7

Visceral Pain Mechanisms

G. F. Gebhart, Department of Pharmacology, College of Medicine, The University of Iowa, Iowa City, Iowa 52242

That visceral pain differs significantly from other types of pains has been appreciated by clinicians for centuries. As recently as the turn of this century, however, investigators were in disagreement about the source(s) of visceral pain. Lennander (24) and MacKenzie (28) maintained that pain was not derived directly from a viscus (see discussion in ref. (25)), whereas others provided evidence for what they called ``true visceral pain'' or ``splanchnic pain'' ((43); discussion in ref. (25)). The issue is no longer contentious, but its consideration emphasizes several points important to our current understanding of visceral pain. First, pain per se does not arise from all viscera (e.g., liver parenchyma), but pain associated with such viscera does arise when the capsule containing that viscus distends or becomes inflamed. Second, tissue injury (or threat of such injury) may not be required or necessary for production of visceral pain, as it is for pain from cutaneous structures (see refs. (6) and (37) for discussion). Thus, unlike cutaneous pain, the adequate stimuli for production of visceral sensation, including pain, are not yet fully appreciated.

CHARACTERISTICS OF VISCERAL PAIN

A number of characteristics of visceral pain are widely appreciated (Table 1). These characteristics have been reviewed previously (6,37) and only a few additional comments will be made here. Localization of the source of visceral pain is understood to be confounded by its referred nature. It should also be appreciated that in addition to referral to cutaneous structures, multiple viscera often converge onto the same spinal cord neurons. Thus, patterns of referred sensation from the gallbladder, esophagus, and heart or from the urinary bladder and colon overlap considerably, creating obvious problems with respect to differential diagnoses. That a cutaneous hyperalgesia is often associated with visceral pain is also not fully appreciated. More than 100 years ago, Sturge (45) noted that attacks of angina are associated with a persistent cutaneous tenderness that remains after the attack (discussed in ref. (25)). MacKenzie (28) and Head (19) both described hyperalgesia of the skin on the head and neck associated with toothache and diseases of the ear, tongue, and nose, and neither investigator apparently considered that somatic or visceral sources produced different forms of hyperalgesia. More recently, Hardy et al. (17) documented the development of cutaneous hyperalgesia after both deep somatic noxious stimulation (6% saline injected into one side of an intraspinous ligament, which produced an ``intense aching pain'') ( Figure 1 ) and visceral stimulation (subphrenic irritation with bubbles of CO), which differed in no significant way from hyperalgesia secondary to an experimental skin injury. These investigators commented that, as regards the properties of cutaneous hyperalgesia, ``it makes little difference whether the source be from the skin, from deep somatic structures or from a viscus'' (17). These and other similar observations have considerable importance with respect to understanding central mechanisms of altered sensations that arise from deep structures (see below). In passing, it is interesting to note that Lewis (25) and Hardy et al. (17) differed in their interpretation of the mechanisms that lead to the development of hyperalgesia (secondary hyperalgesia), which seem clear today to be central in origin, not peripheral.

Chapter 7 Table 1: Characteristics of visceral pain
 
Referral/transferral to cutaneous structures
Diffuse and difficult to localize
Enhanced autonomic and/or motor reflexes
Cutaneous and deep tissue hyperalgesia
 

ADEQUATE VISCERAL STIMULI

Although the adequate stimuli for visceral pain are not fully understood, a variety of natural stimuli are clearly associated with pain from the viscera (Table 2). Experimentally, mechanical stimuli such as traction of the mesentery, stretch of serosal tissues, compression of organs, and particularly distention of hollow organs produce pain in humans and nonhuman animals.

