Peripheral Sensitization And Visceral Pain Syndromes

The current understanding of mechanisms of peripheral sensitization is largely derived from studies examining the effects of injury or inflammation on visceral afferents. Most patients with chronic visceral pain, such as irritable bowel syndrome, nonulcer dyspepsia or interstitial cystitis, do not have signs of inflammation, raising questions about the relevance of these findings. While the definition of such functional diseases excludes active inflammation, up to one-third of patients with...

Abdominal Pain for Life

RAP is regarded by pediatricians to be a short-term phenomenon with no long-standing clinical consequences. However, there is comparatively little literature on the long-term outcome in children with RAP. Studies from clinical samples suggest that between 25 and 50 continue to experience symptoms into adulthood and have higher rates of psychiatric disorders (40). Conversely, medically unexplained symptoms in adult life, including unexplained hospitalizations, are associated with experiencing...

Hydroxytryptamine Receptors

Many efforts to develop drugs for FBDs have been directed at 5-hydroxytryptamine (5-HT) receptors as is discussed in Chapter III 18. Most of the 5-HT present in the body is formed in the GI enterochromaffin cells, wherefrom it is released by a variety of luminal stimuli. Being a paracrine messenger, this indoleamine can activate intrinsic and extrinsic sensory nerve fibers as well as other enteric neurons through activation of multiple 5-HT receptors (1012). There is emerging evidence that the...

Diagnostic and Statistical Manual of Mental DisordersIV

An improved understanding of definitions of addiction, physical dependence, and tolerance would also allow clinicians to more effectively interpret the terminology of the Diagnostic and Statistical Manual of Mental Disorders-IV (21). If one understands the correct definition of physical dependence, it is clear that the DSM-IV misuses the term dependence. By doing so, this has the effect of confusing a pain patient with one with the disease of addiction. Under the section Criteria for Substance...

Clinical Presentation Based On Severity Of Pain And Implications For Treatment

Patients with chronic abdominal and visceral pain can fall under a variety of diagnostic syndromes and categories. This may include longstanding structural diagnoses such as chronic pancreatitis, a variety of functional GI diagnoses (e.g., IBS, functional chest pain or dyspepsia, functional biliary pain, levator syndrome, etc.), or combinations (e.g., inflammatory bowel disease (IBD) with IBS). In this chapter, the proposition is that, independent of diagnosis, the nature and severity of the...

Topography of the Sensory Dysfunction

Several lines of evidence indicate that altered sensitivity in patients with functional gut syndromes affects exclusively the visceral territory. Somatic sensitivity, both to the cold pressure test and to transcutaneous electrical nerve stimulation, is normal or even reduced both in dyspeptic and IBS patients (6,40,47,48). This increased tolerance of somatic pain has been related to the pain reporting behavior characteristic of painful conditions. In contrast to these data showing a selective...

Dyspepsia

Dyspepsia is not a condition, but rather a set of symptoms of which upper abdominal pain or discomfort is the predominant complaint. In cross-sectional surveys, the prevalence of dyspepsia (3,14,23-26) has ranged from 3 to 44 . Why this large variation The first consideration is whether the study included the symptom of heartburn in the definition of dyspepsia. Heartburn is experienced by 20 of the population weekly and 40 annually (27). There is significant overlap between upper abdominal...

Evidence for Genotypic Influences

Anecdotally, FGD appear to cluster in families, and recent research has confirmed these impressions. A large questionnaire-based same-sex twin pair study in Australia suggested a substantial proportion of the liability for FGD was under genetic control with a calculated heritability of 57 , and the remaining 43 being attributed to the individual's unique environment (133). A much larger questionnaire-based study by Levy et al. found a greater concordance for IBS in monozygotic versus dizygotic...

Stressinduced Visceral Hyperalgesia

The body could be subjected to a variety of stressors that have been commonly subdivided into two categories exteroceptive (psychological or neurogenic) and interoceptive (physical or systemic). Exteroceptive stressors become stressful only after being processed in the context of previous experiences and are, therefore, limbic sensitive. Brain circuits mediating the endocrine and autonomic response to exteroceptive stressors encompass the limbic-sensitive neural network, namely, the cortex...

