Abnormal forebrain activity in functional bowel disorder patients with chronic pain.

BACKGROUND: Abnormal cortical pain responses in patients with fibromyalgia and conversion disorder raise the possibility of a neurobiologic basis underlying so-called "functional" chronic pain. OBJECTIVE: To use percept-related fMRI to test the hypothesis that patients with a painful functional bowel disorder do not process visceral input or sensations normally or effectively at the cortical level. METHODS: Eleven healthy subjects and nine patients with irritable bowel syndrome (IBS) underwent fMRI during rectal distensions that elicited either a moderate level of urge to defecate or pain. Subjects continuously rated their rectal stimulus-evoked urge or pain sensations during fMRI acquisition. fMRI data were interrogated for activity related to stimulus presence and to specific sensations. RESULTS: In IBS, abnormal responses associated with rectal-evoked sensations were identified in five brain regions. In primary sensory cortex, there were urge-related responses in the IBS but not control group. In the medial thalamus and hippocampus, there were pain-related responses in the IBS but not control group. However, pronounced urge- and pain-related activations were present in the right anterior insula and the right anterior cingulate cortex in the control group but not the IBS group. CONCLUSIONS: Percept-related fMRI revealed abnormal urge- and pain-related forebrain activity during rectal distension in patients with irritable bowel syndrome (IBS). As visceral stimulation evokes pain and triggers unconscious processes related to homeostasis and reflexes, abnormal brain responses in IBS may reflect the sensory symptoms of rectal pain and hypersensitivity, visceromotor dysfunction, and abnormal interoceptive processing.

L-type Ca(2+) channel expression along feline smooth muscle oesophagus.

Muscle from the proximal smooth muscle (SM) oesophagus of the cat demonstrates contractions of greater amplitude and greater sensitivity to cholinergic stimulation than muscle from the distal SM oesophagus. In the light of the central role of calcium influx in SM contractility, we hypothesized that regional differences in oesophageal contractility may be associated with differential expression of L-type calcium channels (L(Ca)) along the SM oesophagus. L(Ca) expression was compared between proximal and distal regions of the circular SM oesophagus by Western blots. Patch clamp technique was utilized to study L(Ca) currents. Muscle strip studies assessed L(Ca) contribution to contractile activity. The protein expression of L(Ca) and L(Ca) current density was greater in the proximal than distal region. L(Ca) voltage and time-dependent activation and inactivation curves were similar in cells from both regions. Stimulation of muscle strips with acetylcholine (ACh) in the presence of tetrodotoxin resulted in contractions of greater amplitude in the proximal region. The L(Ca) agonist Bay K 8644 caused a greater increase in ACh-induced contraction amplitude in muscle strips from the proximal region. Therefore, regional myogenic differences in L(Ca) expression along the circular SM oesophageal body exist and may contribute to the nature of oesophageal contractions.

Sexual and physical abuse are not associated with rectal hypersensitivity in patients with irritable bowel syndrome.

BACKGROUND: Patients with irritable bowel syndrome (IBS) have reduced pain thresholds for rectal distension. In addition, the prevalence of sexual/physical abuse in referred IBS patients is high and is associated with greater pain reporting, poorer health status, and poorer outcome. This lead to a hypothesis that abuse history may sensitise patients to report pain at a lower threshold. AIM: To compare rectal pain thresholds in women with IBS who had a history of severe abuse to IBS women with no history of abuse. METHODS: We studied 74 IBS patients with a history of severe physical and/or sexual abuse and 85 patients with no history of abuse. Abuse history was assessed by a previously validated self-report abuse screening questionnaire. Rectal sensory thresholds were assessed using an electronic barostat and determined by the ascending method of limit (AML) and by the tracking technique. RESULTS: IBS patients with a history of severe abuse had significantly higher rectal pain thresholds, as measured by AML (F (1, 111) = 6.06; p = 0.015) and the tracking technique (F (1, 109) = 5.21; p = 0.024). Patients with a history of severe abuse also reported a significantly higher threshold for urgency to defecate (F (1, 113) = 11.23; p =.001). CONCLUSION: Severe sexual/physical abuse is associated with higher urge and pain thresholds for rectal distension in IBS patients. This suggests that the greater pain reporting and poorer health status in IBS patients with abuse history are not related to increased rectal pain sensitivity. Further studies are needed to determine the causes of these findings.