Chapter 7 Table 2: Naturally occurring visceral stimuli
 
Hollow organ distention
Ischemia
Inflammation
Muscle spasm
Traction
Because many hollow organs are easily accessible and distention reproduces a natural stimulus that produces pain in humans, there is a rich clinical literature of studies investigating sensation arising from the gastrointestinal tract. For example, Payne and Poulton (40) distended their own esophagi, describing pain as ``continuous and burning'' at lesser volumes/pressures and ``gripping'' at the greatest volumes/pressures tested. Their pain was referred from the area of the suprasternal notch to the xiphoid process and sometimes to the costal angle, with radiation to the angle of the left scapula. Painful distentions also produced alterations in the pattern of breathing, and these investigators also experienced cutaneous hyperesthesia in the skin over the sternum. In an examination of the sensibility of the sigmoid colon and rectum, Goligher and Hughes (14) found that the sensation of pain was related to the pressure within the distending balloon rather than the volume of the balloon. They also made a distinction in their studies between colonic sensation and rectal sensation, suggesting that the former was pain carried by afferents in the sympathetic nerves and that the latter was fullness carried by afferents in the pelvic nerve.

The first investigators to employ controlled, constant pressure stimuli in studies of sensation from the gut were apparently Lipkin and Sleisinger (26). Using balloons to distend the esophagus, ileum, or colon, they documented that the latency from the onset of the stimulus to patient reports of pain was directly related to the intensity of the distending stimulus. At lesser distending pressures, they found that the stimulus was not reported by subjects as painful for up to 1 min after the onset of distention and was preceded by the sensation of pressure over large abdominal or thoracic areas. They determined in their studies that the minimal intraluminal pressures to produce painful sensations from the esophagus, ileum, and colon were 39 to 47, 44 to 59, and 40 to 50 mm Hg, respectively. A more complete description of such studies is available elsewhere (37). With respect to distention of hollow organs, Lewis (25) commented earlier that distention of the gut was most painful when long, continuous segments of the gut were simultaneously distended. Even greater pressures within smaller segments of the gut were not as efficacious in producing painful sensations. Thus, spatial summation is clearly an important contributor to visceral pain mechanisms.

Inflammation or ischemia of a viscus generally leads to altered sensations from the viscus, including pain. The example of Wolf's patient Tom is instructive (49). When Tom's stomach mucosa was ``normal,'' neither pinching a fold of mucosa with a forceps nor electrical stimulation of the mucosa, applied at an intensity sufficient to cause ``intense pain in the tongue,'' was painful. However, after the mucosa was rendered ``red, boggy and edematous'' by application of powdered mustard after removal of the mucus, intense pain occurred with application of these same stimuli to the now inflamed tissue. This should not be surprising and is in some ways analogous to the hyperalgesia associated with inflammation of cutaneous structures.

Interruption of the blood supply to most deep structures, including the viscera, also frequently leads to pain (e.g., myocardial ischemia). Experimentally, occlusion of the blood supply to the colon increases significantly the rates of spontaneous and contraction-related discharges of afferent fibers from the colon (18). Other investigators have examined the effects of ischemia/anoxia on abdominal afferents (gallbladder, pancreas, mesentery, and liver [27]) and cardiac afferents (2,4). In general, although ischemia/anoxia may reproduce a stimulus that arises naturally, occlusion of blood supply to an organ is not a stimulus generally well suited to stimulus-response experimental investigation; ischemia/anoxia is, however, a useful ``conditioning'' stimulus. Like ischemia/anoxia, inflammation also reproduces a visceral stimulus that arises naturally but is similarly associated with changes in experimental parameters only after a relatively long latency. Thus, although ischemia and inflammation are important clinically, they are better suited experimentally to condition organs and thus responses to stimuli delivered to them (e.g., mechanical distentions).

VISCERAL AFFERENTS

The anatomical organization and central termination of afferent fibers that convey information from the viscera to the central nervous system are well understood, even though their adequate stimuli are not. Visceral afferents ``run'' with sympathetic and parasympathetic efferent nerves. It has long been considered that only so-called sympathetic afferents (i.e., visceral afferent fibers running with sympathetic nerves), with cell bodies in dorsal root ganglia, convey nociceptive information from viscera to the central nervous system. This notion is incorrect, and it is clear, for example, that urinary bladder and colonic afferents in the parasympathetic pelvic nerve transmit nociceptive information (21,35), and it is also likely that some afferents from thoracic and upper abdominal organs contained in the vagus nerve also subserve a nociceptive function. Thus, the viscera, in general, receive a dual innervation with afferents reaching the spinal cord (cell bodies in dorsal root ganglia) or brain stem (cell bodies in nodose ganglion) via sympathetic and parasympathetic nerves.

