Introduction

Visceral pain is a common clinical problem and manifests in a wide spectrum of illnesses from acute myocardial infarction to dysmenorrhea or irritable bowel syndrome. Not surprisingly, severity, duration, location and character of pain as well as associated symptoms vary widely. Despite these obvious differences, visceral pain syndromes share some characteristics. Sherrington defined visceral sensations as interoceptive. Such interoceptive signals provide important homeostatic information and are closely linked to autonomic function. Interoception is also associated with a strong motivational dimension. For example, hunger triggers complex behavioral responses that ultimately result in food intake. The level of complexity increases even further as motivation and emotion are closely related, which may explain why humans rate the unpleasantness of visceral events (e.g. rectal distension) higher than that of similarly intense non‐visceral stimuli (e.g. local pressure) [1].

Visceral pain is associated with changes in autonomic function that may be cause and/or consequence of the underlying painful disorder and often complicate treatment. This interrelationship affects pain management, as medications may also influence organ function (e.g. constipation with opioids). The affective dimensions of pain are quite prominent, especially if essential and typically pleasant activities of daily life such as eating become triggers of pain or other unpleasant sensations.

Basic mechanisms of visceral pain

Investigating pain mechanisms largely focuses on nociception, the neural process of encoding noxious stimuli, usually – but not necessarily ‐ linking a noxious stimulus to perception and behavioral responses. This concept is useful, even if not entirely accurate, because it enables us to investigate and treat components that contribute to visceral pain. Those components include the sensory afferent nerves that innervate visceral organs, the second order spinal or brainstem neuronal targets upon which the afferents terminate and the supraspinal sites in brain that process, interpret and modulate visceral input.

Molecular mechanisms of visceral sensation

Based on the link between activation of peripheral afferents and perception, we should be able to blunt or even block pain by interfering with the molecules that translate a noxious stimulus into action potentials discharged by nociceptive neurons. Many candidate molecules have been identified and new ones continue to emerge. Using pharmacologic tools or experiments with genetically modified animals, three members of the transient receptor potential family of ion channels (TRPV1, TRPV4, TRPA1) appear to have an important role in responses to chemical signals, such as acid, and to high intensity mechanical stimulation during visceral distension [2]. Purinergic receptors, which are activated by ATP, may also contribute to visceral sensation and pain. These receptors require ATP release from neighboring cells, thus functionally linking the nervous system to other structures, such as the epithelium. The importance of epithelial signals has long been recognized in gastrointestinal physiology, with specialized enteroendocrine cells releasing mediators, which in turn activate primary afferent neurons. The best‐characterized signaling cascade involves the release of serotonin, which initiates local reflexes and activates extrinsic afferents that may lead to conscious perception of visceral stimuli [3]. Other evidence points to endocannabinoids as another signaling system that modulates visceral sensation and function. Animal experiments and human data have clearly established a role for cannabinoid receptors in regulation of gastrointestinal motility and transit, which may have therapeutic potential but also contribute to adverse effects. While effective as antiemetics, cannabinoid agonists have not yet demonstrated analgesic properties in visceral pain in humans [4]. More recently, changes in luminal content (e.g. trypsin, metabolites of the gut microbiome) have been shown to activate afferent pathways and contribute to visceral pain, potentially opening up new treatment options for colonic visceral pain conditions [5].

Structural elements of visceral sensation

Most viscera are derived from midline structures and consequently are innervated bilaterally and thus activate both hemispheres of the brain. Despite the bilateral innervation, the density of the visceral afferent innervation is sparse relative to the afferent innervation of non‐visceral tissues (principally skin) that convey input to the spinal cord. Unlike sensory neurons innervating non‐visceral tissues, many sensory neurons have multiple receptive fields within an organ. Most visceral afferents are polymodal, meaning they respond to more than one stimulus modality. These and other anatomic and physiologic findings described below correlate well with the clinical observation that visceral sensations are poorly localized and do not reliably reflect the underlying stimulus modality.