Effects Of Stress On Visceral Pain

When nervous, one feels butterflies or a pit'' in the stomach. Gut wrenching'' emotions can also evoke profound changes in heart rate, breathing, and all other visceral functions. There is little doubt that the emotional state can alter sensations from and function of the viscera but the reverse situation also appears to be true visceral pain evokes strong emotions, stronger than those evoked by equal intensities of superficial pain. This has been demonstrated in numerous observational studies,...

Noncardiac Chest Pain Functional Chest Pain

Chest pain is an alarm symptom that brings hundreds of thousands of people to seek health care worldwide each year (33). In the population, 28 of people report experiencing some form of chest pain in the past year (27). Due to the high prevalence and serious morbidity of coronary artery disease, the complaint of chest pain is treated as cardiac in origin until proven otherwise. Still, 10 to 20 of patients admitted to a coronary care unit are shown to have an esophageal disease (34). The...

CRF Receptors

CRF signaling is mediated by CRF receptors, subtype 1 (CRF1) and or subtype 2 (CRF2), cloned from two distinct genes (14,81). Both receptors belong to the class of seven-trans-membrane receptors that signal by coupling to Gs proteins (82,83). One important feature of CRF receptor subtypes is their distinct affinity for mammalian CRF family ligands including CRF and urocortin 1 (also known as urocortin), and the recently discovered urocortin 2 and urocortin 3 (83,84). CRF displays 10- to 40-fold...

Anatomical Identification of Visceral Afferent Endings

Unlike the cutaneous afferent innervation, where A fibers innervate specific anatomical structures like Merkel cells, Ruffini endings, Hair Lanceolates, and Pacinian or Meissner corpuscles, the dogma associated with the vast majority of visceral sensory endings has been for many years that the peripheral arborizations of small myelinated and unmyelinated afferent fibers terminate as free nerve endings without any clear anatomic specialization. Despite this, it is clear from numerous studies...

Cholecystokinin CCK1 Receptors

Cholecystokinin (CCK) is both a hormone released from duodenal endocrine cells and an enteric neurotransmitter. CCK excites vagal afferents (26), which express predominantly CCK1 receptors (27-30). These receptors may be relevant targets for the treatment of functional dyspepsia, since the CCK receptor antagonist dexloxiglumide attenuates the meal-like fullness and nausea associated with intraduodenal lipid administration during gastric distension of normal volunteers and dyspeptic patients...

Mild Symptoms

The most frequently seen group with abdominal pain has intermittent episodes of mild pain. These patients are usually treated in primary care practices. They maintain normal daily Table 1 Spectrum of Clinical Features Among Patients with Functional Gastrointestinal Pain Visceral contribution-altered gut physiology Note 0, generally absent +, mild + +, moderate + activities, have little or no psychosocial difficulties (although they may experience symptom exacerbation with stress) or chronic...

Testing Heat Hyperalgesia in Complex Regional Pain Syndrome Patients

A reliable and valid test of heat allodynia and hyperalgesia consists of patients rating pain intensity on VAS in response to a range of cutaneous heat stimuli that includes those above and below normal pain threshold, evoked by either immersion of a hand or foot into heated water baths or ramp-and-hold contact heat stimuli delivered to the skin in different body areas. Ramp-and-hold heat stimuli have two distinct advantages. They can be adapted to predominately stimulate A-delta (2-10 C sec)...

Modulation of Brain Responses by Pharmacological Treatments

Despite the lack of consensus regarding brain responses to rectal stimuli in healthy controls and group differences between IBS patients and control subjects, several studies have been reported using functional brain imaging to identify changes in cerebral activation associated with various treatment modalities, including pharmacological treatments (75-77) and non-pharmacological treatments (78,79). Only a few of the reported studies were of sufficient quality (statistical power, blinding, and...

Visceral Pain Therapy Current And Future

The current treatment of visceral pain associated, for instance, with functional bowel disorders (FBDs) such as functional dyspepsia and irritable bowel syndrome (IBS) is unsatisfactory. Therapeutic advances are badly needed in view of the high prevalence of chronic or recurrent visceral pain and its socioeconomic burden as outlined in Chapters I 1 and I 2. This gap in the pharmacologic management of visceral pain reflects the incomplete understanding of the underlying mechanisms, which lags...

