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Physiology of Visceral Pain

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ABSTRACT

Pain involving thoracic, abdominal, or pelvic organs is a common cause for physician consultations, including one‐third of chronic pain patients who report that visceral organs contribute to their suffering. Chronic visceral pain conditions are typically difficult to manage effectively, largely because visceral sensory mechanisms and factors that contribute to the pathogenesis of visceral pain are poorly understood. Mechanistic understanding is particularly problematic in “functional” visceral diseases where there is no apparent pathology and pain typically is the principal complaint. We review here the anatomical organization of the visceral sensory innervation that distinguishes the viscera from innervation of all other tissues in the body. The viscera are innervated by two nerves that share overlapping functions, but also possess notably distinct functions. Additionally, the visceral innervation is sparse relative to the sensory innervation of other tissues. Accordingly, visceral sensations tend to be diffuse in character, are typically referred to nonvisceral somatic structures and thus are difficult to localize. Early arguments about whether the viscera were innervated (“sensate”) and later, whether innervated by nociceptors, were resolved by advances reviewed here in the anatomical and functional attributes of receptive endings in viscera that contribute to visceral pain (i.e., visceral nociceptors). Importantly, the contribution of plasticity (i.e., sensitization) of peripheral and central visceral nociceptive mechanisms is considered in the context of persistent, chronic visceral pain conditions. The review concludes with an overview of the functional anatomy of visceral pain processing. © 2016 American Physiological Society. Compr Physiol 6:1609‐1633, 2016.

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Figure 1. Figure 1. Clinical and economic burden of abdominal and chest pain. Annual emergency room encounters (top panel) and hospitalizations (bottom panel) were abstracted from the Nationalwide Emergency Room Databank and the Nationwide Inpatient Sample. The results are based on discharge diagnoses codes that included abdominal (blue) or chest (black) pain.
Figure 2. Figure 2. Illustration of visceral afferent innervation. (A) The vagus nerve, with cell bodies in the nodose ganglion and central terminals in the brainstem nucleus tractus solitarii (NTS), innervates organs in the thoracic and abdominal cavities. Spinal visceral nerves innervate the same thoracic and abdominal organs, as well as those in the pelvic floor. Note that neither the vagal nor spinal innervation of thoracic organs (proximal esophagus, heart, lungs, trachea, etc.) is illustrated. Most spinal afferents pass through para (parav‐)‐ and pre (prev‐)‐ vertebral ganglia (inset boxes 1 and 2, respectively; see B for expanded details). Neither DRG nor distribution of afferents between paravertebral ganglia are illustrated (see B). Prevertebral ganglia: CG, celiac ganglion; IMG and SMG, inferior and superior mesenteric ganglia, respectively; and PG, pelvic ganglion. Paravertebral ganglia are not named and are illustrated as a vertical (sympathetic) chain. Abbreviations: GSN, greater splanchnic nerve; HGN, hypogastric nerve; and S, secretory and M, motor neurons (B).
Figure 3. Figure 3. Illustration of different types of pelvic/rectal nerve afferent endings innervating the mouse colorectum. Varicose endings include those defined anatomically as branching (blue, ), complex (red, ), or simple (green, ), and present in different proportions in various layers of the colorectum: longitudinal muscle (LM), circular muscle (CM), submucosa (SM), and mucosa. Not illustrated are intraganglionic varicose endings (IGVEs), which are common in myenteric ganglia (MG) and rectal intraganglionic laminar endings (rIGLEs) in MG and submucosal ganglia (SG). Note the high proportions complex type endings (14% of the total colorectal innervation) at the level of the Crypts of Lieberkhun (CL) and simple type endings in the submucosa (11%) that consist of axon terminals that encircle the base of the Crypts (with few or no varicosities) and innervate into the mucosa. The smooth muscle vasculature is innervated by simple endings (), but not extensively (5% of the total innervation), and varicose endings were rare in longitudinal muscle (1%). Adapted, with permission, from Spencer and colleagues (228).
Figure 4. Figure 4. Viscerosomatic and viscerovisceral convergence of peripheral afferent inputs onto a second‐order spinal dorsal horn neuron. The area of referred sensation for the urinary bladder (blue) and prostate (brown) includes the lower abdomen. As illustrated, afferent input associated with different individual dorsal root ganglion (DRG) somata from skin/subcutaneous tissue (gray), bladder (blue), and prostate (brown) (or other abdominal/pelvic organs) commonly converge onto a single spinal neuron. Visceral afferent input is conveyed to supraspinal sites by two ascending spinal pathways: the spinothalamic tract (STT) in the ventrolateral spinal cord and a dorsal column medial lemniscal (DCML) pathway in the medial spinal cord.
Figure 5. Figure 5. Areas of referred sensation from balloon distension of the ascending, transverse, and descending human colon in healthy, normal subjects (yellow) and subjects with IBS. Note the increase in area of referred sensation associated with IBS.
Figure 6. Figure 6. Examples of sensitization (red) of behavior (A, increased responses to colorectal distension after intracolonic treatment with an inflamogen), afferent fibers (B, awakening of a “silent,” mechanically insensitive colorectal afferent fiber; C, increase in response of a pelvic nerve afferent fiber to circumferential organ stretch), and single cells [D, responses of dorsal root ganglion neurons innervating the urinary bladder to current injection from a control and bladder‐inflamed rat; E, tetrodotoxin‐resistant (TTX‐r) currents recorded from dorsal root ganglion neuron patches from a control and bladder‐inflamed rat].
Figure 7. Figure 7. Responses of mouse afferent endings to mechanical stimulation of the colorectum. Endings were identified by electrical stimulation (e‐stim; leftmost column; red arrow indicates stimulus artifact) and classified based on responses to different mechanical stimuli. All mechanosensitive endings responded to blunt vertical probing (0.4‐1.4 g) of the colorectal mucosal surface or mesenteric attachment (designated “mesenteric” and present only in the lumbar splanchnic innervation of the colorectum; see Fig. 8). Endings designated muscular were also activated by circumferential stretch (0‐170 mN). Mucosal endings were also activated by stroking the mucosal surface (10 mg) and muscular/mucosal endings were also by both stretch and stroking. Endings previously designated as serosal, and activated only by blunt probing, are here designated “probing only” as there is no evidence that pelvic/rectal nerves innervate the serosa (228). MIAs do not respond to any mechanical stimulus. Mucosal endings are rare (1%) and muscular endings uncommon (5%) in the lumbar splanchnic innervation of the colorectum; mesenteric endings that respond to relatively high intensity probing are unique to the lumbar splanchnic innervation of the colorectum (see Fig. 8). See (32,78) for additional details.
Figure 8. Figure 8. Proportions and topographical distribution of mechanosensitive and mechanoinsensitive afferents recorded from the PN and LSN innervations of the mouse colorectum. Both the proportions and distribution of receptive endings significantly differ between the LSN and PN pathways of innervation. Note the broader and more caudal distribution of endings in the PN pathway relative to the clustering of endings along the mesenteric edge of the colon and high proportion of endings on the mesenteric attachment, which respond only to blunt probing, in the LSN pathway. The proportions of afferent classes are derived from greater than 600 PN and 200 LSN afferent endings; the topographical distributions of these endings are illustrated in proportion to the number of endings studied, but not all endings are illustrated to retain clarity. Adapted, with permission, from (78,80,81).
Figure 9. Figure 9. Proportions and topographical distribution of mechanosensitive afferents recorded from the PN and LSN innervations of the mouse urinary bladder. Both the proportions and distribution of receptive endings significantly differ between the LSN and PN pathways of innervation. Note the widespread distribution of endings in the PN pathway relative to the clustering of endings at the base of the bladder in the LSN pathway. Adapted, with permission, from (261).


