Peripheral Visceral Mechanisms

Embryologically, visceral organs arise from midline structures and thus receive dual innervation by primary afferents through autonomic parasympathetic and sympathetic nerves. This is in contrast to cutaneous somatic tissue, which is innervated by afferent sensory fibers traveling along the spinal nerves to the dorsal horn of the spinal cord. Parasympathetic afferents are typically referenced by the nerve in which they travel, such as the vagal and pelvic afferents. Vagal afferents provide innervation from the upper gastrointestinal system to the splenic flexure. Pelvic afferents provide innervation to the descending colon and remainder of the lower bowel. This is illustrated in Fig. 4.1 . The sympathetic afferents are similar to spinal afferents, given their termination within the dorsal horn of the spinal cord, and are also named after the nerve in which they travel. Examples include the splanchnic spinal afferents projecting to the thoracolumbar segments and the pelvic spinal afferents projecting to the lumbosacral region.

Parasympathetic innervation of the gastrointestinal system. Vagal afferents provide innervation from the upper gastrointestinal system to the splenic flexure, whereas the pelvic afferents provide innervation to the descending colon.

Visceral sensory afferents are primarily composed of thinly myelinated A-delta nerve fibers and unmyelinated C nerve fibers. This is in contrast to cutaneous somatic mechanoreceptors, which are primarily A-beta nerve fibers and have specialized nerve endings including pacinian corpuscles, Meissner corpuscles, and Ruffini endings. Viscerosensory axons are polymodal and exhibit mechanosensitivity as well as chemosensitivity and thermosensitivity. Vagal afferents are thought to be a homogenous group responding primarily to low-intensity mechanical stimulation over a wide range. This is thought to assist with the regulation of physiologic processes. Spinal afferents, in contrast, have two physiologic classes of nociceptive receptors based on their responses. These include high-threshold receptors and low-threshold receptors. High-threshold receptors are activated by a mechanical stimulus intensity within the noxious range. These receptors innervate organs that produce conscious sensations of pain, including the heart, lungs, biliary system, small intestine, colon, ureter, bladder, and kidneys. ^, Low-threshold, or intensity-encoding, receptors are able to respond to a range of stimuli from innocuous to noxious and are able to encode the stimulus intensity based on the magnitude of their discharge.

Viscera are also innervated by a group of visceral afferents termed mechanically insensitive afferents, or silent afferents. These silent afferents are suspected to be normally unresponsive to mechanical stimuli such as stretch and distention and instead are responsive to stimuli such as tissue injury and inflammation. Silent afferents constitute approximately 25% of the afferents innervating the splanchnic and pelvic nociceptive pathways, but the exact mechanisms and clinical importance of these receptors are still under investigation. However, upon activation, they are believed to acquire mechanosensitivity and play a role in persistent visceral pain states.

Central Visceral Mechanisms

As discussed earlier, visceral sensation can be grouped into vagal afferents and spinal afferents. Vagal afferents project centrally to the inferior ganglion of the vagus nerve, or nodose ganglion, before terminating within the nucleus of the solitary tract. The solitary nucleus is located within the dorsal brainstem and assists with integration and regulation of autonomic function. Although vagal afferents are not specifically involved in the perception of pain, the nerve endings are sensitive to similar chemical mediators that affect spinal afferents, such as serotonin, prostaglandins, and capsaicin. This may provide a mechanistic explanation for some of the autonomic symptoms, such as nausea and vomiting, that are frequently reported with visceral pain.

