Fundamentals of Neurogastroenterology Gut: First Published As 10.1136/Gut.45.2008.Ii6 on 1 September 1999

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II6 Gut 1999;45(Suppl II):II6–II16 Fundamentals of neurogastroenterology Gut: first published as 10.1136/gut.45.2008.ii6 on 1 September 1999. Downloaded from

J D Wood, D H Alpers, P L R Andrews Co-Chair, Committee on Basic Science: Brain–Gut, Multinational Working Teams to Develop Abstract Enteric innervation Diagnostic Criteria for Current concepts and basic principles of Neural networks for control of digestive Functional neurogastroenterology in relation to functions are positioned in the brain, spinal Gastrointestinal cord, prevertebral sympathetic ganglia, and in Disorders, functional gastrointestinal disorders are Departments of reviewed. Neurogastroenterology is em- the walls of the specialized organs that make up Physiology and phasized as a new and advancing subspe- the digestive system. Control involves an Internal Medicine, cialty of clinical gastroenterology and integrated hierarchy of neural centers. Starting The Ohio State digestive science. As such, it embraces at the level of the gut, fig 1 illustrates four lev- University College of els of integrative organization. Level 1 is the the investigative sciences dealing with Medicine and Public enteric nervous system (ENS), which has local Health, Columbus, functions, malfunctions, and malforma- circuitry for integrative functions independent Ohio, USA tions in the brain and spinal cord, and the JDWood of extrinsic nervous connections. The second sympathetic, parasympathetic and en- level of integration occurs in the prevertebral Co-Chair, Committee teric divisions of the autonomic innerva- sympathetic ganglia where peripheral reflex on Basic Science: tion of the digestive tract. Somatomotor pathways are influenced by preganglionic sym- Brain–Gut, systems are included insofar as pharyn- pathetic fibers from the spinal cord. Levels 3 Gastroenterology geal phases of swallowing and pelvic floor Division, Department and 4 are within the central nervous system of Medicine, involvement in defecation, continence, (CNS). At the third level, sympathetic and Washington University and pelvic pain are concerned. Inclusion parasympathetic outflow to the gut is deter- School of Medicine, St of basic physiology of smooth muscle, mined in part by reflexes with sensory fibers Louis, Missouri, USA mucosal epithelium, and the enteric that travel with autonomic nerves. The fourth D H Alpers immune system in the neurogastroen- level includes higher brain centers that supply Department of terologic domain relates to requirements descending signals that are integrated with Physiology, St Georges for compatibility with neural control incoming sensory signals at level 3. The neural Hospital Medical mechanisms. Psychologic and psychiatric networks at level 1 within the walls of the gut School, London, UK relations to functional gastrointestinal integrate contraction of the muscle coats, P L R Andrews disorders are included because they are transport across the mucosal lining and intramural blood flow into organized patterns Correspondence to: significant components of neurogastroen- Jackie D Wood, Ph.D, of behavior. These networks form the ENS, terology, especially in relation to projec- http://gut.bmj.com/ Professor of Physiology and which is considered to be one of the three sub- tions of discomfort and pain to the Internal Medicine, divisions of the autonomic nervous system Department of Physiology, digestive tract. together with sympathetic and parasympa- College of Medicine, The (Gut 1999;45(Suppl II):II6–II16) Ohio State University, 302 thetic divisions. Nervous malformations and Hamilton Hall, 1645 Neil malfunctions in these systems are increasingly Avenue, Columbus, Ohio Keywords: enteric nervous system; brain–gut axis; 43210, USA. Email: autonomic nervous system; nausea; gut motility; mast recognized as underlying factors in functional [email protected] cells; gastrointestinal pain; Rome II gastrointestinal disorders (FGID).

The musculature, mucosal epithelium, and on September 30, 2021 by guest. Protected copyright. vasculature are the gut’s eVector systems. Higher brain centers Control level 4 Global behavior of the organ at any moment reﬂects neurally integrated activity of these systems. The nervous system coordinates activity of the primary eVectors to produce meaningful Parasympathetic Sympathetic patterns of behavior for the whole organ. The system system Control level 3 ENS is a local minibrain within which is stored Prevertebral a library of programs for diVerent patterns of ganglia Control level 2 gut behavior. Digestive, interdigestive, and emetic patterns of intestinal behavior reﬂect outputs from three respective programs. For example, during emesis, propulsion in the Enteric nervous system Control level 1 upper small intestine is reversed for rapid movement of the contents toward the open pylorus and relaxed stomach. This program can be called up from the library either by

Muscle/mucosa/vasculature Effector level Abbreviations used in this paper: CNS, central Figure 1 Neural control of the gut is hierarchic with four basic levels of integrative nervous system; ENS, enteric nervous system; FGID, organization. Level 1 is the enteric nervous system (ENS) which behaves like a local functional gastrointestinal disorder; NTS, nucleus minibrain. The second level of integrative organization is in the prevertebral sympathetic tractus solitarius; DVN, dorsal motor nucleus of the ganglia. The third and fourth levels are within the central nervous system (CNS). Sympathetic and parasympathetic signals to the digestive tract originate at level 3 and vagus; IBS, irritable bowel syndrome; ICC, interstitial represent the ﬁnal common pathways for outﬂow of information from the CNS to the gut. cells of Cajal; 5-HT, 5-hydroxytryptamine; TRH The fourth level includes higher brain centers that provide input for integrative functions at thyrotropin releasing hormone; CRF, corticotropin level 3. releasing factor. Fundamentals of neurogastroenterology II7