Visceral afferents terminate in the spinal dorsal horn in superficial laminae (I and IIouter ) and the neck of the dorsal horn in lamina V; visceral afferent fibers also terminate in the area around the central canal (often called lamina X). It is interesting to note that, whereas somatic afferents terminate throughout the spinal dorsal horn (i.e., laminae I-VI), cutaneous nociceptors terminate in the spinal dorsal horn in a pattern similar to visceral afferents: superficial dorsal horn and neck of the dorsal horn.

The functional classification of visceral afferents has been an issue of some disagreement. Some visceral afferents (e.g., biliary system, colon, ureter) have high mechanical thresholds for activation, respond only to apparently noxious intensities of stimulation, and encode the intensity of stimulation in this noxious range (5,18) (see Figure 2 ); these afferents are analogous to those from skin classed as nociceptors and thus appear to subserve a similar nociceptive function from the viscera. A greater proportion of visceral afferents, however, have thresholds for activation in the physiological range and encode the intensity of stimulation throughout the non-noxious and noxious ranges of stimulation (1,21). Some of these afferents also respond to several modalities of stimulation (e.g., mechanical, chemical) (22) and thus may be similar to polymodal afferents from cutaneous structures, although these visceral afferents also respond to presumably non-noxious intensities of stimulation. Several factors likely contribute to our present inability to classify visceral afferents (as cutaneous afferents have been categorized; see ref. 48). First, the issue of the adequate stimulus contributes to the problem; moreover, such stimuli are certainly different for different organs (e.g., mechanical distention of the colon versus ischemia of the myocardia vs inflammation of the urinary bladder). Second, most studies have been done using only a limited array of test stimuli because, experimentally, it is not generally an easy matter to apply a wide range of different stimuli to often difficult-to-access viscera. Although clinical evidence suggests that pain arising from one viscus is similar, if not identical, to pain arising from other viscera in terms of intensity and quality, this does not address the issues above, but simply emphasizes that our interpretation of the sensation is consistent.

Another point to be emphasized is that the number of visceral afferents, relative to the number of afferents from cutaneous structures, is very small. The number of visceral afferents has been variously estimated to be between 2% and 10% of all afferents to the spinal cord (depending on the spinal level of input) (7,12,21). This low number is significantly out of proportion to the relative number of spinal dorsal horn neurons that respond to visceral stimulation in those same spinal segments, estimated to be 50% to 75% (10). This discrepancy is apparently explained by the significantly greater rostrocaudal spread of visceral afferent terminals in the spinal cord than the rostrocaudal spread of the more numerous cutaneous afferent terminals (46).

Further, in studies in which visceral afferents have been found by electrical stimulation, a surprising proportion have been found to not be responsive to the stimuli tested (typically mechanical). Afferents from the joint first found in this manner have been dubbed ``sleeping'' or ``silent'' afferents, awakening only after experimental inflammation of the joint (44). Similarly, irritation/inflammation of the urinary bladder has been shown to lead to increased responses to mechanical stimulation of unmyelinated pelvic nerve afferents that previously gave only weak or no responses to the same mechanical stimuli before inflammation of the bladder (16). It is now apparent that there exists a new and large group of nociceptors from somatic and visceral structures that play an important role in nociception after tissue is inflamed or injured. Accordingly, irritation/inflammation has been employed experimentally in a variety of studies to ``condition'' responses to visceral stimuli. For example, responses of spinal dorsal horn neurons to distention of the urinary bladder or noxious colorectal distention are greater after irritation of these organs with 25% turpentine (30,37). Importantly, behavioral responses of rats also are significantly influenced by prior conditioning of the colon with turpentine. For example, colorectal distention at intensities of 30 mm Hg or less produce no change in rats' behavior in a passive avoidance paradigm (i.e., these intensities are not noxious), but 30 mm Hg colorectal distention does lead to acquisition of the avoidance behavior after conditioning of the colon with turpentine (39).