Broad Anatomical Regions Patient Control Comparisons

Figure 1 Evolution of brain Imaging studies of visceral perception. pairwise associations. This bivariate correlational technique can be labeled functional connectivity analysis and can show important relationships between separate regions, but does not allow for directly testing the nature of these associations over time or across conditions, provides no information on how these associations may come about, and permits only rudimentary inferences regarding the characterization of neural...

Introduction

The first clinical observation of brain-gut interactions dates back to Beaumont's classical monograph published in 1833 that detailed alterations of gastric mucosa in relation with the mental state of his fistulous subject, Alexis St. Martin (1). Seminal reports by Cannon at the beginning of the last century brought experimental proof of the impact of emotion (fear, rage, and hunger) on gastric secretory and motor function in cats (2). However, Selye deserves much of the credit for introducing...

General Overview

The digestive system is controlled by a complex net of feedback mechanisms, by which the gut is able to sense and react to a variety of stimuli. Feedback control of gut function is operated via reflex pathways distributed within the enteric nervous system and both the sympathetic and parasympathetic nervous systems. This organization allows the digestive system a high degree of versatility and adaptation to a wide range of situations. Nevertheless, under some circumstances gut stimuli may...

CRFCRF1 Receptors And The Biochemical Coding Of Stress Brain CRF

CRF (also known as corticotropin-releasing hormone) was characterized by Vale et al. in 1981 as a novel 41-amino acid hypothalamic-releasing peptide that stimulates the synthesis and release of adrenocorticotropy hormone (ACTH) and P-endorphin from the pituitary (71). With the early recognition that various internal or external cues disrupting homeostasis result in the release of ACTH and glucocorticoids into the circulation, the stimulation of the hypothalamic-pituitary-adrenal (HPA) axis...

The Genitourinary Tract The Renal System

Probably the most intense of pains experienced by humans is that resulting from nephrolithiasis (kidney stones), which can be reproduced with some symptomatic accuracy in rats. With any pain model, but especially those of a potentially severe nature, the ethical implications should be addressed. A stimulus that cannot be terminated by either the experimenter or animal (e.g., by escape or an operant response) is of particular concern, and a factor that is more common in visceral than somatic...

Intraluminal Nutrients

Intraluminal nutrients increase gut perception, and this effect depends on the concentration and the type of nutrient. At physiological loads, lipids have a marked effect, but the influence of carbohydrates is much weaker (28). Nutrients modify gut motor activity, but their effects on perception are independent. Indeed, the sensitization induced by lipids seems specifically related to mechano-receptors, because perception of transmucosal electrical stimulation of the gut, which activates gut...

Intraganglionic Laminar Endings

Vagal Ganglia Mice

Vagal IGLEs are special terminal structures that are located within the myenteric plexus throughout the gastrointestinal tract of a variety of species including rats, mice, and guinea pigs. IGLEs, traced from nodose ganglia are distributed throughout the entire gastrointestinal Figure 2 (See color insert) Several different classes of mechanoreceptor within the gastrointestinal tract. Mucosal afferents have been extensively documented throughout the upper gastrointestinal tract in addition to...

YAmino Butyric Acid

Y-Amino butyric acid (GABA) has a major inhibitory role in the CNS, which mediates its effect via three classes of receptors, the ionotropic GABAA, GABAC receptors, and the G-protein-coupled GABAB receptors. GABAB receptor agonists inhibit vagal afferent mechanosensitivity in the upper gastrointestinal tract and GABAB receptors are expressed on gastric vagal afferent neurons. This peripheral action is associated with a reduction in triggering of transient lower esophageal relaxations (TLESRs)...

References

Somatic and visceral primary afferents in the lower thoracic dorsal root ganglia of the cat. J Comp Neurol 1984 228(3) 422-431. 2. Chandler MJ, Zhang J, Foreman RD. Vagal, sympathetic and somatic sensory inputs to upper cervical (C1-C3) spinothalamic tract neurons in monkeys. J Neurophysiol 1996 76(4) 2555-2567. 3. Randich A, Gebhart GF. Vagal afferent modulation of nociception. Brain Res Brain Res Rev 1992 17(2) 77-99. 4. Cervero F. Visceral pain-central...