the response in the wall of the intestine to dis-

tension or mucosal stroking is a reflex contrac- Gut: first published as 10.1136/gut.45.2008.ii6 on 1 September 1999. Downloaded from tion of the circular muscle coat above the site of stimulation and inhibition of the circular muscle below the site. This pattern of behavior is Effector systems reproduced each time mechanoreceptors are activated by stretch of the wall or deformation Interneurons Muscle of the mucosa. This behavioral pattern, like Reflexes that of all reflexes, mirrors the output of a set of Sensory Motor Secretory fixed “hardwired” connections within the Program glands neurons library neurons interneuronal circuitry. Blood Pattern generators are neural networks that Information vessels processing generate rhythmic or repetitive behavior in eVector systems of animal phyla ranging from Integrated Integrated system invertebrates to higher vertebrates including synaptic circuits behavior humans. They are formed by interneuronal Figure 2 The conceptual model for the enteric nervous system (ENS) is the same as for synaptic connections that are preprogramed to the central nervous system (CNS). Sensory neurons, interneurons, and motor neurons are produce an adaptive pattern of eVector behav- connected synaptically for flow of information from sensory neurons to interneuronal integrative networks to motor neurons to eVector systems. The ENS organizes and ior. Pattern-generating circuitry consists of coordinates the activity of each eVector system into meaningful behavior of the integrated motor programs that signal motor neurons for organ. Bi-directional communication occurs between the CNS and ENS. control of repetitive cyclical behaviors. The commands from the brain or by local sensory sequence of events in stereotyped repetitions of detection of noxious substances in the lumen. motor outflow to the eVector system is Structure, function, and neurochemistry of determined by the program circuit. Pro- enteric ganglia diVer significantly from other grammed motor behavior, unlike reflex behav- autonomic ganglia. Unlike other autonomic ior, does not require sensory input to start the ganglia that function mainly as relay distribu- program, and feedback information from tion centers for signals transmitted from the sensory neurons is unnecessary for sequencing CNS, ENS ganglia are interconnected to form of the steps in the program. For many of the a nervous system with mechanisms for integra- behaviors generated by programmed motor tion and processing of information like those circuits (e.g., chewing, swallowing, breathing), found in the brain and spinal cord. On this the entire sequence of the motor program may basis, the ENS is sometimes referred to as the be initiated by input signals from a single neu- brain-in-the-gut or enteric minibrain. ron called a command neuron. Cyclic patterns Many properties of the ENS resemble the of secretory and contractile behavior seen in CNS12 and the conceptual model is the same the large intestine in response to histamine (fig 2). Like the CNS, the ENS works with release from enteric mast cells is an example of the output of pattern generating circuitry in the http://gut.bmj.com/ three functional categories of neurons identi- 34 fied as sensory, inter-, and motor neurons. ENS. Sensory neurons have receptor regions specialized for detecting changes in thermal, Central command signals chemical, or mechanical stimulus energy. The The vagus nerves have long been recognized as receptor regions transform changes in stimulus the major transmission pathway for control energy into signals coded by action potentials signals from the brain to the digestive tract, whereas the general neurophysiological mecha- that subsequently are transmitted along sen- on September 30, 2021 by guest. Protected copyright. sory nerve fibers to other points in the nervous nisms underlying the eVects of vagal nerve system. stimulation on the upper gut have been Interneurons are connected by synapses into clarified only recently. New awareness of the networks that process sensory information and independent integrative properties of the ENS control the behavior of motor neurons. Multi- has led to revision of earlier concepts of ple connections among many interneurons mechanisms of vagal influence. Earlier con- form “logic” circuits that decipher action cepts of vagal innervation presumed that potential codes from sensory neurons and sig- ganglia of the digestive tract were the same as nals from elsewhere in the nervous system. parasympathetic ganglia in other visceral sys- These are recognized as integrative or reflex tems where the ganglia generally have a relay circuits because they organize reflex responses distribution function. These previous concepts to sensory inputs. supposed that parasympathetic innervation of Motor neurons are the final common the gut was similar. EVerent vagal fibers were pathways for transmission of control signals to believed to form synapses directly with gan- the eVector systems. In the digestive tract, glion cells that innervated the cells of the eVec- motor signals may initiate, sustain, or suppress tor systems. This concept, illustrated in fig 3, is the behavior of the eVector depending on the inconsistent with current evidence and should kind of transmitter released. be abandoned. The earlier concept placed the “computer” entirely within the brain, whereas, current con- Reflexes and pattern generators cepts place “microprocessor” circuits within Reflexes are a form of neurally-mediated the wall of the gut in close proximity to the behavior of eVector systems that occurs in eVector systems. Numbers of neurons equal to response to stimulation of sensory neurons. those of the spinal cord are present in the ENS Reflex behavior is stereotypical. For example, (i.e., ∼1×108). This large amount, which II8 Wood,Alpers, Andrews

Classic concept Current concept rons in the sacral region. Several higher brain regions transmit to these outflow centers. Frontal regions of the cerebral cortex, bed nucleus of the stria terminalis, paraventricular Vagal Vagal nucleus of the hypothalamus, and the central afferent Vagal efferent nucleus of the amygdala project to the vagal Vagal afferent efferent Interneurons outflow center in the medulla oblongata. These areas share information with the limbic regions Sensory Reflexes neurons Program library where emotional responses to sensory input Information processing from the outside world as well as signals of volitional origin are processed. Vagal aVerent fibers from the upper gastro- Enteric Enteric motor motor intestinal tract form synapses in the nucleus neurons neurons tractus solitarius (NTS). They are thought to mediate non-painful physiologic sensations (e.g., distension, satiety and nausea). Evidence Effector Effector for a role in the perception of noxious stimula- system system tion is equivocal. The NTS is the relay station Figure 3 Classic outmoded and current concepts of relations between the brain and the for transfer of vagal aVerent information from digestive tract. The classic concept viewed parasympathetic eVerents (e.g., vagal eVerents) the gut to higher brain centers. Information as synapsing directly with enteric motor neurons, as illustrated on the left side of the diagram. In the current concept, parasympathetic eVerent fibers transmit command signals relayed by the NTS influences the outflow of from the brain to the integrative and motor program circuitry of the enteric nervous system both volitional and non-volitional signals from minibrain as shown on the right side of the diagram. higher brain centers. evidently is required for program control of the Linked interactions between higher brain digestive processes, would greatly expand the centers, emotional state and gastrointestinal volume of the CNS if situated there. Rather disorders are well recognized. Abdominal pain, than having the neural control circuits packed diarrhea, nausea, altered food intake, and exclusively within the CNS and transmitting emesis can all be manifestations of emotional every byte of control information over long or traumatic stress. The same symptoms transmission lines, vertebrate animals have following stress can occur in psychiatrically most of the circuits for automatic feedback normal individuals, as well as in those with control located in close proximity to the eVec- psychiatric illness. Findings that antidepressant tor systems. medications relieve some FGID symptoms is Figure 3 illustrates the current concept of evidence of disorder in the higher brain centers central involvement in gut function. Local that influence the outflow of commands to the integrative circuits of the ENS are organized gut. Nevertheless, the eVect is not evident for for program operations independent of input all antidepressants and is not necessarily

5 http://gut.bmj.com/ from the CNS. Subsets of neural circuits are related to eVects on mood. The stress-related preprogramed for control of distinct patterns of symptoms and behavioral changes (i.e., sleep behavior in each eVector system and for the disturbances, muscle tension, pain, altered coordination of activity of multiple systems. diet, abnormal illness behavior) associated with Enteric motor neurons are the final common FGIDs probably reflect subtle malfunctions in transmission pathways for the variety of diVer- the brain circuits responsible for interactions of ent programs and reflex circuits required for higher cognitive functions and central centers that determine outputs to the gastrointestinal ordered gut function. on September 30, 2021 by guest. Protected copyright. Rather than controlling individual motor tract, and not to psychiatric illness alone. neurons, messages transmitted by parasympathetic eVerent fibers are command signals for Vago–vagal reflexes the activation of expanded blocks of integrated Vagal integrative centers in the brain are more circuits positioned in the gut wall. This explains directly involved in the control of the special- the strong influence of a small number of vagal ized digestive functions of the esophagus, eVerent fibers (approximately 10% of vagal fib- stomach and the functional cluster of duode- ers are eVerent) on motility and other eVector num, gall bladder, and pancreas than in the systems over extended regions of the stomach distal small bowel and large intestine. The cir- or intestine. In this respect, the ENS is cuits in the dorsal vagal complex and their analogous to a microcomputer with its own interactions with higher centers are responsible independent software, whereas the brain is like for the rapid and more precise control required a larger mainframe with extended memory and for adjustments to rapidly changing conditions processing circuits that receive information in the upper digestive tract during anticipation, from and issue commands to the enteric ingestion, and digestion of meals of varied computer. composition. A reflex circuit known as the vago–vagal reflex underlies moment-to-moment adjust- Higher brain centers ments required for optimal digestive function Final common pathways for output from in the upper digestive tract. The sensory side of higher centers to the gut exit the brain in eVer- the reflex arc consists of vagal aVerent neurons ent vagal fibers and descending pathways in the connected with a variety of sensory receptors spinal cord that connect to sympathetic specialized for detection and signaling of preganglionic neurons in the thoraco-lumbar mechanical parameters such as muscle tension region and parasympathetic preganglionic neu- and mucosal brushing, or luminal chemical Fundamentals of neurogastroenterology II9