As a result of increased interest and investigation into mechanisms of visceral pain, including the discovery of silent afferents and the use of conditioning stimuli that more closely approximate clinical situations, our thinking about visceral pain is undergoing rapid change. Whether there exist specific visceral nociceptors is no longer at issue, because some afferents from visceral (as well as somatic) structures have been shown to acquire new response properties, including responses to noxious stimuli, when tissue is injured or inflamed. Thus, some visceral afferents may function in all conditions to convey nociceptive information (e.g., from gallbladder or ureter), whereas afferents from other viscera undergo a change in their sensitivity to applied stimuli after irritation/inflammation of a viscus (i.e., previously silent afferents become active/responsive). In the clinical circumstance, in which irritating and/or inflammatory conditions are common, visceral nociceptors are likely active.

It should be emphasized, however, that whereas many afferents from a viscus may become active during an experimentally induced inflammation and presumably in disease (e.g., pancreatitis, malignancies), investigators are not at present able to account for the function(s) of a significant number of afferents that cannot be activated by any stimuli tested, even after irritation/inflammation of the organ. This is a recently appreciated situation, best exemplified by the work of J;auanig and colleagues (15,16). They studied unmyelinated afferent fibers innervating the pelvic viscera in cats and found that less than 10% of the afferents in the pelvic nerve could be activated by noxious mechanical distention of the urinary bladder. They also described a small number of unmyelinated afferents that were chemosensitive (mustard oil or turpentine), some of which acquired mechanosensitivity after inflammation of the bladder by these irritants. Thus, there remain a very large number of unmyelinated afferents in the pelvic nerve (perhaps as much as 90% of the total) for which no function is apparent. Extrapolating from these investigations, for which adequate stimuli were identified for a small number of afferent fibers, an obvious conclusion is that adequate stimuli have not been identified for the majority of visceral afferents in the body. Clearly, not all visceral afferents need play a role in sensation, and perhaps some of these ``unresponsive'' visceral afferents are important to other functions (e.g., monitoring gut or bladder content by sensitivity to pH, nutrients, gases, and various ions). Further, it is not to be expected that the relatively acute irritation/inflammation produced experimentally reproduces the clinical circumstance in which such insults are generally slower in onset and longer in duration. That is, it may be that more afferents are ``recruited'' into function over time as the severity of the insult progressively worsens.

VISCERAL HYPERALGESIA

Finally, there is considerable evidence now accumulated that indicates that altered central mechanisms play an important role in visceral sensations. It has been well established in peripheral, cutaneous models of tissue injury or inflammation that secondary hyperalgesia and central sensitization contribute to the altered sensations arising from the area of the insult. Two alterations are prominent: previously non-noxious stimuli (e.g., brushing of the skin) applied to the area now produce pain (i.e., the phenomenon of allodynia) and responses to threshold intensities of noxious stimuli are greatly enhanced (i.e., the phenomenon of hyperalgesia). There is no reason to expect that similar mechanisms of hyperalgesia and central sensitization do not also obtain from visceral organs and may be important to a variety of clinical problems of altered sensations from the viscera.