Referred Hyperalgesia

As already discussed above, most forms of visceral pain produce an increased tenderness of remote and superficial areas of the body known as referred visceral hyperalgesia (22). The fact that referred hyperalgesia appears to originate from otherwise healthy tissues strongly suggests that their locus of origin is in the CNS rather than in the periphery. The conceptual framework underpinning the central organization of visceral hyperalgesia originates from James MacKenzie, who in his classical...

Functional Gut Disorders

More than half of the patients in a gastroenterological clinic complain of abdominal symptoms, without demonstrable cause by conventional diagnostic tests. In the absence of positive findings, unexplained abdominal symptoms have been categorized as functional gastrointestinal disorders, and several syndromes, such as noncardiac chest pain, functional dyspepsia, and the irritable bowel syndrome (IBS), have been defined. Non-cardiac chest pain refers to patients with thoracic symptoms without...

Is Hyperalgesia Limited to the Gut in Irritable Bowel Syndrome

The first studies to investigate visceral sensitivity in IBS concluded that enhanced sensitivity in IBS was limited to the gut (43-46). Interestingly, two prior studies have examined cutaneous pain in IBS patients using electrocutaneous stimulation (43,44). In one study, 13 patients with Crohn's disease, 13 control subjects, and 12 patients with IBS had electrodes positioned on the Figure 3 IBS patients' and normal control subjects' M-VAS pain Intensity ratings of rectal distension pressures of...

Psychological Modulation of Pain Processing

Perception of visceral sensation is mediated at a cortical level and is therefore influenced by cognitive mechanisms such as stress, attention, and anxiety. Attention to gastrointestinal (GI) stimuli has been shown to increase their perception (45), and there is evidence that psychological mechanisms such as anxiety play a role in modulating visceral sensory perception (46). Stress can be defined as an intrinsic or extrinsic disturbing force that threatens to disturb the homeostasis of an...

The Biopsychosocial Continuum

The biopsychosocial model (5) proposes that illness and disease result not from a single (biological) etiology, but from simultaneously interacting systems at the cellular, tissue, organism, interpersonal, and environmental level. Furthermore, psychosocial factors have direct physiological and pathological consequences and vice versa. Finally, it is the unique contributions of both psychosocial and pathophysiological factors that determine the nature of the illness or disease and its severity...

The Bladder

The most common form of bladder pain in the clinic is that caused by infection, resulting in cystitis, although overdistension of the bladder in acute urinary retention is also very painful. These two mechanisms have been employed in the design of rodent models of bladder pain, using direct distension of the bladder, or instillation of chemical or infectious agents. Environmental stressors have also been used, as stress is known to exacerbate symptoms in human disease. Ness et al. demonstrated...

Sensory Neurons And Gi Hypersensitivity

Studies of the possible mechanisms underlying FBDs have shown that abdominal hypersensi-tivity is an important factor in noncardiac chest pain, functional dyspepsia, and IBS (see Chapters II 3, II 6, II 7, II 9 and II 10). The concept that primary afferents are a relevant target for treating abdominal pain implies that these neurons are sensitized in states of hyper-algesia or undergo other functional changes that are relevant to hypersensitivity. Indeed, most extrinsic afferents innervating...

Section Iv Clinical Syndromes Pathophysiology Diagnosis And Management

Irritable Bowel Syndrome and Functional Abdominal Pain Syndromes Pathophysiology 341 Andrew W. DuPont and Pankaj Jay Pasricha Introduction and Nature of the Problem 341 Is Pain Secondary to Motility Abnormalities in IBS 342 Is Pain Secondary to Disturbances in Sensory Processing (Visceral Hypersensitivity) 343 Visceral Hypersensitivity Central or Peripheral 345 Etiopathogenesis of Visceral Hypersensitivity 350 Conclusions . . . . 353 References 353 Irritable Bowel Syndrome and Functional...