parameters such as pH, osmolarity and glucose nodose ganglia, dorsal root ganglia, and in the

concentration. The sensory neurons are synap- ENS. Mechanoreceptors sense mechanical Gut: first published as 10.1136/gut.45.2008.ii6 on 1 September 1999. Downloaded from tically connected with neurons in the dorsal events in the mucosa, musculature, serosal sur- motor nucleus of the vagus (DVN) and in the face, and mesentery. They supply both the NTS. The NTS, which lies directly above the enteric minibrain and the CNS with infor- DVN, makes synaptic connections with the mation on stretch-related tension and muscle neuronal pool in the DVN. A synaptic length in the wall and on the movement of neuropile formed by processes from neurons in luminal contents as they brush the mucosal both nuclei tightly links the two into an surface. Mesenteric receptors code for gross integrative center, which together with the area movements of the organ. Chemoreceptors gen- postrema and nucleus ambiguus, form the dor- erate information on the concentration of sal vagal complex. The dorsal vagal neurons are nutrients, osmolarity and pH in the luminal second or third order neurons representing the contents. Thermoreceptors supply the brain eVerent arm of the reflex circuit. They are the with deep-body temperature data used in regu- final common pathways out of the brain to the lation and perhaps sensations of temperature enteric circuits responsible for control and change in the lumen. Presence in the gastro- coordination of the behavior of the muscular, intestinal tract of nociceptors (“pain recep- secretory, and circulatory systems of the gut. tors”), equivalent to those connected with EVerent vagal fibers form synapses with C-fibers and A-delta fibers elsewhere in the neurons in the ENS to activate circuits which body, is likely but not unequivocally ultimately drive outflow of signals in motor confirmed.6 neurons to the eVector systems. When the Sensory information on the mechanical state eVector system is the musculature, its innerva- of the musculature and distension of the tion consists of both inhibitory and excitatory visceral wall is coded by mechanoreceptors. motor neurons that participate in reciprocal Whether the neuronal cell bodies of intramus- control. If the eVector systems are gastric cular and mucosal mechanoreceptors belong to glands or digestive glands of the duodenal dorsal root ganglia, enteric ganglia, or both, is cluster unit, the secretomotor neurons are uncertain.27 Stretch sensitive mechanorecep- excitatory and stimulate secretory behavior. tors have pathophysiologic importance because The circuits for central nervous control of a consistent finding in patients diagnosed with the upper gastrointestinal tract are organized the irritable bowel syndrome (IBS) is abnor- much like those dedicated to control of skeletal mally high sensitivity to stretch that translates muscle movements where fundamental reflex into pain.89 The heightened sensitivity to circuits are located in the spinal cord. Inputs to distension and conscious awareness of the the spinal reflex circuits (e.g., monosynaptic gastrointestinal tract experienced by patients reflexes) from higher order integrative centers with IBS is a generalized phenomenon in the brain (e.g., motor cortex and basal gan- throughout the gut including the esophagus.10

glia) complete the neural organization of The mechanism is unclear. However, three http://gut.bmj.com/ skeletal muscle motor control. Memory, general explanations are apparent: (1) exagger- processing of incoming information from ated signals from sensitized mechanoreceptors outside the body and integration of proprio- may be accurately decoded by the brain as ceptive information are ongoing functions of hyperdistension; (2) malfunctioning brain cir- higher brain centers responsible for intelligent cuits may be misinterpreting accurate infor- organization of the outflow to the skeletal mus- mation; (3) combined sensing and central cles emanating from the basic spinal reflex cir- processing malfunction could be involved. on September 30, 2021 by guest. Protected copyright. cuits. The basic connections of the vago–vagal Hyposensory perception, particularly in the reflex circuit are like somatic motor reflexes in rectosigmoid region, is at the opposite extreme being “fine tuned” by higher brain centers. of gastrointestinal sensory abnormality. Sen- The dorsal vagal complex has extensive con- sory suppression in this region of the gut, either nections for information-sharing with both in the pathway for recto-anal stretch reflexes or forebrain and brainstem centers. Sensory in the transmission pathway from the rectosig- information into the NTS and area postrema is moid to conscious perception of distension, relayed to several rostral centers. The same can be an underlying factor in the pathogenesis rostral centers reciprocate by projecting higher of chronic constipation and associated order information in descending connections symptoms.11 to the vago–vagal reflex circuits. These interac- Conscious sensations arising from mechani- tions account for the eVects of emotional state cal stimulation in the specialized compart- and external stimuli from the environment on ments of the digestive tract in humans include functions of the digestive tract. pressure, fullness, nausea, and pain. Chemical Synaptic transmission in the microcircuits of stimuli (e.g., glucose, fatty acids, and amino the dorsal vagal complex involves more than 30 acids) evoke discharge in gastrointestinal aVer- neurotransmitters. These include acetylcho- ent fibers; nevertheless, it is unlikely that this line, biogenic amines, amino acids, nitric oxide, normally gives rise to conscious sensation other and peptides, most of which are identified as than perhaps hunger and satiety. Sensations of neurotransmitters elsewhere in the brain and in pain are transmitted mainly by dorsal root the ENS. aVerents that accompany the splanchnic nerves. Electrical stimulation of splanchnic Sensory physiology nerves in humans evokes severe pain that is not The gut has mechano-, chemo-, and thermo- relieved by vagotomy.12 Splanchnic aVerents receptors. Cell bodies of these neurons are in seem to be involved in the sensation of nausea II10 Wood,Alpers, Andrews

because nausea can be evoked by gastric oxide are implicated as inhibitory neurotrans- 13