Abnormal rectal motor physiology in patients with irritable bowel syndrome.

A contentious issue is whether irritable bowel syndrome (IBS) patients have abnormal rectal motor physiology. Our aim was to determine whether IBS patients have abnormal rectal responses to low (urge producing) or high (pain producing) distension pressures. The IBS patients and healthy controls underwent five series of isobaric rectal distensions to examine volume-pressure relationships and rectal accommodation: (i) ascending stepwise distensions terminating upon report of moderate pain, (ii) phasic and (iii) tonic distensions at a single low pressure producing a moderate sensation of urge to defecate (iv) phasic and (v) tonic distensions at a single high pressure producing a moderate pain sensation. The IBS patients demonstrated a lower rectal volume-pressure ratio during repetitive single-pressure phasic distensions, and a slower rate of rectal accommodation during low (but not high) pressure tonic distensions. However, dynamic compliance during ascending stepwise distensions and the change in rectal volume during tonic distension were not significantly different from controls. Rectal abnormality was readily demonstrated by determining the volume-pressure ratio using a small number of repetitive single-pressure distensions, supporting the hypothesis that IBS patients have abnormal rectal motor physiology. We propose that a peripheral neuromuscular substrate may contribute to the pathogenesis of IBS.

Release of nitric oxide in the central nervous system mediates tonic and phasic contraction of the cat lower oesophageal sphincter.

Nitric oxide (NO) in the brainstem is implicated in the control of swallowing and oesophageal peristalsis. This study examines the role of brainstem NO in the maintenance of lower oesophageal sphincter (LOS) tone, relaxation and contraction. In urethane-anaesthetized cats, oesophageal peristalsis and sphincter pressures were continuously monitored. Drugs were administered into the fourth ventricle. Oesophageal peristalsis and sphincter relaxation and contraction were induced by superior laryngeal nerve stimulation or intra-oesophageal balloon distention. Basal sphincter pressure was significantly reduced after the i.c.v. administration of the nitric oxide synthase (NOS) inhibitor, l-Ng-monomethyl arginine. The inhibitor's d-isomer had no significant effect on basal sphincter pressure, while l-arginine partially reversed the effect. The NOS inhibitor had no effect on sphincter relaxation, whereas the contraction of the sphincter following relaxation was significantly inhibited. Central nitric oxide synthase inhibition reduces basal LOS tone and contraction amplitude but has no effect on swallow or balloon distention induced sphincter relaxation. Therefore, central release of NO acts in the pathway to stimulate dorsal motor nucleus of the vagus neurones projecting to excitatory neurones in the sphincter. Inhibition of nitric oxide synthase in the CNS does not prevent relaxation of the LOS, suggesting that other pathways that do not utilize NO are important in the induction of LOS relaxation.

Distinct regional expression of SNARE proteins in the feline oesophagus.

Abstract Soluble N-ethylmaleimide-sensitive factors attachment protein receptors (SNAREs), initially found to mediate membrane fusion, have now been shown to also bind and regulate a number of membrane ion channels in neurones and neuroendocrine cells. We recently reported that the SNARE protein SNAP-25 regulates Ca(2+)- activated (K(Ca)) and delays rectifier K(+) channels (K(V)) in oesophageal smooth muscle cells. This raised the possibility that cognate and other SNARE proteins could also be present in the oesophageal smooth muscle cell to regulate these and other functions. Circular muscle tissue sections and single freshly isolated muscle cells from the oesophageal body circular and longitudinal layers, and from lower oesophageal sphincter clasp and sling regions were studied. The subcellular location of SNAP-23, SNAP-25, syntaxins 1 to 4, and vesicle-associated membrane protein (VAMP)-2 were explored using a laser scanning confocal imaging system. Feline oesophageal smooth muscle of all regions examined demonstrated the presence of SNAP-23, SNAP-25, syntaxins 1 to 4, and VAMP-2 on the plasma membrane. The intensity of these syntaxins and SNAP-25/-23 proteins varied between the different muscle groups of the oesophagus. In some regions, some SNARE proteins were also noted in the muscle cell cytoplasm. No differential expression was found for VAMP-2. The differential expression of SNAP-25 and its regulation of K(+) channels indicate the important role of SNAP-25 in regulating the distinct membrane excitability and contractility along the smooth muscle of the oesophagus. This is further contributed by its interactions with the cognate syntaxins, which are also differentially expressed in the muscle groups of the oesophageal body and lower oesophageal sphincter (LOS). These SNARE proteins probably have other functions in the smooth muscle cell, such as regulating vesicular transport processes.