Experimentally, evidence for one or more altered central mechanisms is provided by changes in the size of receptive fields of spinal dorsal horn neurons after some conditioning stimulus. Hylden et al. (20) documented that inflammation of a hindpaw of the rat led to a significant increase in the size of convergent, cutaneous receptive fields of spinal neurons studied in dorsal horn lamina I. Also in the rat, the cutaneous receptive fields of spinal dorsal horn neurons have been shown to increase in size after repetitive esophageal distention (Figure 3), repetitive gallbladder distention (8), and repetitive colorectal distention (figure 4). That these convergent, cutaneous receptive fields expand in size after repetitive distention of a viscus unquestionably implicates one or more central mechanisms, because there is no convincing evidence for the existence of a large number of bifurcating or dichotomizing neurons that simultaneously innervate a cutaneous structure and a viscus. Thus, the repetitive visceral input to the dorsal horn must alter the excitability of central neurons, leading to several changes, including a significant increase in the size of the receptive field from the convergent cutaneous input. Repetitive colonic distention in humans similarly leads to an increase in the area of referred sensation and also to a change (increase) in the reported qualities of the stimulus (38). In these experiments, 10 consecutive distentions (60 mm Hg given 4 min apart) lead to an obvious and significant increase in the areas of referred sensation (Figure 5A). Comparing visual analog scale ratings during the first and last of the 60 mm Hg distentions also reveals that the stimulus was considered painful at the end of the series of distentions, whereas it was not uniformly considered to be painful during the first distention (Figure 5B). Analysis of verbal descriptors of the quality of the sensation produced by sigmoid colon distention also revealed that subjects reported a significant increase in the magnitude of the descriptors selected for the sensations produced (38).

In continuing electrophysiological investigations in the rat, the convergent, cutaneous receptive fields that increased in size after repetitive colonic distention were found to further increase in size after conditioning of the colon with 25% turpentine. It is interesting to note in figure 4 that the convergent, cutaneous fields, after instillation of turpentine into the colon, grew to include the contralateral side of the rats' dorsal body; converging, cutaneous receptive fields in untreated rats never included an area on the contralateral body surface (36). These results suggest that two different mechanisms may be operative, because there appear to be two stages to the increase in size of convergent, cutaneous receptive fields. It is possible that the receptive field would continue to grow with repeated colorectal distention to the size finally determined after treatment with turpentine. Results to date, however, suggest that receptive fields increase in size during repetitive colorectal distention over the course of 1 to 2 hr and do not increase further. Therefore, it seems likely that an additional mechanism is engaged by the chemical insult (e.g., recruitment of previously silent afferents from the colon and enhanced excitability of a greater number of dorsal horn neurons than affected by repetitive colorectal distention alone). It is understandable, on the basis of such results, why patients' complaints of pain increase over time.

In a recent review (29), it was suggested that a number of visceral disorders (e.g., noncardiac chest pain, nonulcer dyspepsia, irritable bowel syndrome) may be reflections of a form of visceral hyperalgesia and/or may involve mechanisms analogous to neuropathic conditions. In support, there are a number of clinical observations of lowered pain thresholds in response to distention of hollow organs (esophagus, stomach, and colon) in some of these patients (23,41,42). In general, these studies find that normal visceral sensations are experienced in these patients at reduced distending pressures. It has been known for some time, for example, that individuals with irritable bowel syndrome have reduced thresholds to colonic distention and report a greater incidence of pain associated with distention than do normals (42) (Figure 6). Further, the area of referred sensation in normals and patients with irritable bowel syndrome clearly differ (47) (Figure 7). These clinical observations complement the experimental results briefly described above, suggesting that central mechanisms best understood in cutaneous models of hyperalgesia and central sensitization likely also explain altered sensations from the viscera.

Central sensitization refers to alterations in the excitability of spinal cord neurons to a variety of normal inputs following peripheral tissue damage or irritation (50). Central sensitization is manifest as a prolonged facilitation of reflexes and an increase in receptive field size of dorsal horn neurons (e.g., see Figs. 3 and 4 and ref. 50). The central mediators involved in the development of central sensitization are incompletely understood at present. The release of neuropeptides (e.g., substance P, calcitonin gene-related peptide) from the central terminals of primary afferent fibers appears to play an important role, as does activation of the N -methyl-d-aspartate (NMDA) receptor (11,51). Most recently, a role for nitric oxide (NO) in NMDA-receptor-mediated facilitation of a nociceptive reflex (33) and in the thermal hyperalgesia produced in experimental models of hind limb inflammation and neuropathic pain in the rat has been suggested (34; Meller, Cummings, Traub, and Gebhart, unpublished ). NMDA receptor activation results in an influx intracellularly of calcium that, acting at a calmodulin site on NO synthase, leads to the production of NO (or an NO-containing moiety) (13). NO is a small, rapidly diffusible molecule that is believed to escape from its site of synthesis and act as a ``retrograde'' messenger in the presynaptic terminal or to influence activities in adjacent neurons and/or glia (see ref. 32 for a recent review relative to NO and nociception). NO ultimately leads to the production of cGMP, which has well-documented second messenger functions.