Referred Pain Phenomena In The Clinical Context Referred Pain Hyperalgesia

Referral of pain to distant structures is a typical feature of visceral nociception 2,8 . It is only in the very first episode, or early phases of the first episode, in fact, that pain symptoms from internal organs are perceived in a common site for all viscera i.e., usually along the midline, in the thorax or abdomen, anteriorly, or posteriorly . At this stage, the symptom is a vague and poorly defined sensation, accompanied by marked neurovegetative signs and emotional reactions the so-called...

Modulation of Pain by the Hypothalamic PituitaryAdrenal Axis

Mast Cell Crh Stress

The hypothalamus is sited at the base of the brain around the third ventricle and above the pituitary stalk, which leads down to the pituitary itself, carrying the hypophyseal portal blood supply. It contains vital centers for functions including appetite, thirst, thermal regulation, and the sleep cycle, and acts as an integrator of many neuroendocrine inputs to control the release of pituitary hormone-releasing factors. Amongst other important influences, it plays a role in the circadian...

CRF Antagonists

In addition to the mimicry in the responses triggered by stress and central injection of CRF, the evidence for a role of brain CRF-signaling pathways in the stress response came from studies using CRF receptor antagonists injected into the cerebrospinal fluid. Among the specific nonselective CRF1 CRF2 antagonists are a-helical CRF9-41 88 , D-Phe12CRF12-41 89 , and the recently developed, more potent and long acting peptides, astressin 90,91 and astressin B 92 . The potential therapeutic...

Section Ii The Neurobiology And Psychobiology Of Chronic Visceral Pain

Overview of Pain and Sensitization 17 Michael S. Gold What is Pain 17 Pain Terminology 18 Summary and Conclusions 27 References 27 4. Neuroanatomy of Visceral Pain Pathways and Processes 33 Elie D. Al-Chaer and William D. Willis Peripheral Pathways 33 Central Pathways 34 Representation of Visceral Sensation in the Brain 38 References 39 5. The Neurobiology of Visceral Nociceptors 45 Stuart M. Brierley and L. Ashley Blackshaw Introduction 45 Irritable Bowel Syndrome 45 Sensory Innervation of...

The Small Intestine

Tunel Short Bowel Syndrome Rats

Distension and resection 26 of the ileum, jejunum including traction of the mesentery 27 , and duodenum has been described in rodents for the purposes of this review, we shall Figure 2 Acetic acid produces gastric ulcers in the rat. Kissing ulcers A , induced in a rat three days after intraluminal application of 60 acetic acid. Arrows indicate round ulcers on the posterior and anterior walls. Using a different method injection of 20 acetic acid into the stomach wall , the visceromotor response...

Temporal Summations of Second Pain in Normal Control Subjects and Fibromyalgia Patients Second Pain

A brief noxious stimulus, such as a heat tap at 51 C or percutaneous electrical stimulation of A and C axons, can evoke two distinct pain sensations called, first and second pain 22,29-31 . First pain is usually an immediate sharp sensation, whereas second pain occurs Figure 2 Mean VAS ratings of FMS and normal control subjects to single heat taps top left , graded three-second heat stimuli top right , repeated thenar heat taps bottom left , and repeated cold taps bottom right . Abbreviations...

Visceral Hypersensitivity Historical Background

Some reports in the 1970s described disturbances of gut perception in patients with the irritable bowel and related syndromes, but these studies remained largely ignored. These classic observations were later reconfirmed and expanded, clearly showing a colonic and rectal hypersensitivity in these patients. Further studies tested whether symptoms after meal ingestion in patients with functional dyspepsia were due to a sort of gastric rigidity, that is, to altered compliance and an abnormal...

Visual Analog Scales Satisfy Several Criteria for Optimum Pain Measurement

Direct scales include numerical rating scales NRSs , verbal rating scales VRSs , verbal descriptor scales, magnitude estimation, and visual analog scales VASs . VAS has emerged as having psychometric properties that are superior to other pain scaling methods just mentioned because they fulfill multiple criteria for ideal pain measurement and assessment 2,3 . These criteria include ratio scale properties 4-7 , high test-retest reliability and repeatability 8 , the capacity to detect small...