Regional differences in the response of feline esophageal smooth muscle to stretch and cholinergic stimulation.

There are no objective differences in neural elements that explain regional differences in neural influences along the smooth muscle (SM) esophageal body (EB). Regional differences in muscle properties are present in the lower esophageal sphincter (LES). This study examines whether regional differences in SM properties exist along the EB and are reflected in length-tension relationships and responses to cholinergic excitation. Circular SM strips from feline EB at 1 cm (EB1) and 3 cm (EB3) above LES and from clasp and sling muscle bundles of LES were assessed in normal and calcium-free solutions with and without bethanechol stimulation. Neural inhibition was assessed by electrical field stimulation (EFS). EB3 developed significantly higher tension in response to stretch and to bethanechol than did EB1. The relaxation response to EFS in bethanechol-precontracted strips was less in EB3 than in EB1. In LES, clasp developed higher resting tension than sling but less active tension in response to bethanechol. EFS-induced relaxations of sling and clasp tissues precontracted by bethanechol were not different. In calcium-free solution, length-tension differences between EB3 and EB1 persisted, but those of LES clasp and sling were abolished. Therefore, regional myogenic differences exist in feline EB circular SM as well as in LES and may contribute to the nature of esophageal contraction.

Dysphagia in a patient with lateral medullary syndrome: insight into the central control of swallowing.

BACKGROUND & AIMS: Central control of swallowing is regulated by a central pattern generator (CPG) positioned dorsally in the solitary tract nucleus and neighboring medullary reticular formation. The CPG serially activates the cranial nerve motor neurons, including the nucleus ambiguus and vagal dorsal motor nucleus, which then innervate the muscles of deglutition. This case provides insight into the central control of swallowing. METHODS: A 65-year-old man with a right superior lateral medullary syndrome presented with a constellation of symptoms, including dysphagia. The swallow was characterized using videofluoroscopy and esophageal motility and the results were compared with magnetic resonance imaging (MRI) findings. RESULTS: Videofluoroscopy showed intact lingual propulsion and volitional movements of the larynx. Distal pharyngeal peristalsis was absent, and the bolus did not pass the upper esophageal sphincter. Manometry showed proximal pharyngeal contraction and normal peristaltic activity in the lower esophagus (smooth muscle), but motor activity of the upper esophageal sphincter and proximal esophagus (striated muscle) was absent. MRI showed a lesion of the dorsal medulla. CONCLUSIONS: These findings are compatible with a specific lesion of the connections from a programming CPG in the solitary tract nucleus to nucleus ambiguus neurons, which supply the distal pharynx, upper esophageal sphincter, and proximal esophagus. There is functional preservation of the CPG control center in the solitary tract nucleus and of the vagal dorsal motor nucleus neurons innervating the smooth muscle esophagus.

Induction of cortical swallowing activity by transcranial magnetic stimulation in the anaesthetized cat.