Figure 1. Clinical and economic burden of abdominal and chest pain. Annual emergency room encounters (top panel) and hospitalizations (bottom panel) were abstracted from the Nationalwide Emergency Room Databank and the Nationwide Inpatient Sample. The results are based on discharge diagnoses codes that included abdominal (blue) or chest (black) pain.


Figure 2. Illustration of visceral afferent innervation. (A) The vagus nerve, with cell bodies in the nodose ganglion and central terminals in the brainstem nucleus tractus solitarii (NTS), innervates organs in the thoracic and abdominal cavities. Spinal visceral nerves innervate the same thoracic and abdominal organs, as well as those in the pelvic floor. Note that neither the vagal nor spinal innervation of thoracic organs (proximal esophagus, heart, lungs, trachea, etc.) is illustrated. Most spinal afferents pass through para (parav‐)‐ and pre (prev‐)‐ vertebral ganglia (inset boxes 1 and 2, respectively; see B for expanded details). Neither DRG nor distribution of afferents between paravertebral ganglia are illustrated (see B). Prevertebral ganglia: CG, celiac ganglion; IMG and SMG, inferior and superior mesenteric ganglia, respectively; and PG, pelvic ganglion. Paravertebral ganglia are not named and are illustrated as a vertical (sympathetic) chain. Abbreviations: GSN, greater splanchnic nerve; HGN, hypogastric nerve; and S, secretory and M, motor neurons (B).


