Inside information – The unique features of visceral sensation

Most of what is written and believed about pain and nociceptors originates from studies of the “somatic” (non-visceral) sensory system. As a result, the unique features of visceral pain are often overlooked. In the clinic, the management of visceral pain is typically poor, and drugs that are used with some efficacy to treat somatic pain often present unwanted effects on the viscera. For these reasons, a better understanding of visceral sensory neurons—particularly visceral nociceptors—is required. This review provides evidence of functional, morphological, and biochemical differences between visceral and non-visceral afferents, with a focus on potential nociceptive roles, and also considers some of the potential mechanisms of visceral mechanosensation.

The Visceral Sensory System

The principal extrinsic afferent nerves innervating visceral organs are anatomically associated with sympathetic and parasympathetic nerves and are accordingly named (e.g., pelvic nerve afferent), although they are not part of these efferent, autonomic, pathways. Most extrinsic visceral afferent neurons have cell bodies in dorsal root ganglia (DRG) and terminate in the spinal cord (spinal afferents); visceral afferent fibers in the vagus nerve, with cell bodies in the nodose and adjacent jugular ganglia, terminate in the brainstem nucleus tractus solitarius. There are two features that are unique to the visceral sensory innervation: 1) most organs also have an intrinsic innervation (e.g., the enteric nervous system of the gastrointestinal tract) and 2)each organ is innervated by two different extrinsic nerves (e.g., the distal colon and urinary bladder are innervated by the pelvic and splanchnic nerves). Although there are likely important functional interactions between the intrinsic and extrinsic visceral innervations, their anatomical relationship and means of intercommunication are largely unknown. Figure 1 summarizes the visceral sensory innervation, using the gut as an example.

Visceral Afferents are Anatomically Different 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 electrical energy (e.g., Merkel cells, Ruffini endings, Pacinian corpuscles), whereas only two types of specialized ending have been reported in visceral afferents: intraganglionic laminar endings (IGLEs) and intramuscular arrays (IMAs). Both types have limited distributions (e.g., near sphincters), are specific to muscular vagal or pelvic innervation, and are less intricate than their non-visceral counterparts [for review, see (1, 2)]. IGLEs and IMAs appear 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 (like non-visceral nociceptors), with no specialized structure and one or a few punctate receptive fields.

Visceral Afferents Transmit Unique Sensations

Visceral and non-visceral afferents encode different types of information: the conscious experiences generated by the visceral sensory system are not initiated by non-visceral afferents. For example, the sensation of nausea does not arise from the skin, and vice versa, one cannot detect cutting of the gut [for review, see (3, 4)]. Conscious sensations arising from the viscera, in addition to pain, include organ filling, bloating and distension, dyspnea, and nausea, whereas non-visceral afferent activity gives rise to sensations such as touch, pinch, heat, cutting, crush, and vibration. Both sensory systems can detect chemical stimuli.

The Visceral Nociceptor Defined

Nociceptors were originally defined as receptors that respond to noxious stimuli, particularly those that damage or threaten to damage skin. Thus, they were defined in a functional context. As our understanding of nociceptors has increased, however, attempts to redefine the nociceptor have generated much debate and little agreement. Furthermore, a “noxious stimulus” is semantically distinct from a “painful stimulus,” a concept that has evolved from the descriptions of “nocicipient” cutaneous receptors by Sherrington at the beginning of the twentieth century (5).

“Pain” is a psychological state, defined by the International Association for the Study of Pain (IASP) as “an unpleasant sensory and emotional experience associated with actual 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 following quotation from 1900 shows (7):

The stimuli which evoke pain may be characterised as ‘excessive.’ It might almost be asserted that ‘excess’ is that quality of a stimulus in virtue of which it becomes ‘adequate’ for the sense of pain. ‘Excessive’ in this application connotes ‘harmful,’ or ‘to be avoided,’ e.g. by muscular action for resistance or escape. The ‘excess’ of the stimulus may lie in its intensity, or in its extensity (spatial or temporal).

Potential confusion arises from the IASP’s definition (6) of a noxious stimulus as “one which is damaging to normal tissues,” thereby excluding the potential for damage 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 central terminals and soma) that signals actual tissue damage.