Sensory Innervation Of The Gastrointestinal Tract

The sensory, or afferent, innervation of the gastrointestinal tract mediates sensations from the gut and initiates reflex control of digestive function. The afferent fibers innervating the gastrointestinal tract follow two main anatomical branches, the vagal pathway and the spinal pathway. Vagal afferents have axons which project directly into the brainstem to the nucleus tractus solitarius whereas their cell bodies are located in the nodose ganglia. Vagal afferents are important in the sensory...

Pathways in the Dorsal Funiculus

The dorsal funiculus, also referred to as the dorsal column in animals or the posterior column in man, contains collateral branches of primary afferent fibers that ascend from the dorsal root entry level all the way to the medulla 31 . In addition, it contains the ascending axons of tract cells of the dorsal horn 60-65 . These tract cells form the postsynaptic dorsal column pathway, which along with primary afferent axons, travels in the dorsal column and synapses in the dorsal column nuclei....

Psychophysical Studies Of Visceral Sensation

To determine whether uncontrolled clinical observations are indeed representative of responses evoked by visceral pain rather than a nonspecific characterization of chronic pain, psychophysical studies have been performed using controlled visceral and nonvisceral stimuli in both healthy subjects and those with clinical diagnoses of painful visceral disorders. Visceral stimuli have included chemical, electrical, thermal, and mechanical stimuli 15 . Most studies have not attempted to compare...

Functional Classification of Afferent Subtypes

Much of the terminology used in the classification of visceral afferents has been translated from that used in the study of cutaneous sensation. These physiological classifications are based on afferent conduction velocities, which in turn, relate to axon diameter and the degree of myeli-nation and their responsiveness to mechanical and thermal stimuli 61 . Cutaneous afferents can be subdivided into three classes based on conduction velocity alone Ap fibers, AS fibers, and C-fibers. Each of...

Relationships of Temporal Summation of Mechanical Allodynia to Severity of Clinical Pain

Regardless of the exact mechanisms by which temporal summation of allodynia is generated, the phenomenon is likely to be at least part of the basis for CRPS patients' ongoing ''spontaneous'' pain. It has been suggested that temporal summation of A-beta allodynia provides at least part of the basis for ongoing background pain in neuropathic pain patients 17 . This relationship could occur if continuous input from A-beta low threshold afferents evoked in the normal course of mechanical...

Visceral Hypersensitivity

Although FGD patients show marked heterogeneity in their clinical presentation and response to treatment, common features have become apparent, as our knowledge of these disorders has increased. It was documented over 30 years ago by Ritchie that recto-sigmoid balloon distension was perceived as painful at lower volumes in IBS patients than in controls 3 . This heightened pain sensitivity to experimental gut stimulation, a phenomenon known as visceral hypersensitivity, has been repeatedly...

Bradykinin Receptors

Bradykinin is one of the best-established chemical nociceptive stimuli and most physiologically relevant to tissue injury and pain. The direct effects of bradykinin are mediated via two G protein-coupled receptors Bx, which is highly inducible in states of inflammation or injury 135 and B2, which is constitutively expressed 135,136 . Evidence suggests a role for B2 receptors in acute inflammatory events, such as edema and inflammatory pain, whereas B1 receptors appear to be involved in chronic...

Distension of Hollow Viscera

Gut distension has been widely used to test sensitivity, both in experimental animals and in conscious man. Gastrointestinal distension in healthy subjects induces sensations such as abdominal pressure and fullness, referred to the epigastrium and the paraumbilical region. The type of sensations induced by distension is rather homogeneous from the stomach down to the mid small bowel 5-8 , which indicates that the expression of the gut in response to stimuli, and the discriminative value of...

Neurophysiological Basis Of Referred Pain

While the sparse innervation of internal organs 60 and the widespread divergence of visceral afferents in the central nervous system CNS explain the dull, vague, and not well-localized nature of the first phase of a visceral pain sensation 5 , the referral of visceral sensations to areas of the body away from the injured organ has always been interpreted as the consequence of convergence of somatic and visceral afferent information onto the same sensory neurons. The rationale for this...