Figure 3. Illustration of different types of pelvic/rectal nerve afferent endings innervating the mouse colorectum. Varicose endings include those defined anatomically as branching (blue, ), complex (red, ), or simple (green, ), and present in different proportions in various layers of the colorectum: longitudinal muscle (LM), circular muscle (CM), submucosa (SM), and mucosa. Not illustrated are intraganglionic varicose endings (IGVEs), which are common in myenteric ganglia (MG) and rectal intraganglionic laminar endings (rIGLEs) in MG and submucosal ganglia (SG). Note the high proportions complex type endings (14% of the total colorectal innervation) at the level of the Crypts of Lieberkhun (CL) and simple type endings in the submucosa (11%) that consist of axon terminals that encircle the base of the Crypts (with few or no varicosities) and innervate into the mucosa. The smooth muscle vasculature is innervated by simple endings (), but not extensively (5% of the total innervation), and varicose endings were rare in longitudinal muscle (1%). Adapted, with permission, from Spencer and colleagues (228).


Figure 4. Viscerosomatic and viscerovisceral convergence of peripheral afferent inputs onto a second‐order spinal dorsal horn neuron. The area of referred sensation for the urinary bladder (blue) and prostate (brown) includes the lower abdomen. As illustrated, afferent input associated with different individual dorsal root ganglion (DRG) somata from skin/subcutaneous tissue (gray), bladder (blue), and prostate (brown) (or other abdominal/pelvic organs) commonly converge onto a single spinal neuron. Visceral afferent input is conveyed to supraspinal sites by two ascending spinal pathways: the spinothalamic tract (STT) in the ventrolateral spinal cord and a dorsal column medial lemniscal (DCML) pathway in the medial spinal cord.


Figure 5. Areas of referred sensation from balloon distension of the ascending, transverse, and descending human colon in healthy, normal subjects (yellow) and subjects with IBS. Note the increase in area of referred sensation associated with IBS.


Figure 6. Examples of sensitization (red) of behavior (A, increased responses to colorectal distension after intracolonic treatment with an inflamogen), afferent fibers (B, awakening of a “silent,” mechanically insensitive colorectal afferent fiber; C, increase in response of a pelvic nerve afferent fiber to circumferential organ stretch), and single cells [D, responses of dorsal root ganglion neurons innervating the urinary bladder to current injection from a control and bladder‐inflamed rat; E, tetrodotoxin‐resistant (TTX‐r) currents recorded from dorsal root ganglion neuron patches from a control and bladder‐inflamed rat].


Figure 7. Responses of mouse afferent endings to mechanical stimulation of the colorectum. Endings were identified by electrical stimulation (e‐stim; leftmost column; red arrow indicates stimulus artifact) and classified based on responses to different mechanical stimuli. All mechanosensitive endings responded to blunt vertical probing (0.4‐1.4 g) of the colorectal mucosal surface or mesenteric attachment (designated “mesenteric” and present only in the lumbar splanchnic innervation of the colorectum; see Fig. 8). Endings designated muscular were also activated by circumferential stretch (0‐170 mN). Mucosal endings were also activated by stroking the mucosal surface (10 mg) and muscular/mucosal endings were also by both stretch and stroking. Endings previously designated as serosal, and activated only by blunt probing, are here designated “probing only” as there is no evidence that pelvic/rectal nerves innervate the serosa (228). MIAs do not respond to any mechanical stimulus. Mucosal endings are rare (1%) and muscular endings uncommon (5%) in the lumbar splanchnic innervation of the colorectum; mesenteric endings that respond to relatively high intensity probing are unique to the lumbar splanchnic innervation of the colorectum (see Fig. 8). See (32,78) for additional details.


Figure 8. Proportions and topographical distribution of mechanosensitive and mechanoinsensitive afferents recorded from the PN and LSN innervations of the mouse colorectum. Both the proportions and distribution of receptive endings significantly differ between the LSN and PN pathways of innervation. Note the broader and more caudal distribution of endings in the PN pathway relative to the clustering of endings along the mesenteric edge of the colon and high proportion of endings on the mesenteric attachment, which respond only to blunt probing, in the LSN pathway. The proportions of afferent classes are derived from greater than 600 PN and 200 LSN afferent endings; the topographical distributions of these endings are illustrated in proportion to the number of endings studied, but not all endings are illustrated to retain clarity. Adapted, with permission, from (78,80,81).


Figure 9. Proportions and topographical distribution of mechanosensitive afferents recorded from the PN and LSN innervations of the mouse urinary bladder. Both the proportions and distribution of receptive endings significantly differ between the LSN and PN pathways of innervation. Note the widespread distribution of endings in the PN pathway relative to the clustering of endings at the base of the bladder in the LSN pathway. Adapted, with permission, from (261).
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G. F. Gebhart, Klaus Bielefeldt. Physiology of Visceral Pain. Compr Physiol 2016, 6: 1609-1633. doi: 10.1002/cphy.c150049