distension in patients with bilateral vagotomy. mitters at neuromuscular junctions in the Gut: first published as 10.1136/gut.45.2008.ii6 on 1 September 1999. Downloaded from This suggests that stimulation of splanchnic gut.18 19 aVerents can evoke the sensation, but does not The functional significance of inhibitory exclude vagal involvement. Vagal stimulation motor neurons is related to the specialized has long been implicated as a factor in nausea.14 physiology of the musculature.2 The intestinal In contrast to vagal aVerents, stimulation of musculature behaves as a self-excitable electri- greater splanchnic nerves does not evoke an cal syncytium consisting of interstitial cells of emetic response in animal models. Cajal (ICCs) that function as pacemakers inte- Low-threshold aVerents respond to innocu- grated with the bulk musculature, which ous levels of distension and contraction; generates forces for propulsion. This implies high-threshold aVerents respond only when that action potentials and pacemaker potentials distension is greater than a set threshold. Low- spread from muscle fiber to muscle fiber in threshold mechanoreceptors are presumed to three dimensions. The action potentials trigger be the sensory component of normal auto- phasic contractions as they spread through the nomic regulatory reflexes (e.g., vago–vagal musculature. The ICCs are a non-neural pace- reflexes). It is unknown for certain whether maker system of electrical slow waves that activity in low-threshold pathways reaches the account for the self-excitable characteristics of level of conscious perception; nevertheless, it is the integrated system. In this construct, the likely that some non-painful sensations such as electrical slow waves are an extrinsic factor to fullness, the presence of gas, or perhaps nausea which the circular muscle responds. are derived from this kind of activity. High- Consideration of the functional characteris- threshold aVerents are thought to be the tics of the musculature raises the question of sensory analogs of sharp-localized pain in why the circular muscle fails to respond with organs such as the gall bladder where pain is action potentials and contractions to all the only consciously perceived sensation.15 pacemaker cycles and why action potentials Cervero and Jänig6 suggested that distension and contractions do not spread in the syncy- can evoke sensations ranging from mild tium throughout the entire length of intestine fullness to intense pain and that activation of each time they occur? Answers to the these diVering proportions of low- and high- questions lie in the functional significance of threshold mechanoreceptors could account for enteric inhibitory motor neurons. the range of sensations. Acute visceral pain may The circular muscle can only respond to a emerge from activation of high-threshold noci- myogenic pacemaker (electrical slow wave) ceptive fibers; whereas, chronic forms of when the inhibitory motor neurons in a visceral pain could be attributed to sensitiza- segment of intestine are switched oV by input tion of both types of mechanoreceptors by from other neurons in the control circuits. conditions such as inflammation or ischemia. Likewise, action potentials and associated con-

Application of irritants to the large intestinal tractions can propagate only into disinhibited http://gut.bmj.com/ mucosa in animals lowers the threshold and regions of the musculature. This means that sensitizes both the high- and low-threshold activity states of inhibitory neurons determine distension sensitive aVerents. Another class of when the omnipresent slow waves initiate a splanchnic aVerents termed silent nociceptors contraction, as well as the distance and is also suspected in chronic pain. direction of propagation once the contraction Silent nociceptors are sensory aVerents that has begun. normally do not respond to the strongest of Inhibitory motor neurons to the circular on September 30, 2021 by guest. Protected copyright. distending stimuli. This group of normally muscle discharge continuously and action silent receptors appears to become sensitized potentials and contractions in the muscle occur by inflammatory mediators. Spontaneous ac- only when the inhibitory neurons are switched tion potential discharge and responses to oV by input from interneurons in the control normally innocuous mechanical distension circuits. In sphincters, the inhibitory neurons occur after sensitization. are normally quiescent and are switched on with timing appropriate for coordination of the opening of the sphincter with physiological Enteric motor physiology events in adjacent regions. When this occurs, The motor neuron pool of the ENS consists of the inhibitory neurotransmitter relaxes ongo- excitatory and inhibitory neurons (fig 2). Exci- ing muscle contraction in the sphincteric mus- tatory motor neurons release neurotransmit- cle and prevents excitation-contraction in the ters that evoke muscle contractions and adjacent muscle from spreading into and clos- mucosal secretion. Acetylcholine and sub- ing the sphincter. In non-sphincteric circular stance P are the main neurotransmitters muscle, the state of activity of inhibitory motor released from excitatory motor neurons to neurons determines the length of a contracting evoke contraction of the muscles.16 Acetylcho- segment by controlling the distance of spread line and vasoactive intestinal peptide are of action potentials within the three- excitatory neurotransmitters that evoke secre- dimensional electrical geometry of the syncy- tion from intestinal crypts.17 tium. Contraction can occur in segments in Inhibitory motor neurons release neuro- which ongoing inhibition has been switched transmitters that suppress contractile activity oV, while adjacent segments with continuing of the musculature. Adenosine triphosphate, inhibitory activity cannot contract. The vasoactive intestinal peptide, pituitary ade- boundaries of the contracted segment reflect nylate cyclase activating peptide, and nitric the transition zone from inactive to active Fundamentals of neurogastroenterology II11

inhibitory motor neurons. The directional nervous control of the muscles that are

sequence in which the inhibitory motor self-excitable (autogenic) when released from Gut: first published as 10.1136/gut.45.2008.ii6 on 1 September 1999. Downloaded from neurons are switched oV establishes the the braking action imposed by inhibitory direction of propagation of the contraction. motor neurons. Chronic pseudo-obstruction in Normally, they are switched oV in the aboral these cases appears to be symptomatic of direction, resulting in contractile activity that advanced stages of a progressive enteric propagates in the aboral direction. During neuropathy. Retrospective review of patients’ vomiting, the inhibitory motor neurons must records suggests that FGID symptoms can be be switched oV in the reverse sequence to an expression of early stages of the neuropathy. account for small intestinal propulsion that Degenerative non-inflammatory and inflam- travels toward the stomach. matory enteric neuropathies are two forms of In general, any treatment or condition that the disease that culminate in pseudo- ablates the intrinsic inhibitory neurons results obstruction. Non-inflammatory neuropathies in tonic contracture and “achalasia” of the can be either familial or sporadic.21 In the auto- intestinal circular muscle. Several circum- somal recessive form, the neuropathologic stances that involve functional ablation of the findings include a notable reduction in the intrinsic inhibitory neurons are associated with number of neurons in both myenteric and sub- conversion from a hypocontractile condition of mucous plexuses, and the presence of round, the circular muscle to a hypercontractile state. eosinophilic intranuclear inclusions in about All evidence suggests that some of the intrinsic 30% of the residual neurons. Histochemical inhibitory neurons are tonically active, and that and ultrastructural analysis revealed that the blockade or ablation of these neurons releases inclusions are not viral particles, but rather the circular muscle from the inhibitory proteinaceous material forming filaments.22 23 influence.2 The behavior of the muscle in these Degenerative inflammatory enteric neuropa- cases is tonic contracture and disorganized thies are characterized by a dense inflamma- phasic contractile activity reminiscent of fibril- tory infiltrate confined to enteric ganglia. Para- lation. neoplastic syndrome, Chagas disease and idiopathic degenerative disease are recogniz- Disinhibitory motor disease able forms of pseudo-obstruction related to The physiology of neuromuscular relations in inflammatory neuropathies. the intestine predicts that spasticity and “acha- Idiopathic inflammatory degenerative neu- lasia” will accompany any condition where ropathy occurs unrelated to neoplasms, infec- inhibitory motor neurons are destroyed. With- tious conditions or other known diseases.24–26 out inhibitory control, the self-excitable DeGiorgio and colleagues25 and Smith and smooth muscle contracts continuously and colleagues26 described two small groups of behaves as an obstruction. This happens patients with early complaints of symptoms because the muscle is freed to respond to the similar to FGID, which progressively wors-