Transcranial magnetic stimulation (TMS) over human fronto-central areas of scalp can activate short latency responses in the muscles of the face, pharynx and oesophagus. However, the physiological relationship between this early activity and the swallowing activity programmed by the brainstem central pattern generator (CPG) remains unclear. The aim of this study was to explore the relationship between TMS-induced early muscle and late swallowing activities in the feline model. Twelve adult cats were studied under light anaesthesia. Mylohyoid and oesophageal EMG, together with pharyngeal, upper oesophageal sphincter (UOS) and upper oesophageal manometry, were recorded to single-pulse TMS of cat cortex. TMS at low stimulation intensities evoked consistent short latency EMG responses in the mylohyoid and oesophageal muscles (6.1 +/- 1.2 ms and 12.7 +/- 0.7 ms, respectively), and early contractile activity in the UOS (latency 31.8 +/- 3.6 ms). By contrast, TMS at high intensities induced swallowing activity as indicated by mylohyoid EMG, and UOS relaxation (latencies 1.1 +/- 0.4 s and 0.8 +/- 0.1 s, respectively). Both the early muscle and late swallowing activities were intensity-dependent, increasing stimulus strength producing a reduction in latency and greater number of swallows. The characteristics of the early response suggest an oligosynaptic projection from cortex to swallowing muscles. The induction of swallows at high intensities suggests a requisite for greater recruitment of cortical motoneurones, or associated swallowing regions.

Inwardly rectifying K(+) channels in esophageal smooth muscle.

The whole cell patch-clamp technique was used to investigate whether there were inwardly rectifying K(+) (K(ir)) channels in the longitudinal muscle of cat esophagus. Inward currents were observable on membrane hyperpolarization negative to the K(+) equilibrium potential (E(k)) in freshly isolated esophageal longitudinal muscle cells. The current-voltage relationship exhibited strong inward rectification with a reversal potential (E(rev)) of -76.5 mV. Elevation of external K(+) increased the inward current amplitude and positively shifted its E(rev) after the E(k), suggesting that potassium ions carry this current. External Ba(2+) and Cs(+) inhibited this inward current, with hyperpolarization remarkably increasing the inhibition. The IC(50) for Ba(2+) and Cs(+) at -60 mV was 2.9 and 1.6 mM, respectively. Furthermore, external Ba(2+) of 10 microM moderately depolarized the resting membrane potential of the longitudinal muscle cells by 6.3 mV while inhibiting the inward rectification. We conclude that K(ir) channels are present in the longitudinal muscle of cat esophagus, where they contribute to its resting membrane potential.

Central nervous system nitric oxide induces oropharyngeal swallowing and esophageal peristalsis in the cat.

BACKGROUND & AIMS: The functional role of brainstem nitric oxide (NO) in swallowing and esophageal peristalsis remains unknown. We examined the effects of blockade of central nervous system (CNS) NO synthase (NOS) on swallowing and on primary and secondary peristalsis. METHODS: (1) The effect of intravenous (IV) NOS inhibitor N(G)-nitro-L-arginine (L-NNA) on swallowing and swallowing-induced peristalsis was examined. (2) An NOS inhibitor (N(G)-monomethyl-L-arginine [L-NMMA]) was administered into the fourth ventricle intracerebroventricularly (ICV), and its effects on swallowing and primary and secondary peristalsis were examined. RESULTS: (1) IV L-NNA significantly reduced the number of oropharyngeal swallows and the induction of primary peristalsis in the smooth muscle portion of the esophageal body; the change was not significant within the striated muscle portion. (2) L-NMMA given ICV significantly reduced the number of oropharyngeal swallows and the incidence of primary peristalsis in both smooth and striated muscle, but the reduction in amplitude was significant only for the smooth muscle contraction. There was a significant reduction in both the amplitude and incidence of secondary peristalsis, only in the smooth muscle portion. CONCLUSIONS: CNS NO is an important neurotransmitter in the induction of oropharyngeal swallowing and esophageal peristalsis. The neural substrates mediating striated and smooth muscle peristalsis may be both anatomically and neurochemically distinct.

What determines severity among patients with painful functional bowel disorders?