Evidence for Autonomic Nervous System Dysfunction

A number of studies have addressed the role of the ANS in modulating visceral perception in FGD. Chen and Orr demonstrated enhanced sympathetic dominance to esophageal acid infusion in patients with gastroesophageal reflux disease GERD , which appeared to be secondary to decreased vagal tone in these subjects 121 . During acid infusion, there was a significant decrease in LF band power a measure of sympathetic tone in the control group, which was unchanged in the patient group, whereas the HF...

Viscerovisceral Convergence

Convergence Spinal

Mechanistically, viscerovisceral convergence is similar to viscerosomatic convergence. The extensive divergence of the visceral afferent fibers in the spinal cord results in primary afferents that innervate different viscera converging onto a single dorsal horn neuron 37,52-55 . This may result in stimulation of two viscera exciting the same dorsal horn neuron Fig. 4A or stimulation of one viscus, through interneurons, inhibiting a dorsal horn neuron while stimulation of another organ excites...

The Large Intestine Rectum and Anus

Colorectal distension CRD is the most widely used model of organ distension, and has been characterized in both the rat 6 and the mouse 42,43 . This method reproducibly generates painful responses in both animals and humans as the result of a natural visceral stimulus, and is minimally invasive a balloon or similar device can be inserted anally. Such techniques produce acute pain and can be combined with intracolonic treatment with chemicals that produce insult or inflammation such as acetic...

Differences in Brain Responses to Visceral and Somatic Pain Stimuli

Extensive visceral esophageal balloon distension and somatic contact heat on the midline chest animal and human experimental studies have demonstrated that the perceptual, auto-nomic, and behavioral responses to noxious stimulation of somatic structures differ from those of the viscera 28,29 . These differences have been explained based on the functional neuro-anatomic differences between visceral and somatic pain processing. Experimentally induced aversive visceral sensations in humans are...

Divergence of Visceral Afferents in the Spinal Cord

Nociceptor Afferent Fiber

In addition to the dual innervation of viscera by sensory afferent fibers, the central projection and terminal arborization of these visceral afferent fibers are highly divergent compared to somatic afferents. Somatic afferents project to well-defined regions within the dorsal horn Fig. 2A 22-26 . Small diameter myelinated and unmyelinated fibers, most of which are associated with nociceptors, terminate in the superficial dorsal horn and to a lesser extent in Figure 1 The sensory innervation of...

Glutamate

Glutamate is a major transmitter in the CNS and can act via the activation of four separate receptor types. i ionotropic N-methyl-d-aspartate NMDA receptors, ii acid AMPA receptors, iii kainate receptors, and iv metabotropic glutamate mGlu receptors. Peripheral ionotropic GluR iGluR receptors have been suggested to be involved in visceral pain transmission, via activation by endogenous glutamate. This follows from the observation that NMDA receptor antagonists reduce responses to mechanical...

Evidence for Spinal and Supra Spinal Pain Modulation

A number of animal and human studies have assessed the role of spinal nociceptive processes using DNIC paradigms. Recently, Coffin et al. assessed the spinal process of nociceptive signals in IBS patients by analyzing the effects of rectal distensions on electromyographic recordings of the somatic nociceptive flexion RIII reflex 107 . They reported a significant progressive inhibition of the RIII reflex in healthy volunteers during slow ramp distension, with biphasic effects facilitation and...

Neuroanatomy Of Visceral Pain

Celiac Ganglion

Basic science studies have demonstrated that from the level of gross anatomy to the microscopic determination of both peripheral and central afferent terminals, visceral sensory pathways are diffusely organized and distributed diagrammatic summary in Fig. 1 . Rather than mimicking the precise organization of cutaneous sensory afferent pathways, which travel in defined peripheral nerves and extend into a limited number of spinal segmental nerves organized in a unilateral, somatotopic fashion,...

Central Sensitization

Central Sensitization

As mentioned, peripheral injury of primary afferent sensory neurons can be associated with peripheral sensitization. Also, recruitment of previously silent nociceptive neurons can occur which remain active after the injury heals. The increase in nociceptive information arriving at the spinal cord from these peripheral sites can enhance the excitability of dorsal horn neurons, Figure 1 See color insert The potential receptor mechanisms mediating depolarization and sensitization of visceral...