pacemaker (electrical slow waves) with con- ened, and were later diagnosed as idiopathic http://gut.bmj.com/ tractions that propagate without amplitude, degenerative inflammatory neuropathy based distance, or directional control. Contractions on full-thickness biopsy samples taken during spreading in the uncontrolled syncytium col- exploratory laparotomy that revealed chronic lide randomly resulting in fibrillation-like intestinal pseudo-obstruction. Each patient behavior in the aVected intestinal segment. had inflammatory infiltrates localized to the Loss or malfunction of inhibitory motor myenteric plexus. Serum samples from the two neurons is the pathophysiologic basis of disin- cases reported by Smith had circulating et al on September 30, 2021 by guest. Protected copyright. hibitory motor disease. It underlies several antibodies against enteric neurons similar to forms of chronic intestinal pseudo-obstruction those found in secondary inflammatory neu- and sphincteric achalasia. Neuropathic degen- ropathies (i.e., anti-Hu), but with diVerent eration is a progressive disease that in its earlier immunolabeling patterns characterized by stages may be manifest as symptoms confused prominent cytoplasmic rather than nuclear with FGID. staining.26 Recognition of the complex functions of the Functional gastrointestinal disorders and enteric minibrain prompts the conclusion that chronic intestinal pseudo-obstruction early neuropathic changes are expected to be The neuropathic form of chronic intestinal manifest as functional symptoms that worsen pseudo-obstruction is linked with neuropathic with progressive neuronal loss. In diagnostic degeneration in the ENS. Failure of propulsive motility studies (e.g., manometry) degenera- motility in the aVected length of neuropathic tive loss of enteric neurons is reflected by bowel reflects loss of the neural microcircuits hypermotility and spasticity20 because inhibi- that program and control the repertoire of tory motor neurons are included in the missing motility patterns required for the necessary neuronal population. functions of that region of bowel. Pseudo- obstruction occurs in part because contractile Nausea and vomiting behavior of the circular muscle is hyperactive Nausea and vomiting are common symptoms but disorganized in the denervated regions.20 of FGIDs. Both are viewed as components of a Manometrically determined hyperactivity is a neuroprotective mechanism against acciden- diagnostic sign of the neuropathic form of tally ingested toxins.27 Nausea is responsible for chronic small bowel pseudo-obstruction. The the genesis of an aversive response either by hyperactive and disorganized contractile be- taste, sight, or smell such that the animal avoids havior reflects the absence of inhibitory the toxin on future occasions. Vomiting expels II12 Wood,Alpers, Andrews

the toxin from the upper gastrointestinal tract, that this class of drugs may have potential for

much like diarrhea and power propulsion modifying other non-painful sensations arising Gut: first published as 10.1136/gut.45.2008.ii6 on 1 September 1999. Downloaded from accomplish a similar function in the lower gut. from the upper digestive tract. Nausea induces an aversive response linking the sensation to recently ingested food that contained the toxin. In humans, nausea can be Neuroimmunophysiologic paradigm for more aversive than pain. EVects of inappropri- functional gastrointestinal disorders ate induction of nausea in the clinic are seen in The enteric immune system is colonized by patients undergoing anti-cancer chemotherapy populations of immune/inflammatory cells that who may experience reduced food intake, are constantly changing in response to luminal anticipatory emetic responses, and aversion to conditions and during pathophysiologic states. further courses of therapy. Aside from its adap- In its position in the colon, the mucosal tive advantage in evolution, some animals, immune system encounters one of the most including humans, experience nausea and contaminated of bodily interfaces with the out- vomiting as a symptom in response to an side world. The system is exposed daily to extended range of drugs, therapies, disease dietary antigens, bacteria, viruses, and toxins. processes, and altered mental states. Physical and chemical barriers at the epithelial The somatic motor acts of retching and interface do not exclude the large antigenic vomiting are preceded by changes mediated by load in its entirety, causing the mucosal the autonomic nervous system including saliva- immune system to be chronically challenged. tion, tachycardia, cutaneous vasoconstriction, Motor and secretory responses in the gut of sweating, relaxation of the proximal stomach, animals sensitized to specific antigens (e.g., and retrograde propulsive contractions in the parasites, food antigens, bacterial toxins) sug- upper small bowel. Vomiting center is a short- gest direct communication between the im- hand term for the brainstem structures that mune system and the ENS that may be normal contain the neural program for organization of or become pathologic. The communication both the autonomic and somatic motor outflow results in adaptive behavior of the bowel in components in generation of the emetic response to circumstances within the lumen response. Input to the vomiting center from that are threatening to the functional integrity vagal aVerents, the area postrema, vestibular of the whole animal. Communication is system, and higher brain structures can induce paracrine in nature and incorporates special- nausea and trigger the emetic pattern generator ized sensing functions for specific antigens in humans. Input from abdominal vagal together with the capacity of the ENS for intel- aVerents is also a trigger for the vomiting ligent interpretation of the signals. Flow of center. information in immuno-neural integration Several lines of evidence suggest that para- starts with immune detection and signal trans- crine signaling from mucosal enteroendocrine fer to the ENS. The enteric minibrain inter-

cells to vagal aVerent terminals, with major prets the signal and responds by calling up http://gut.bmj.com/ involvement of 5-hydroxytryptamine (5-HT) from its program library a speciﬁc program of as the mediator, underlies signal transduction coordinated mucosal secretion and propulsive at the aVerent terminal. This is assumed to motility that functions to clear the antigenic

underlie the eYcacy of 5-HT3 antagonists as threat from the intestinal lumen. Side eVects of antiemetic drugs. The vomiting center itself the program are symptoms of abdominal pain should be an ideal target for antiemetic drug and diarrhea (ﬁg 4). therapy because a drug acting there could The enteric immune system becomes sensi- on September 30, 2021 by guest. Protected copyright. potentially block retching and vomiting irre- tized by foreign antigens in the form of spective of the initial trigger. Animal studies foodstuVs, toxins and invading organisms. have identiﬁed several classes of agents that Once the system is sensitized, a second

may work in this way. These include 5-HT1A exposure to the same antigen triggers predict- receptor agonists,28 opiate receptor agonists,29 able integrated behavior of the intestinal eVec- the capsaicin analog resiniferatoxin,30 and neu- tor systems.32 Neurally coordinated activity of rokinin NK-1 receptor antagonists.31 Neuroki- the musculature, secretory epithelium and nin antagonists block retching and vomiting blood vasculature results in organized behavior induced by activation of vagal aVerents with of the whole intestine that rapidly expels the electrical stimulation, intragastric irritants, cis- antigenic threat. Recognition of an antigen by platin, and radiation. They also block retching the sensitized immuno-neuro-apparatus leads and vomiting evoked by stimulation of the area to activation of a specialized propulsive motor postrema with apomorphine or loperamide and program that is integrated with copious stimulation of the vestibular system with secretion of water, electrolytes, and mucus into motion. Early results from clinical trials suggest the intestinal lumen. Detection by the enteric that the neurokinin antagonists block the immune system and signal transmission to the sensation of nausea as well as retching and enteric minibrain initiates the defensive behav- vomiting. This suggests action at a site before ior which is analogous to emetic defense in the divergence of the pathways responsible for the upper gastrointestinal tract. The neurally sensation of nausea and the motor behavior of organized pattern of muscle behavior that emesis. The most likely site of action is the occurs in response to an oVending antigen in NTS in the brain stem.31 Observations that a the sensitized intestine is called power propul- non-peptide neurokinin-1 receptor antagonist sion. This specialized form of propulsive motil- can block the emetic response to abdominal ity forcefully and rapidly propels any material vagal aVerent stimulation raises the possibility in the lumen over long distances and effectively Fundamentals of neurogastroenterology II13