Spinal afferent pathways are known to be involved in the transmission of visceral pain. These afferents pass through the sympathetic ganglia and synapse along the dorsal horn of the spinal cord primarily in laminae I and V, but some also in laminae II and X. ^, Afferents then project rostrally along the dorsal column, spinothalamic, and spinoparabrachial pathways. The dorsal column and spinothalamic pathways are shown in Fig. 4.2 . The dorsal column travels ipsilaterally within the spinal cord to the nucleus gracilis and nucleus cuneatus within the brainstem. Nociceptive input from there is transmitted to the ventral posterolateral (VPL) nucleus of the thalamus. The spinothalamic tract projections are relayed from deeper within the dorsal horn and also synapse within the VPL nucleus of the thalamus. Third order neurons from the VPL travel to the primary and secondary somatosensory cortex. Nociceptive projections to these areas contribute to the sensory discriminative aspects of pain perception such as location, duration, and intensity. The ventral posteromedial nuclei of the thalamus are the main target of the vagal afferents, as depicted in Fig. 4.3 . Along with superficial dorsal horn projections from the spinoparabrachial pathway, this nociceptive input is transmitted to the limbic structures including the amygdala, insula, and anterior cingulate cortex to provide motivational and affective aspects of pain processing. ^,

Visceral pain afferent signals traveling along the dorsal column and spinothalamic pathways. Third-order neurons from the ventral posterolateral nucleus of the thalamus travel to the primary and secondary somatosensory cortices.

Vagal afferent pathways from the gastrointestinal tract to the nucleus tractus solitarius (NTS) and ventral posteromedial (VPM) nuclei of the thalamus that allow for processing of the affective aspects of pain.

Output traveling along descending pathways from the cortical and limbic areas in response to visceral pain input also plays a role in pain modulation, although these mechanisms are not well understood. The periaqueductal gray (PAG) and rostral ventromedial medulla (RVM) are the most studied structures involved. Nociceptive input is received in both the PAG and RVM, and in turn the PAG additionally projects to the RVM. The RVM acts as a supraspinal modulatory system providing facilitatory and inhibitory influences on spinal cord excitability. Descending inhibitory projections to the dorsal horn of the spinal cord can assist in decreasing the intensity and emotional components of pain.

The transmission and modulation of visceral afferents is only one aspect of the central mechanisms that may contribute to chronic visceral pain pathophysiology and symptom development. There is growing interest in the functional and structural alterations in brain regions and their association with various visceral pain conditions such as IBS, functional dyspepsia, and IC. This is often evaluated by the use of functional magnetic resonance imaging (fMRI) of the brain. Early fMRI studies identified pain-related brain regions that included the insular cortex, anterior cingulate cortex, primary sensory cortex, prefrontal cortex, and the thalamus. These pain-related regions have been shown to have close connectivity with regions associated with emotional arousal, such as the amygdala. In a study comparing rectal distension in patients with IBS to healthy controls, the patients with IBS showed increased activation in regions associated with emotional arousal. Healthy controls showed increased activation in the prefrontal cortex, possibly leading to suppression of arousal and to greater activation of descending inhibitory systems. Some of these brain regions are described as a salience network, which recognizes and interprets salient stimuli, modulating the organism’s behavioral response to internal or external stimuli. In a review by Mayer et al., structural and functional changes in the salience network, sensorimotor network, and emotional arousal networks are the most commonly reported findings in visceral pain syndromes such as IBS. The use of neuroimaging studies has allowed for a greater understanding of the role of anticipation and context in visceral pain disorders, making it clear that the pain reported by patients is not solely related to peripheral input. Further studies are needed to understand these areas and identify possible central targets for treatment beyond our current options.

Viscerosomatic and Viscerovisceral Convergence

Both visceral and somatic afferent signals synapse on the dorsal horn of the spinal cord. Visceral afferents are thought to represent approximately 10% of all afferent signal inflow into the spinal cord, a relatively small number. The convergence of afferent visceral and somatic signals into the supraspinal centers is thought to generate the symptoms of referred pain felt by many patients. Despite these neurons initially being activated by visceral nociceptors, central processing can create the perception that the input is arising from various somatic dermatomes, resulting in pain perception distant to the primary site. This is illustrated in Fig. 4.4 . Sites of convergence may also be sources of nociceptive sensitization, although the exact mechanisms are not well understood.

Convergence of afferent visceral and somatic signals into the dorsal horn of the spinal cord. This viscerosomatic convergence can contribute to pain perception distant to the primary site. In this case, pain from the gallbladder can sometimes be felt in the abdominal region as well as the shoulder and scapular region.

