Modulation of Pain by the HypothalamicPituitaryAdrenal Axis
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...
Abnormal Triggering of Temporal Summation by Primary Mechanoreceptive Neurons
Regardless of whether the mechanical allodynia is A-beta or high threshold, it often has characteristics similar to pains evoked by unmyelinated C nociceptive afferents described above for second pain 6 . Thus, repeated brief mechanical stimulation of allodynic patients often evokes slow temporal summation of burning pain, as shown in Figure 1 right panel . For some CRPS patients, slow temporal summation of burning pain occurs when gentle mechanical stimuli or electrical stimulation of A-beta...
Section Ii The Neurobiology And Psychobiology Of Chronic Visceral Pain
3. 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
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
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...
Chronic Functional Abdominal Pain Syndrome
Functional abdominal pain syndrome is defined as pain for at least six months that is poorly related to gut function and is associated with some loss of daily activities'' 32 . In functional abdominal pain syndrome, there is no disordered bowel motility, and thus bowel disruption is not a prominent feature. Pain is judged functional only when an organic reason can be safely excluded and is considered to exist in the absence of structural or biochemical abnormalities. Functional abdominal pain...
Visceromotor Response
The visceromotor response is a whole body motor reflex to an acute visceral stimulus Fig. 5 . During distention of a hollow organ, muscles of the abdomen, trunk, and limbs contract. The magnitude of the electromyogram recorded from these muscles is positively correlated with the stimulus intensity providing a readily quantifiable measure of the response to dis-tention in an awake or lightly anesthetized animal. This visceromotor response is commonly used to study responses to distention or...
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
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...
Visceral Pain Is Referred to Somatic Structures
The initial perception of pain from the viscera is described as diffuse pain along the midline of the trunk 3,2 . It is poorly localized relative to the originating tissue. This likely results from the divergent central projection of visceral afferent fibers synapsing with scores of dorsal horn neurons in many segments. As the pain intensifies, it is more clearly referred to somatic tissue. It is perceived as originating from the area of the body that is innervated by somatic primary afferent...
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...
References Lab
1. Richter JE, Bradley LA, Castell DO. Esophageal chest pain current controversies in pathogenesis, diagnosis, and therapy. Ann Intern Med 1989 110 1 66-78. 2. Fullerton S. Functional digestive disorders FDD in the year 2000-economic impact. Eur J Surg Suppl 1998 582 62-64. 3. Ritchie J. Pain from distension of the pelvic colon by inflating a balloon in the irritable colon syndrome. Gut 1973 14 2 125-132. 4. Richter JE, Barish CF, Castell DO. Abnormal sensory perception in patients with...
Anorectal Pain Proctalgia
Little epidemiologic data exist on functional anorectal pain. Proctalgia can be associated with organic or functional disorders the two most common functional disorders are levator ani syndrome and proctalgia fugax. The main differences between them are the nature and duration of pain. The pain of levator ani syndrome is described as a dull ache or pressurelike discomfort that can last for hours. The estimated prevalence of levator ani syndrome lies between 7 and 11.3 , with a higher rate seen...
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...
Advantages of Combining Visual Analog Scale Measures with Sensory Tests
It is not widely recognized that the VAS has measurement properties that are superior to other commonly used scales such as the NRS. Unlike VAS, the 11 point-NRS definitely does not have ratio scale properties and has no distinct zero point Fig. 4 of Ref. 13 . Compared to VAS ratings, NRS ratings have been shown to be artificially higher for both clinical and experimental pain 13 . The notion that NRS ratings can easily substitute for VAS ratings because they are highly correlated with each...
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...
Referred Hyperalgesia Arising from Normal Somatic Tissue
As visceral afferent input increases over time, it sensitizes dorsal horn neurons inducing a state of hyperexcitability or central sensitization. At this point, convergent somatic input onto sensitized dorsal horn neurons evokes greater responses than normal. For example, the response to pinch increases and cells may start responding to innocuous somatic stimuli Fig. 3D . In addition, the size of the somatic receptive field of individual dorsal horn neurons increases as normally subliminal...
Viscerovisceral Convergence
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...
References Bfh
1. Grundy D, Scratcherd T. Sensory afferents from the gastrointestinal tract. In Wood JD, ed. Handbook of Physiology The Gastrointestinal System, Motility, and Circulation. Vol. 1. Bethesda, Maryland American Physiological Society, 1989 593-620. 2. Wood JD. Physiology of the enteric nervous system. In Johnson LR, Alpers DH, Christensen J, et al., eds. Physiology of the Gastrointestinal Tract. 3rd ed. Vol. 1. New York Raven Press, 1994 423-482. 3. Berkley KJ, Hubscher CH, Wall PD. Neuronal...
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
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 SupraSpinal 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
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
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 SupraSpinal Modulation of Pain Perception
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
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
Elie D. 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...