3 musculature. Histamine H2 receptors on CNS enteric neurons initiate the cyclic behavior. Several days after sensitization to either a para-

Brain Mast cell neural connection site or food antigen, re-exposure to the antigen evokes a pattern of cyclical behavior like that Enteric 35 36 nervous system Effector systems seen during histamine application. The combination of evidence suggests that recogni- Program library Muscle tion of sensitizing antigens by intestinal mast Information processing Secretory epithelium cells leads to release of histamine, which signals Reflexes Blood activation of a neuronal pattern generator from Feedback control the library of programs stored in the local neural network. Histamine Antibody Behavior Brain–mast cell connection for functional Chemoattractant factors Hyper-secretion gastrointestinal disorders (Power propulsion ( Enteric mast cells seem to be involved in Antigen MAST CELL defense mechanisms apart from local antigen Symptoms Substance P Inflammation sensing and signaling to the ENS. An hypoth- Diarrhea esis that mast cells are relay nodes for pain ( ( transmission of selective information from the Figure 4 Conceptual model for enteric neuro-immunophysiology. The enteric nervous brain to the ENS is plausible and of suYcient system (ENS) is a minibrain located in close apposition to the gastrointestinal eVectors it significance to justify attention. Evidence from controls. Enteric mast cells are in position to detect foreign antigens and signal their presence to the ENS. Stimulated mast cells release several paracrine mediators simultaneously. Some ultrastructural and light microscopic studies of the mediators signal the ENS whereas others act as attractant factors for suggests that enteric mast cells are innervated polymorphonuclear leucocytes responsible for acute inflammatory responses. The ENS by projections from the CNS.37–39 Functional responds to the mast cell signal by initiating a program of coordinated secretion and propulsive motility that expels the source of antigenic stimulation from the bowel. Symptoms evidence supporting the brain to mast cell con- of abdominal pain and diarrhea result from operation of the neural program. Neural inputs nection is found in reports of Pavlovian condi- to mast cells from the brain stimulate simultaneous release of chemoattractant factors for tioning of mast cell degranulation in the inflammatory cells and chemical signals to the ENS with symptomatic consequences that gastrointestinal tract.40 Release of mast cell mimic antigenic stimulation. CNS, central nervous system. protease into the systemic circulation is a empties the lumen. Its occurrence is accompa- marker for degranulation of enteric mucosal nied by abdominal discomfort and diarrhea.33 mast cells. This can be demonstrated as a con- Output of the enteric defense program ditioned response in laboratory animals to reproduces the same stereotyped motor behav- either light or auditory stimuli and in humans ior in response to exposure to radiation, as a conditioned response to stress,41 indicative mucosal contact with noxious stimulants, or of a brain to enteric mast cell connection. antigenic detection by the sensitized enteric Findings that stimulation of neurons in the

immune system.34 Whether FGID symptoms brain stem by thyrotropin releasing hormone http://gut.bmj.com/ sometimes reflect paradoxical output of the (TRH) evokes degranulation of mucosal mast program is unresolved. The neural program cells in the rat small intestine are additional incorporates connections between myenteric evidence for brain–mast cell interactions.42 In and submucous plexuses that coordinate mu- the upper gastrointestinal tract of the rat, cosal secretion with propulsive motor behavior. intracerebroventricular injection of TRH The program is organized to stimulate copious evokes the same kinds of gastric inflammation secretion that flushes the mucosa and suspends and erosions as cold-restraint stress. In the on September 30, 2021 by guest. Protected copyright. the oVensive material in solution in the large bowel, restraint stress exacerbates nocic- segment ahead of the powerful propulsive eptive responses and these eVects are associ- contractions, which, in turn, empty the lumen. ated with increased release of histamine.43 The overall benefit is rapid excretion of Intracerebroventricular injection of corticotro- material recognized by the immune system as pin releasing factor (CRF) mimics the re- threatening. sponses to stress. Intracerebroventricular injec- Several kinds of immune/inflammatory cells tion of a CRF antagonist or pretreatment with including lymphocytes, macrophages, polymor- mast cell stabilizing drugs suppresses stress- phonuclear leucocytes, and mast cells are puta- induced responses. tive sources of paracrine signals to the ENS. Mast cell degranulation may release media- Signaling between mast cells and the neural tors that sensitize silent nociceptors in the large elements of the local microcircuits is the best intestine. In animal models, degranulation of understood. Antigen-evoked degranulation of intestinal mast cells results in a reduced mast cells releases a variety of paracrine threshold for pain responses to balloon messengers that may include serotonin, hista- distension44 that was prevented by treatment mine, prostaglandins, leukotrienes, platelet- with mast cell stabilizing drugs. activating factor, and cytokines (fig 4). Among these, histamine is implicated as a significant Implications of the brain–mast cell messenger in communication between the connection for functional gastrointestinal enteric immune system and the ENS in animal disorders models. The brain to mast cell connection appears to be Applications of histamine, to simulate de- a mechanism that can link psycho-emotional granulation of mast cells in a guinea pig model, status to irritable states of the digestive tract. evokes rhythmic bursts of electrolyte/water The irritable state of the bowel (abdominal secretion coordinated with contraction of the discomfort and diarrhea), known to result from II14 Wood,Alpers, Andrews