Visceral pain conditions rarely occur in isolation and there is often significant symptom overlap. This is thought to occur as a result of viscerovisceral convergence, where pathology in one visceral organ can induce disease states in nearby organs. As an example, both colonic and bladder afferents enter the spinal cord at similar levels resulting in possible cross-organ sensitization. This can explain why some studies have shown that patients with colitis can sometimes develop hypersensitivity of the bladder.

Visceral Hyperalgesia

Visceral hyperalgesia and hypersensitivity are defined as an exaggerated response to a painful stimulus or a decreased pain threshold following nociceptor activation. This can often occur in chronic visceral pain states, making it difficult to identify the initial insult or pathology. Modulation in pain processing of visceral afferents can occur both peripherally and centrally resulting in hyperalgesia. Moshiree et al. describe four potential mechanisms for visceral hypersensitivity. The first includes sensitization of primary afferent neurons innervating the viscera. The second is a result of spinal sensitization due to tonic impulse input from primary afferent neurons. The third potential mechanism involves descending facilitation from the brain to the spinal cord, and the final mechanism is a result of selective alteration in cortical processing of the afferent input.

Local ischemia, inflammation, and hypoxia can sensitize visceral afferent receptors in the periphery as mentioned previously with silent nociceptors. Degranulation of mast cells and secretion of inflammatory mediators causes an acute initial pain. This results in increased transmission and augmentation of the visceral afferents into the dorsal horn of the spinal cord. This persistent afferent stimulation can ultimately lead to sensitization, even after the initial insult has resolved.

The mechanisms by which central sensitization contributes to visceral hyperalgesia have not been well studied in humans. Centrally, positive feedback loops between spinal and supraspinal structures are thought to increase excitability and influence the development of visceral hyperalgesia. Additionally, psychologic stress and trauma can have significant effects on the perception of visceral pain. ^, Clearly, emotional states and a tendency to have heightened anticipation to threat can play a role in chronic persistent visceral pain.

Visceral Referral Patterns

Visceral symptoms are most often experienced as a diffuse, generalized, and poorly defined pain within the abdominal region. However, pain from different visceral sources can refer to various somatic locations. Thought to be a response to viscerosomatic convergence, this can help explain some common pain referral patterns that are seen in visceral pain conditions.

Klineberg et al. described examples of some visceral pain referral patterns that can be seen in patients presenting with back pain. For example, patients with aortic aneurysms can report mid-thoracic back pain that can be severe and described as tearing. Patients with gallbladder or liver pathology can have referred pain in the posterior scapular and shoulder region. This can be especially important in patients with spinal cord injury when there is sensation impairment below the level of injury and referred pain may be the only presenting symptom suggesting the underlying pathology. Ectopic pregnancy, kidney stones, and prostatitis may also present with referred pain to the back region. Pain and tenderness at McBurney point, located one-third the distance from the anterior superior iliac spine to the umbilicus, can suggest underlying appendicitis. Commonly referred pain patterns are shown in Fig. 4.5 .

Common visceral pain referral patterns.

Risk Factors for Visceral Hyperalgesia

Symptoms of visceral hyperalgesia and hypersensitivity make the clinical evaluation and treatment of visceral pain disorders difficult. It is unclear exactly why patients’ experience with these disorders can be highly variable, sometimes self-limiting and at other times causing significant pain and disability. Psychosocial factors are thought to influence the development of chronic visceral pain symptoms. Genetic factors and the body’s stress response systems may also play a role.