The theme of visceral hyperalgesia and its ability to explain many of the clinical features of noncardiac chest pain, nonulcer dyspepsia, and irritable bowel syndrome patients is discussed in detail elsewhere (29). A further analogy considered in greater detail elsewhere (29) is that between neuropathic or sympathetically maintained pains and unknown insult to a ``visceral'' nerve. It is possible that an initiating insult, which would likely be minor and may even be missed, could produce persistent, altered sensations arising from a viscus, including pain. Campbell and colleagues have offered a unifying hypothesis to explain sympathetically maintained pain (3). They suggest that sympathetically maintained pain is a receptor disorder and that activity in cutaneous nociceptors leads to an up-regulation of adrenoceptors on the terminals of the nociceptors. If this is the case, the phentolamine test advocated by Campbell and colleagues could be useful in determination of whether a circumstance analogous to sympathetically maintained pain is associated with viscera.

SUMMARY

Our understanding of visceral pain mechanisms has advanced appreciably over the past several years. The cutaneous hyperalgesia associated with visceral pain and the central mechanisms likely associated with expansion of receptive fields/areas of referral appear to be analogous to those better studied from cutaneous structures. That repeated visceral stimulation or irritation/inflammation of a viscus may awaken silent nociceptors has helped understand how pain sensation likely increases as disease processes progress. Thus, we may now consider visceral hyperalgesia as a common factor among a number of visceral disorders, many previously poorly classified as motility disorders (29). This hypothesis requires testing, but appears to be reasonable in light of experimental evidence obtained from nonhuman animals.

There remain, however, some unresolved issues. Foremost among them is the function of what is apparently the majority of visceral afferent fibers. It may be that all afferents from some organs have an identified function, but it appears that afferents from much of the viscera have no function yet associated with them. It seems unlikely that all visceral afferents are associated with sensation, and many may be associated with other aspects of visceral function, including reflex functions and monitoring visceral content. Often not considered are possible functions of visceral afferents associated with local, trophic modulation of a viscus (31). As investigators identify adequate stimuli for visceral afferents, appreciating that it is likely that these adequate stimuli are different for different viscera, our understanding of visceral sensation, and particularly visceral pain, will improve and perhaps suggest improved treatment for pain control.
 

ACKNOWLEDGMENTS

The excellent secretarial assistance of Marilynn Kirkpatrick is gratefully acknowledged. The author has been supported by NIH awards NS 19912, DA 02897 and HL 32295 and by a Pain Research Award from Bristol-Myers Squibb Company.