degranulation of intestinal mast cells and Directions for the future

release of signals to the ENS, is expected to NEUROGASTROENTEROLOGY Gut: first published as 10.1136/gut.45.2008.ii6 on 1 September 1999. Downloaded from occur irrespective of the mode of stimulation of Many lines of evidence implicate dysfunction the mast cells (fig 3). Degranulation and in the nervous system as a significant factor release of mediators evoked by neural input will underlying symptomatology in patient com- have the same eVect on motility and secretory plaints and behavior that fit criteria for FGID. behavior as degranulation triggered by antigen This justifies future attention to the develop- detection. This may explain the similarity of ment of the subspeciality of neurogastroenter- bowel symptoms between those associated with ology. Neurogastroenterology encompasses the noxious insults in the lumen and those associ- investigative sciences dealing with functions, ated with stress in susceptible individuals. malfunctions, and malformations in the brain The immunoneurophysiologic evidence and spinal cord and the sympathetic, parasym- leads to the inescapable conclusion that the pathetic, and enteric divisions of the auto- moment-to-moment behavior of the gut, nomic innervation of the digestive tract. whether it be normal or pathologic, is deter- Psychologic and psychiatric relations to FGID mined by integrative functions of the ENS. are significant components of the neurgastro- Informational input processed by the enteric enterologic domain. Acceptance of neurogas- minibrain is derived from local sensory recep- troenterology as the name for the subspeciality tors, immune/inflammatory cells (mast cells), of gastroenterology where the bulk of future and the CNS. Mast cells utilize the capacity of progress in understanding FGID is expected the immune system for detection of new and will undoubtedly escalate in the future. antigens and long term memory that permits This should signal its acceptance as a bona fide field of gastroenterologic research and clinical recognition of the antigen if it ever reappears in 50 51 the gut lumen. Should the antigen reappear, practice. mast cells signal its presence to the enteric minibrain. The minibrain interprets the mast CENTRAL NERVOUS SYSTEM The CNS is key to understanding conscious cell signal as a threat and calls up from its pro- perception of real gastrointestinal pain, genesis gram library, secretory and propulsive motor of non-painful sensations, the emotional conse- behavior organized for quick and eVective quences of real pain perception, and psycho- eradication of the threat. Operation of the pro- logic origins of projection of discomfort to the gram protects the integrity of the bowel, but at bowel. Spinal pathways and gating mechanisms the expense of the side eVects of abdominal for nociceptive and non-nociceptive sensations distress and diarrhea. The same symptomatol- of gastrointestinal origin are poorly explored ogy is expected to result from activation of areas amenable to investigation with potential neural pathways that link psychologic states in for understanding disordered sensory aspects the brain to the mast cells in the gut. The of FGID. Advances in understanding the basic

immunoneurophysiology in this respect is sug- neurophysiology of nausea and vomiting are http://gut.bmj.com/ gestive of mechanisms with susceptibility to expected to focus on origins in the CNS. Tar- malfunctions that could result in symptoms geting of basic mechanisms of nausea and resembling FGID. vomiting for pharmacotherapy with agents such as the non-peptide NK-1 receptor antagonists holds future promise. Nevertheless, future research should not ignore evidence that the Central neurophysiology in psychiatric peripheral nervous system, especially vagal on September 30, 2021 by guest. Protected copyright. disorders and functional gastrointestinal aVerents, is of equal importance in the basic disorders physiology and pharmacology of nausea and Modern methods of brain imaging45 have made vomiting. it possible to map regions of the brain involved New technologies for imaging or otherwise in cognitive processing and to compare normal detecting activity in the functioning brain have subjects and patients with psychiatric disor- strong potential for better understanding of ders. Changes—for example, have been found how malfunctions of central processing are in the ventral prefrontal cortex in patients with related to symptoms in patients with FGID. unipolar and familial forms of depression when These approaches will be necessary for distin- compared with normal subjects. Decreased guishing peripheral sensitization of sensory vascular perfusion seen in image scans of local- detection from abnormalities of central ized regions of the prefrontal cortex normalizes processing as underlying neuropathology in the after recovery from the depressed state.46 Puta- hypersensitivity to gut pain in patients with tive relationships between psychiatric disorders IBS. They oVer promise for improved insight and FGIDs47 underscore a need for compari- into abnormality of processing in the brain son of psychiatric and FGID patients with nor- nuclei involved in cognitive perception of gut mal subjects. Application of brain imaging in sensations, integration into emotional con- FGIDs has begun, but is at an early stage.48 49 sciousness and psychogenic aspects of behavio- In view of the fact that brain imaging has iden- ral phenotype. tiﬁed abnormalities associated with psychiatric disorders, there is a need to repeat the same ENTERIC NERVOUS SYSTEM studies in well deﬁned groups of patients with Consideration that the ENS is an independent FGIDs in order to start the process of integrative nervous system with most of the understanding the relationships for brain neurophysiologic complexities found in the dysfunction in the two groups of disorders. CNS suggests that FGID symptoms may origi- Fundamentals of neurogastroenterology II15

nate there as well. Lack of understanding of 3 Cooke HJ, Wang YZ, Rogers R. Coordination of Cl– secretion and contraction by a histamine H2-receptor

how subtle malfunctions may occur in the syn- agonist in guinea pig distal colon. Am J Physiol 1993;265: Gut: first published as 10.1136/gut.45.2008.ii6 on 1 September 1999. Downloaded from aptic microcircuits of the ENS is the basis of G973–8. 4 Wood JD. Histamine signals in enteric neuroimmune inter- “functional” as the descriptor for several forms actions. AnnNYAcadSci1992;664:275–83. of disordered gastrointestinal motility. This is 5 Magni G. The use of antidepressants in the treatment of chronic pain. A review of the current evidence. Drugs reminiscent of neurologic disorders, such as 1991;42:730–48. Parkinsonian tremors, ballisms, and choreas, 6 Cervero F, Janig W. Visceral nocireceptor: a new world that were classified as functional prior to order? Trends Neurosci 1992;15:374–8. 7 Furness JB, Kunze WAA, Bertrand PP, et al. Intrinsic understanding of neurotransmission in micro- primary aVerent neurons of the intestine. Prog Neurobiol circuits of somatic motor centers in the brain. 1998;54:1–18. 8 Whitehead WE, Holtkotter B, Enck P, et al. Tolerance for Like somatic motor control centers in the brain rectosigmoid distension in irritable bowel syndrome. a half century in the past, the ENS remains a Gastroenterology 1990;98:1187–92. 9 Lembo T, Munakata J, Mertz H, et al. Evidence for the virtual black box that must be opened scientifi- hypersensitivity of lumbar splanchnic aVerents in irritable cally in order to acquire real understanding of bowel syndrome. Gastroenterology 1994;107:1686–96. 10 Richter JE, Barish CF, Castell DO. Abnormal sensory FGID. perception in patients with esophageal chest pain. Gastroen- Acquisition of new knowledge of the neuro- terology 1986;91:845–62. 11 Löning-Baucke V. Sensitivity of the sigmoid colon and rec- biology of the enteric minibrain will require tum in children treated for chronic constipation. J Pediatr application of the same methodologies that Gastroenterol Nutr 1984;3:454–9. 12 White J. Sensory innervation of the viscera. Res Publ Assoc unified functional concepts for the CNS. Elec- 1943;23:373–90. trophysiologic and synaptic behavior of indi- 13 Troncon LEA, Thompson DG, Ahuwalia NK, et al. Relations between upper abdominal symptoms and gastric vidual enteric neurons, identification of neuro- distension abnormalities in dysmotility like functional dys- transmitters, how specific neuronal types are pepsia and after vagotomy. Gut 1995;37:17–22. wired into synaptic circuits and the emergent 14 Lewis T. Pain. New York: Macmillan, 1942. 15 Cervo F. AVerent activity evoked by natural stimulation of properties of microcircuits in the programing the biliary system in the ferret. Pain 1982;13:137–51. of motor and secretory behavior are areas open 16 Maggi CA, Catalioto RM, Criscuoli M, et al. Tachykinin receptors and intestinal motility. Can J Physiol Pharmacol to innovative investigation. Further investiga- 1997;75:696–703. tion of enteric sensory physiology and the 17 Cooke HJ. Role of the “little brain” in the gut in water and electrolyte homeostasis. FASEB J 1989;3:127–38. influence of inflammation and noxious insult 18 Burnstock G. Purinergic neurons. Pharmacol Rev 1972;34: holds promise for understanding why the 509–81. 19 Jin JG, Murthy KS, Grider JR, et al. Stoichiometry of digestive tract is sensitized to distension in neurally induced VIP release, NO formation, and relaxa- patients aZicted with IBS, functional dys- tion in rabbit and rat gastric muscle. Am J Physiol 1996;34: G357–69. pepsia, or non-cardiac chest pain. 20 Stanghellini V, Camilleri M, Malagelada JR. Chronic idiopathic intestinal pseudo-obstruction. Clinical and intestinal manometric findings. Gut 1987;23:824–8. ENTERIC NEUROIMMUNE INTERACTIONS 21 Camilleri M, Phillips S. Disorders of small intestinal motil- Study of the interactions of the enteric immune ity. Gastroenterol Clin North Am 1989;18:405–24. 22 Palo J, Haltia M, Carpenter S, et al. Neurofilament subunit- system and the ENS is an area where progress related proteins in neuronal intranuclear inclusion. Ann can be expected in understanding FGID. Neurol 1984;15:316–21.

