afferent fiber responses to stretch (48); similarly, urinary bladder and jejunal afferent subpopulations showroom reduced mechanosensitivity (57, 58). It as well appears that TRPV1 plays a role in hypersensitivity to mechanical stimulation in models of colon (48) and bladder hypersensitivity (interstitial cystitis) (59). This evidence of a part for TRPV1 in visceral hypersensitivity—and thus, presumably, in visceral pain—extends to non-visceral tissues, considering mice that lack the TRPV1 receptor practice non exhibit the enhanced referred mechanical hypersensitivity to the hind paw following cystitis that is seen in wild type controls (59).
A relative of TRPV1, the TRPV4 receptor, has besides been implicated in visceral mechanosensation and may exist most important in the colon; TRPV4 receptor mRNA content is significantly greater in colonic DRG cell bodies (with more in splanchnic than pelvic nervus DRG) compared to the cell bodies of gastric or non-visceral afferents (56). Furthermore, mechanical responses of colon afferents are reduced, and response thresholds are greater, in TRPV4 receptor knockout mice, consistent with reduced behavioral responses to colorectal distension (56). Conversely, the intracolonic administration of a TRPV4 receptor–selective agonist results in a dose-dependent increase in the responses of mice to colorectal distension (lx).
The proton-sensing ion channels of the ASIC family have been investigated as potential visceral mechanotransducers using knockout mice that lack ASIC1a, ASIC2, or ASIC3 channels. The loss of ASIC1a appears to result in an increase in mechanosensitivity throughout the gastrointestinal tract, including the colon, whereas deficiency in ASIC2 results in dissimilar mechanical responses, depending on the target (in the colon it also results in increased mechanosensitivity) (61, 62). CGRP release from the colon is unchanged by knockout of ASIC2 (63). In contrast, knocking out ASIC3 leads to reduced colonic mechanosensitivity, both with respect to stretch in single-fiber experiments and behavioral assessment of the visceromotor response to colorectal amplification (48, 62).
Conclusion
Nosotros accept reviewed bear witness hither that visceral nociceptors—or, more accurately, visceral afferents with the potential to transmit nociceptive information—differ from not-visceral (somatic) afferents in a number of means, including their morphology and the channels and receptors they contain. They likewise differ in the consequences of their activation. In humans, visceral pain has a number of characteristics that distinguish it from hurting originating from non-visceral structures, and these differences are near likely responsible for the symptoms experienced past patients with a visceral disease such equally IBS. Somatic pain relief strategies typically work poorly for the management of visceral hurting, and a meliorate agreement of the visceral nociceptor (along with cardinal mechanisms not discussed here) is vital to the development of new therapies for visceral pain management. The fashion frontward would be easier if we were able to place visceral nociceptors by characteristics other than response to noxious stimuli. Although CGRP- and TRPV1-containing DRG somata are more common in visceral sensory neurons, these and other potential surrogates do not reliably distinguish visceral from non-visceral nociceptors. Until such a marker (or constellation of markers) is found, identification of nociceptors requires functional assessment.
Biographies
David R. Robinson, PhD, received his doctoral degree, with a PhD studentship from GlaxoSmithKline, from the University of Cambridge, where he studied the label of the distal colon with particular emphasis on colonic hypersensitivity. He is now a Postdoctoral Acquaintance at the Pittsburgh Eye for Hurting Research, Academy of Pittsburgh, where his research interests remain focused around colonic hypersensitivity.
Gerald F. Gebhart, PhD, is Professor and Director of the Center for Pain Research at the University of Pittsburgh School of Medicine. He has published more than 350 articles in journals and books. His interests in the pain field include descending modulation of pain (mechanisms of descending facilitation, secondary hyperalgesia, and chronic pain atmospheric condition) and visceral pain.
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