Tillisch and Mayer posit that an altered cognitive-emotional modulation of visceral afferent stimuli influences the clinical presentation of chronic visceral abdominal pain. In experimental fMRI studies, patients who have visceral pain with chronic pain, in contrast to healthy subjects, show activation of pain-related regions in the anticipation of pain, prior to pain delivery. This lends support to the notion that the perception of visceral pain is modulated by a psychologic state and helps explain why psychologic stressors and maladaptive coping strategies can thus pose a common risk factor for the development of chronic visceral pain. Clinically, patients with IBS, IBD, and IC have been seen to have symptoms that are exacerbated during periods of emotional distress. Psychologic conditions such as depression, anxiety, and posttraumatic stress disorder, as well as chronic somatic pain syndromes, commonly overlap with chronic visceral pain and further reinforce the reporting of pain symptoms. Emotional trauma early in life, such as sexual abuse and maternal separation, can also be a risk factor for the development of chronic visceral pain in adulthood. Clinical evaluation for potential psychologic comorbidities is essential in the diagnostic workup of chronic visceral pain symptoms, as these may be targets for potential treatment modalities.

Genetic disposition may play a role in the development of functional gastrointestinal disorders (FGIDs). This has been seen in twin and family studies associated with IBS, although no specific gene has been associated. Organic causes of visceral pain, including IBD and celiac disease, are also known to have familial components. More recent research has sparked interest in possible epigenetic mechanisms that can alter gene expression without changing the underlying DNA sequence. These mechanisms include DNA methylation, histone modification, and microRNA activity. These environmental factors can play a role in the transfer of visceral pain characteristics and were seen in maternally separated rats exposed to stress. It was noted that offspring cared for by maternally separated rats showed visceral hypersensitivity, whereas offspring cared for by conventionally raised rats did not show these symptoms in adulthood.

The autonomic nervous system and hypothalamic-pituitary-adrenal (HPA) axis both may be implicated in the development of chronic visceral pain in a response to stress. Autonomic dysfunction may be present in many conditions where chronic pain predominates, such as IBS, fibromyalgia, and chronic pelvic pain . There appears to be a sex difference, with an altered autonomic nervous system responsiveness to a visceral stimulus being more prominent in men with IBS compared with women, as reported by Tillisch. The HPA axis and specifically corticotropin-releasing factor (CRF) are influential in the body’s stress response. CRF can be upregulated by intestinal inflammation as well as psychologic stressors and conditions, leading to enhanced visceral nociception. In rodent studies, CRF injections induced hyperalgesia to colorectal distention, while CRF receptor antagonism reduced visceral hyperalgesia. Human studies to date have not been successful in achieving positive clinical outcomes with CRF receptor antagonists despite the strong preclinical models.

Clinical Evaluation

A comprehensive clinical history and physical examination are essential in the evaluation of visceral pain syndromes. Psychosocial assessment is also very important, as the use of psychometric inventories and scales can help reveal underlying psychologic comorbidities and catastrophizing. Although functional disorders are not life threatening, they can have a significant impact on a patient’s quality of life. FGIDs account for a large portion of chronic visceral abdominal pain; however, it is important not to overlook organic causes that could signal more serious or emergent conditions. Certain clues in the clinical history and physical examination can point toward organic disease such as weight loss, bloody or steatorrheic stools, jaundice, a history of malignancy, or a palpable abdominal mass.

It is also important to be aware of factors that can aggravate and alleviate visceral pain symptoms to assist clinicians in the evaluation of patients. Food intake, for example, may worsen with reflux disease but does not often exacerbate IBS symptoms. Symptom relief after bowel movements may be associated with IBS. A history of recent life stressors such as bereavement, financial distress, and trauma is often associated with functional disorders, but can also be reported in IBD and gastroesophageal reflux disease.

In the case of chronic visceral pain from suspected urogenital and pelvic disorders, symptoms may often involve more than one organ system. Additionally, there may be an association of psychologic comorbidities, such as anxiety, depression, and history of sexual abuse, with these disorders. Symptoms include private bodily functions such as sexual activity, voiding, and defecation. Thus it is important to establish good rapport with patients in order to create a strong physician-patient relationship. Essential components in the history may include cyclic patterns of pain, pain with intercourse, history of sexually transmitted diseases, prior abdominal or pelvic surgeries, and history of traumatic relationship or abuse. The physical examination should be performed in a methodical way minimizing discomfort to the patient. Utilization of a chaperone should be offered to patients during any sensitive physical examination.