23 Monoz-Garcia D, Ludwin S. Adult-onset neuronal http://gut.bmj.com/ Enteric mast cells may be a key cell type intranuclear hyaline inclusion disease. Neurology 1986;36: responsible for signaling the ENS to program 785–90. 24 Krishnamurthy S, ShuZer MD. Pathology of neuromusc- behavior that results in FGID-like symptoms, ular disorders of the small intestine and colon. Gastroenter- and for initiating inﬂammatory cascades that ology 1997;93:610–39. 25 DeGiorgio R, Bassotti G, Stanghellini V, et al. Clinical, generate chemical mediators (e.g., cytokines) morpho-functional and immunological features of idio- currently known to have potent actions on pathic myenteric ganglionitis [abstract]. Gastroenterology 1996;110:A655. enteric neurons. Evidence that activation of 26 Smith V, Gregson N, Foggensteiner L. Acquired intestinal

enteric mast cells can occur by central nervous aganglionosis and circulating autoantibodies without neo- on September 30, 2021 by guest. Protected copyright. plasia or other neural involvement. Gastroenterology 1997; signals as well as local insults requires further 112:1366–71. exploration to determine whether a brain–mast 27 Andrews PLR, Davis CJ. The physiology of emesis induced cell connection underlies gut reactions to by anti-cancer therapy. In: Reynolds DJ, Andrews PLR, Davis CJ, eds. Serotonin and the scientific basis of anti-emetic psychogenic stress. therapy. Oxford: Oxford Clinical Communications, 1995: Cases where autoimmune attack is targeted 525–49. 28 Lucot JB. 5-HT1A receptor agonists as anti-emetics. In: Rey- to enteric neurons require future investigative nolds DJ, Andrews PLR, Davis CJ, eds. Serotonin and the scientific basis of anti-emetic therapy. Oxford: Oxford Clinical scrutiny because current evidence suggests that Communications, 1995:222–7. FGID-like symptoms may signal the onset of 29 Rudd JA, Naylor RJ. Opioid receptor involvement in emesis the immunologic event that culminates in and anti-emesis. In: Reynolds DJ, Andrews PLR, Davis CJ, eds. Serotonin and the scientific basis of anti-emetic symptoms of chronic pseudo-obstruction. This therapy. Oxford: Oxford Clinical Communications, 1995: appears to be true for explained forms of neu- 208–21. 30 Andrews PLR, Bhandari P. Resiniferatoxin, an ultrapotent ropathic autoimmunity (paraneoplastic syn- capsaicin analogue, has anti-emetic properties in the ferret. drome and Chagas disease) and the idiopathic Neuropharmacology 1993;32:799–806. 31 Watson JW, Gonsalves SF, Fossa AJ et al. The role of the form. Future directions should include atten- NK1 receptor in emetic responses: the anti-emetic eVects tion to development of tests for enteric neuro- of CP-99,994 in the ferret and the dog. Br J Pharmacol 1995;115:84–94. pathic autoimmunity that can be applied in 32 Wood JD. Neuro-immunophysiolgy of colon function. Phar- diagnostic workups during early indications of macology 1993;47(suppl 1):7–13. 33 Phillips SF. Motility disorders of the colon. In: Yamada T, FGID. Alpers DH, Owyang C, et al,eds.Textbook of gastroenterology. Philadelphia: JB Lippincott, 1995:1856–75. 34 Sarna SK, Otterson MF, Cowles VE, et al. In vivo motor 1 Wood JD. Electrical and synaptic behavior of enteric response to gut inflammation. In: Collins SM, Snape WJ, neurons. In: Wood JD, ed. Handbook of physiology. The eds. EVects of immune cells and inflammation on smooth mus- gastrointestinal system, motility and circulation. Bethesda, cle and enteric nerves. Boca Raton: CRC Press, 1991:181– MD: American Physiological Society, 1989:465–517. 95. 2 Wood JD. Physiology of the enteric nervous system. In: 35 Frieling T, Cooke HJ, Wood JD. Neuroimmune communi- Johnson LR, Alpers DH, Christensen J, et al,eds.Physiology cation in the submucous plexus of guinea-pig colon after of the gastrointestinal tract. New York: Raven Press, sensitization to milk antigen. Am J Physiol 1994;267: 1994:423–82. G1087–93. II16 Wood,Alpers, Andrews

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ROME II

The Functional Gastrointestinal Disorders

Publication date — January 2000

This book (over 500 pages) presents the full reports from 10 multinational working teams http://gut.bmj.com/ from which these articles have been summarized. Rome II not only details the criteria for system based diagnosis of functional gastrointestinal disorders but also presents the latest information on pathophysiology, diagnostic approach and treatment of 24 functional GI disorders. The book includes an introductory overview chapter by Douglas Drossman on the functional gastrointestinal disorders and the rationale for the Rome process, a chapter by William Whitehead on the deﬁnition of responders in clinical trials resulting from a consen-

sus conference in Vienna, and an historical chapter by Grant Thompson on the development on September 30, 2021 by guest. Protected copyright. of the multinational working teams over the past 10 years. A unique feature of this book is the inclusion of a questionnaire that can be used for surveys and clinical trials which contains all the Rome Criteria in questionnaire form. This book will be used as both a textbook and an up-to-date reference source for anyone interested in clinical care of a comprehensive review of the field. It is must reading for primary care clinicians and researchers. In bringing this new medical knowledge from the multinational working teams to primary care physicians and gastroenterologists throughout the world, this book advances a symptom-based classification system developed as a new paradigm for the diagnosis and treatment of functional GI disorders so that patients suVer- ing from these conditions may find the promise of relief contained in Rome II. For additional information, visit our website at: www.romecriteria.org or e-mail inquiries to: [email protected]