REFERENCES

  1. Blumberg B, Haupt P, J;auanig W, K;auohler W. Encoding of visceral noxious stimuli in the discharge patterns of visceral afferent fibers from the colon. Pflugers Arch 1983;398:33-40.
  2. Brown AM. Excitation of afferent cardiac sympathetic nerve fibers during myocardial ischemia. J Physiol (Lond) 1967;190:35-53.
  3. Campbell JN, Meyer RA, Davis KA, Raga SN. Sympathetically maintained pain: a unifying hypothesis. In: Willis WD, ed. Hyperalgesia and allodynia. New York: Raven Press, 1992:141-150.
  4. Casati R, Lombardi F, Malliani A. Afferent sympathetic unmyelinated fibers with left ventricular endings in cats. J Physiol (Lond) 1979;292:135-148.
  5. Cervero F. Afferent activity evoked by natural stimulation of the biliary system in the ferret. Pain 1982;13:137-151.
  6. Cervero F. Visceral pain. In: Dubner F, Gebhart GF, Bond MR, eds. Vth World Congress on Pain. Amsterdam: Elsevier, 1988:216-226.
  7. Cervero F, Connel LA, Lawson SN. Somatic and visceral primary afferents in the lower thoracic dorsal root ganglia of the cat. J Comp Neurol 1984;228:422-431.
  8. Cervero F, Laird JMA, Pozo MA. Selective changes of receptive field properties of spinal nociceptive neurons induced by noxious visceral stimulation in the cat. Pain 1992;51:335-342.
  9. Cervero F, Sann H. Mechanically evoked responses of afferent fibers innervating the guinea-pig's ureter: An in vitro study. J Physiol (Lond) 1989;412:245-266.
  10. Cervero F, Tattersall JEH. Cutaneous receptive fields of somatic and viscerosomatic neurons in the thoracic spinal cord of the cat. J Comp Neurol 1985;237:325-332.
  11. Dubner R, Ruda MA. Activity-dependent neuronal plasticity following tissue injury and inflammation. Trends Neurosci 1992;15:96-103.
  12. Foreman RD, Weber RN. Responses from neurons of the primate spinothalamic tract to electrical stimulation of afferents from the cardiopulmonary region and somatic structures. Brain Res 1980;186:464-468.
  13. Garthwaite J. Glutamate, nitric oxide and cell-cell signaling in the nervous system. Trends Neurosci 1991;14:60-67.
  14. Goligher JC, Hughes ESR. Sensibility of the rectum and colon: its role in the mechanism of anal continence. Lancet 1951;1-2:543-548.
  15. H;auabler H-J, J;auanig W, Koltzenberg M. A novel type of unmyelinated chemosensitive nociceptor in the acutely inflamed urinary bladder. Agents Actions 1988;25:219-221.
  16. H;auabler H-J, J;auanig W, Koltzenberg M. Activation of unmyelinated afferent fibers by mechanical stimuli and inflammation of the urinary bladder in the cat. J Physiol (Lond) 1990;425:545-562.
  17. Hardy JD, Wolff HG, Goodell H. Experimental evidence on the nature of cutaneous hyperalgesia. J Clin Invest 1950;29:115-140.
  18. Haupt P, J;auanig W, K;auohler W. Response pattern of visceral afferent fibers, supplying the colon, upon chemical and mechanical stimuli. Pflugers Arch 1983;398:41-47.
  19. Head H. On disturbances of sensation, with special reference to the pain of visceral diseases. Brain 1893;16:1-133.
  20. Hylden JLK, Nahin RL, Traub RJ, Dubner R. Expansion of receptive fields of spinal lamina I projection neurons in rats with unilateral adjuvant-induced inflammation: the contribution of dorsal horn mechanisms. Pain 1989;37:229-243.
  21. J;auanig W, Morrison JFB. Functional properties of spinal visceral afferents supplying abdominal and pelvic organs, with special emphasis on visceral nociception. In: Cervero F, Morrison JFB, eds. Progress in brain research, vol 67. Amsterdam: Elsevier, 1986:87-114.
  22. Kumazawa T. Sensory innervation of reproductive organs. In: Cervero F, Morrison JFB, eds. Progress in brain research, vol 67. Amsterdam: Elsevier, 1986:115-132.
  23. Lemann M, Dederding JP, Flourie B, Franchisseur C, Rambaud JC, Jian R. Abnormal perception of visceral pain in response to gastric distension in chronic idiopathic dyspepsia. The irritable stomach syndrome. Dig Dis Sci 1991;36:1249-1254.