Spinal and Supra Spinal Modulation of Pain Perception

Descending Pain Modulatory System

Working with rats and using simple withdrawal reflexes as pain measures, Reynolds 31 showed that stimulation of a specific region of the midbrain periaqueductal gray PAG inhibited behavioral responses to noxious stimulation, giving rise to the term stimulation produced analgesia.'' Stimulation of these sites inhibited responses of spinal neurons to noxious stimuli suggesting that the brain could modulate spinal activity. The PAG receives direct inputs from the hypothalamus and from the limbic...

Mechanotransduction Mechanisms in Visceral Afferents

Mechanotransduction is fundamental to the perception of distension, contraction, mucosal contact, and a number of other visceral stimuli. Understanding the molecular basis of mechanotransduction may therefore hold the key to designing effective therapies for visceral pain. The number of candidate molecules as mechanotransducers is increasing with the discovery of novel molecules and improved understanding of established molecules. The major candidates are two families of ion channels the...

Visceral vs Somatic Pain

In contrast to the somatic system a misleading term since the viscera are certainly of the body , relatively little is known about the mechanisms of visceral pain sensation. We do know, however, that whereas some characteristics are shared between the visceral and nonvisceral somatic systems, there are also significant differences. Therefore, results from experiments on somatic tissue cannot automatically be assumed to correlate with the visceral organs. The major features 4 that differentiate...

Viscerosomatic Inhibition

Patients with IBS or other disorders with visceral hypersensitivity report referred somatic hypersensitivity in the dermatomes where referred pain is perceived. However, outside the area of referred pain, as long as there is not a codiagnosis of another ailment such as fibro-myalgia, patients report normal or hyposensitivity to noxious electric and mechanical somatic stimuli 4,126-131 . In contrast, thermal stimulation is more painful in IBS patients compared to controls, although this...

The Neuroanatomy of Visceral Pain

While Chapter 4 provides a review of the neuroanatomy of visceral pain, a basic understanding is advantageous when considering the models presented here. We therefore begin with a brief overview of the basic afferent innervation of the viscera. The visceral organs are innervated by extrinsic afferent nerves that run alongside the sympathetic and parasympathetic nervous systems, but are not part of these efferent pathways however, they are referred to by the name of the respective autonomic...

Central Pathways

Spinoparabrachial Tract

Upon entering the dorsal horn, visceral afferents terminate in spinal cord laminae I, II, V, and X 11 . Visceral afferents constitute less than 10 of afferent inflow into the spinal cord. This is a relatively small percentage when one considers the large surface area of some organs. Both anatomical and electrophysiological studies have demonstrated viscerosomatic convergence in both the dorsal horn and supraspinal centers 11-15 . There is also evidence of viscero-visceral convergence onto these...

Distensiontension Sensitive Afferents

Afferents within the wall of the gastrointestinal tract that respond broadly to distension or stretch of a region of gut have been extensively characterized. However, to add complexity, these afferents have been described by a variety of names including distension-sensitive, tension-sensitive, stretch-sensitive, muscular afferents, tonic, phasic, and low-threshold, high-threshold and wide dynamic range fibers to name but a few. Recent reviews indicate differences in the signals generated by...

Heat Allodynia and Hyperalgesia in Fibromyalgia Patients

There are pain conditions that, unlike CRPS described above, are characterized by diffuse pains and hyperalgesia over large areas of body. The ability to use the same patients as their own control in establishing hyperalgesia and allodynia is therefore more challenging in these patient populations. An alternative approach is to compare their ratings of experimental heat stimuli to groups of age- and sex-matched control subjects. For example, heat hyperalgesia has been shown to be a prevalent...

Contributors

Al-Chaer Departments of Pediatrics, Neurobiology and Developmental Sciences, Center for Pain Research, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas, U.S.A. Q. Aziz Department of Gastrointestinal Science, University of Manchester, Hope Hospital, Salford, U.K. Fernando Azpiroz Digestive System Research Unit, University Hospital Vall d'Hebron, Autonomous University of Barcelona, Barcelona, Spain Jane C. Ballantyne Department of Anesthesia and...