OBJECTIVE: For patients with painful functional bowel disorders (FBD), physicians frequently make diagnostic and treatment decisions based on the severity of the pain reported; patients with severe painful complaints may receive extensive diagnostic tests and treatments. Therefore, it would be important to determine what clinical factors contribute to the judgment of severity among patients with FBD. The aim of this study was to identify the psychosocial, behavioral, and physiological (visceral sensitivity) factors that predicted severity in patients with moderate to severe FBD. METHODS: Two hundred eleven female patients with moderate or severe FBD, as determined by the Functional Bowel Disorder Severity Index, entered a multicenter treatment trial at the University of North Carolina and the University of Toronto. Patients filled out diary cards and were given questionnaires and physiological testing (rectal sensitivity using barostat). Analysis of covariance and logistic regression adjusting for demographic factors were performed to determine which factors distinguished patients at study entry with moderate from those with severe FBD. RESULTS: Patients with severe FBD were characterized by greater depression and psychological distress, poorer physical functioning and health-related quality of life, more maladaptive coping strategies, and greater health care utilization. There was a trend for patients with severe FBD to have lower rectal sensation thresholds. Regression analysis indicated that severity was best predicted by behavioral features: poorer daily physical function, difficulties related to eating, more phone calls to the physician, and more days in bed for GI symptoms. CONCLUSIONS: We conclude that patient illness behaviors are best correlated with severity in FBD. The use of psychopharmacological agents (e.g., antidepressants) and psychological treatments to treat psychiatric comorbidity and to improve behavioral coping styles is recommended. Training to help medical physicians identify and respond to psychosocial and behavioral features of these conditions is likely to improve patient satisfaction with their care and the clinical outcome.

Further validation of the IBS-QOL: a disease-specific quality-of-life questionnaire.

OBJECTIVE: There has been growing interest in the investigation of health-related quality of life (HRQOL) among patients with gastrointestinal (GI) disorders. We recently reported on the development and preliminary validation of the IBS-QOL, a specific quality-of-life measure for irritable bowel syndrome (IBS). The aim of this study was to determine the longitudinal construct validity (responsiveness) of the IBS-QOL. METHODS: Female patients enrolled in a multicenter treatment trial for functional bowel disorders were studied pre- and posttreatment with the IBS-QOL and other health status measures. Based on the response to treatment for several variables (pain/14-day score, daily function, and days in bed/3 months), patients were stratified into Responders, Partial Responders, and Nonresponders. Change scores in the IBS-QOL were then statistically compared with changes in the other variables to determine their correlation and whether Responders were significantly different from non- and Partial Responders on the IBS-QOL. RESULTS: There was a significant correlation between change scores on the IBS-QOL and the other measures of treatment effect (Pain/14 days, r = 0.25, p < 0.002; Sickness Impact Profile [SIP] Total Score, r = 0.28, p < 0.0004). In addition, the IBS-QOL scores significantly differentiated Responders from Nonresponders for most of the variables tested (regression trend test for Pain/14 days, p < 0.04; SIP Total, p < 0.0001; SIP Physical, p < 0.0001; SIP Psychosocial, p < 0.002, and SIP Eating, p < 0.04). CONCLUSION: The IBS-QOL is responsive to treatment in a referral-based clinical population of patients with functional bowel disorders.

Emotional abuse, self-blame, and self-silencing in women with irritable bowel syndrome.

OBJECTIVE: The purpose of this study was to investigate the presence of emotional abuse and two psychosocial constructs (self-blame and self-silencing) in a sample of women diagnosed with irritable bowel syndrome (IBS) relative to a comparison sample of women diagnosed with inflammatory bowel disease (IBD). METHODS: Women diagnosed with IBS (N = 25) were compared with women diagnosed with IBD (N = 25) on measures of history of abuse, self-blame, and self-silencing. RESULTS: It was found that women in the IBS sample scored significantly higher on emotional abuse, self-blame, and self-silencing than did women in the IBD sample. These three variables were also found to be significantly intercorrelated in both the IBS and IBD samples. Finally, emotional abuse was significantly higher in IBS patients than in IBD patients beyond the differences accounted for by physical and/or sexual abuse history. CONCLUSIONS: These findings empirically demonstrate an association between IBS and emotional abuse, as well as a possible connection with psychosocial variables, that may mediate the connection between emotional abuse and functional bowel symptoms. We suggest that these variables be further evaluated in the context of clinically relevant research on IBS.