  24. Lennander KB. Ueber die Sensibilit;auat Bauchhohle und ;auuber lokale und allgemeine An;auasthesie bei Bruch und Bauchoperationen. Zentralbl Chir 1901;28:200-223.
  25. Lewis T. Pain. London: MacMillan, 1942.
  26. Lipkin M, Sleisinger MH. Studies of visceral pain: measurements of stimulus intensity and duration associated with the onset of pain in esophagus, ileum and colon. J Clin Invest 1957;37:28-34.
  27. Longhurst JC, Dittman LE. Hypoxia, bradykinin and prostaglandins stimulate ischemically sensitive visceral afferents. Am J Physiol 1987;253:H556-H567.
  28. MacKenzie J. Symptoms and their interpretation. London: Shaw, 1909.
  29. Mayer EM, Gebhart GF. Functional bowel disorders and visceral hyperalgesia. N Engl J Med (in press).
  30. McMahon SB. Neuronal and behavioral consequences of chemical inflammation of rat urinary bladder. Agents Actions 1988;25:231-233.
  31. McMahon SB, Koltzenburg M. The changing role of primary afferent neurons in pain. Pain 1990;43:269-272.
  32. Meller ST, Gebhart GF. Nitric oxide (NO) and nociceptive processing in the spinal cord. Pain 1993;52:127-136.
  33. Meller ST, Dykstra C, Gebhart GF. Production of endogenous nitric oxide and activation of soluble guanylate cyclase are required for N-methyl-D-aspartate-produced facilitation of the nociceptive tail-flick reflex. Eur J Pharmacol 1992;214:93-96.
  34. Meller ST, Pechman PS, Gebhart GF, Maves TJ. Nitric oxide mediates the thermal hyperalgesia produced in a model of neuropathic pain in the rat. Neuroscience 1992;50:7-10.
  35. Ness TJ, Gebhart GF. Colorectal distension as a noxious visceral stimulus: physiologic and pharmacologic characterization of pseudoaffective reflexes in the rat. Brain Res 1988;450:153-169.
  36. Ness TJ, Gebhart GF. Characterization of neurons responsive to noxious colorectal distension in the T13-L2 spinal cord of the rat. J Neurophysiol 1988;60:1419-1438.
  37. Ness TJ, Gebhart GF. Visceral pain: a review of experimental studies. Pain 1990;41:167-234.
  38. Ness TJ, Metcalf AM, Gebhart GF. A psychophysiological study in humans using phasic colonic distension as a noxious visceral stimulus. Pain 1990;43:377-386.
  39. Ness TJ, Randich A, Gebhart GF. Further behavioral evidence that colorectal distension is a noxious visceral stimulus in rats. Neurosci Lett 1991;131:113-116.
  40. Payne WW, Poulton EP. Visceral pain in the upper alimentary tract. Q J Med 1923;17:53-80.
  41. Richter JE, Barish CF, Castell DO. Abnormal sensory perception in patients with esophageal chest pain. Gastroenterology 1986;91:845-852.
  42. Ritchie J. Pain from distension of the pelvic colon by inflating a balloon in the irritable colon syndrome. Gut 1973;14:125-132.
  43. Ross J. On the segmental distribution of sensory disorders. Brain 1888;10:333-361.
  44. Schaible H-G, Schmidt RF. Time course of mechanosensitivity changes in articular afferents during a developing experimental arthritis. J Neurophysiol 1988;60:2180-2195.
  45. Sturge WA. The phenomena of angina pectoris and their bearing upon the theory of counter-irritation. Brain 1883;5:492-510.
  46. Sugiyura Y, Terui N, Hosoya Y. Differences in distribution of central terminals between visceral and somatic unmyelinated (C) primary afferent fibers. J Neurophysiol 1989;62:834-840.
  47. Swarbrick ET, Bat L, Heggarty JE, Williams CB, Dawson AM. Site of pain from the irritable bowel. Lancet 1980;2:443-446.
  48. Willis WD, Coggeshall RE. Sensory mechanisms of the spinal cord. New York: Plenum Press, 1991.
  49. Wolf S. The stomach. New York: Oxford, 1965.
  50. Woolf CJ. Excitability changes in central neurons following peripheral damage: role of central sensitization in the pathogenesis of pain. In: Willis WD, ed. Hyperalgesia and allodynia. New York: Raven Press, 1992:221-244.
  51. Woolf CJ, Thompson SW. The induction and maintenance of central sensitization is dependent on N-methyl-D-aspartic acid receptor activation: implications for the treatment of post-injury pain hypersensitivity states. Pain 1991;44:293-299.