Except for pelvic structures, all viscera receive a dual sensory innervation from spinal and vagal afferents. Pelvic organs are also innervated by two distinct sensory pathways, both of which project to the spinal cord via the lower splanchnic and pelvic nerve, respectively. The cell bodies of vagal sensory fibers are located in the nodose and the slightly more rostral jugular ganglion, with central terminations projecting directly to brainstem nucleus of the solitary tract and from there via the parabrachial nucleus and ventromedial thalamus to the insular cortex. Vagal afferent input has a role in the regulation of autonomic and homeostatic functions and is important in nausea, cough and dyspnea or complex sensations, such as hunger and satiety, but likely contributes little to acute pain. Spinal afferents have their cell bodies in dorsal root ganglia and project to second order neurons within the spinal cord, which send information rostrally through the spinothalamic tract and dorsal column. Second order neurons in the spinal cord typically receive convergent input from cutaneous sites, which provides the structural basis for pain referral to cutaneous as well as to other, typically nearby viscera, thus contributing to organ cross‐sensitization (see [6] for a recent review).

Central processing of visceral sensation

Perception requires the activation of higher cortical structures. Detailed psychophysical experiments coupled with functional brain imaging reveal a matrix of structures activated by painful stimuli, discussed in more detail in Chapter 3. Functional brain imaging has not, however, demonstrated striking qualitative differences between the processing of visceral and non‐visceral sensations. Notably, visceral pain more strongly activates the perigenual portion of the anterior cingulate cortex, while non‐visceral pain is primarily represented in the mid‐cingulate cortex [7].

Sensitization and visceral pain

The relationship between stimulus intensity and the related sensory response, whether neuronal or perceptual, is represented as a stimulus‐response function. In 1973, James Ritchie first demonstrated in clinical studies in patients with irritable bowel syndrome (IBS) a left‐ward shift of this stimulus–response function to greater sensitivity [8] (e.g. Figure 34.1). The increase in sensitivity to a stimulus, and the left‐ward shift of the stimulus‐response function, operationally defines sensitization. Many studies have since documented that sensitization of sensory pathways and sensory processing contributes to the pathogenesis of chronic visceral pain syndromes. Sensitization can be caused by peripheral and/or central mechanisms. Experimentally induced gastric, urinary bladder, colonic or other organ inflammation increases the excitability of primary afferent neurons. A variety of endogenous mediators have been identified as likely contributors, including prostaglandins, bradykinin, interleukins, cytokines as well as several neurotrophic factors, which are important in maintaining or modulating the function of nerve cells and thus may have a role in chronic pain syndromes. Extensive experimental data show changes in the properties of second order spinal neurons and more rostrally located areas of the central nervous system, which are at least in part mediated through glutamate acting on N‐methyl ‐D‐aspartate (NMDA) receptors.

Pain without peripheral input

The mechanisms of peripheral and central sensitization described above are all based on shifts in the causal relationship between a stimulus, its perception and the reaction of the organism. However, the model fails to explain chronic pain that is present without apparent peripheral input. While such a scenario runs counter to our training and practice, it is clinically quite relevant. For example, patients with IBS reported visceral pain in response to a visual stimulus that had previously been linked to painful colorectal distension. Functional brain imaging performed during such “conditioned” pain showed activation patterns that were quite like those seen during actual painful visceral stimulation [9]. Neuroaxial blocks to the point of complete surgical anesthesia eliminated pain in less than 50% of patients with chronic pancreatitis. These examples demonstrate the importance of ‘top‐down’ mechanisms, which modulate afferent input through descending inhibition or facilitation or even generate the above‐mentioned pain perception without any peripheral input. Anxiety with heightened attention (hypervigilance) to and altered processing of visceral input (catastrophizing) play key roles as central drivers of such pain experiences and may contribute to functional changes and structural remodeling that has been shown in brain imaging studies.