One problem with these definitions is demonstrated by the existence in visceral organs of low-threshold mechanosensory afferents (sometimes also 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 skin encode into the noxious range, or sensitize (see below). 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 will not signal 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.

Accordingly, we propose that a visceral nociceptor (or indeed, a nociceptor in any tissue) is a sensory receptor that, when activated, can produce a reflex or response that is protective or adaptive (e.g., withdrawal, guarding, vocalization); can 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 most of the visceral sensory innervation is nociceptive in character, particularly during organ insult. Most (70-80%) mechanosensitive visceral afferents have low thresholds for activation in the physiological range; the remainder have high thresholds and are commonly considered to represent the population of visceral nociceptors. Nevertheless, most low-threshold mechanosensitive visceral afferents encode into the noxious range and generally give greater responses than their high-threshold counterparts (Figure 2A). They also sensitize after organ insult, giving increased responses to both innocuous and noxious intensities of stimulation. These findings argue for potential roles of both low- and high-threshold mechanoreceptive visceral afferents in visceral pain 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 small-diameter, capsaicin-sensitive DRG neurons (that is, those that either express the capsaicin receptor TRPV1 or respond to application of capsaicin) are sometimes considered as nociceptors. The reliability of biochemical targets, such as TRPV1, to act as nociceptor markers is discussed below.

Visceral Pain is Different from Non-Visceral Pain

The ability to identify the source (spatial location) of cutaneous pain is excellent, and the ability to identify that of joint and muscle pain is generally good; in contrast, visceral pain is diffuse in character and poorly localized. Two factors contribute to this difference. First, relative to non-visceral structures, the viscera are sparsely innervated. It is estimated that fewer than seven percent of spinal afferents in the DRG project to the viscera [see (1,8,9,10)], and only a fraction of these convey input to the central nervous system that will be perceived. This sparse innervation is compensated for in the spinal cord, where visceral terminations arborize widely over several spinal segments and even to the contralateral spinal cord (11). Second, 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 (but skin, joint, or muscle pain is not referred from shoulder to heart). In addition, whereas pain can be evoked from virtually all non-visceral structures, parenchymous viscera (e.g., liver and pancreas) do not give rise to pain unless the organ is inflamed or the organ capsule is distorted, for example by a tumor. Finally, visceral pain is commonly associated with greater emotional valence and exaggerated autonomic reflexes, although the former is a central phenomenon not to be confused with nociception.

Morphological Considerations

The most obvious parameter for distinguishing cell types is size. It is generally 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 have myelinated A-fibers and somata with dense neurofilament (typically detected using antibodies raised against neurofilament protein, such as 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).

Generally, smaller-diameter neurons have myelinated Aδ- or unmyelinated C-fiber processes, whereas myelinated Aα/β-fibers can be found on cells of most sizes. Up to eighty percent of visceral DRG somata can have C-fibers, whereas fewer than forty percent generally have Aδ-fibers (15,16). An exception, however, can be found in the perianal mucosa, where the distribution is reversed: 23% C-fibers, 77% Aδ-fibers (16). Visceral Aβ-fibers are rarely encountered. In contrast, L4 DRG neurons with projections in the sciatic nerve (a non-visceral nerve that innervates skin and muscle) show a bias towards Aα/β-fibers (≥ 69%), with few Aδ- (approximately 15%) or C- (7-17%) fibers (17, 18). A similar pattern 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 can also have Aβ-fibers [for review, see (20)]. It is important to appreciate that studies such as these do not necessarily reflect the exact proportions of each type of fiber present; 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 V, and around the central canal, an area also referred to as lamina X (21, 22). In contrast, the terminal fields of cutaneous nociceptive afferent neurons are much smaller than those of visceral afferents and terminate throughout the spinal dorsal horn (11, 23). Non-visceralnociceptors also terminate in the superficial dorsal horn and lamina V, 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 terminal regions in different laminae and at multiple levels of the spinal cord) than the “nest-like” terminations of non-visceral C-fibers that are found principally in laminae I and II (11).

Biochemical Considerations