Opioid Analgesics Do Not Improve Abdominal Pain or Quality of Life in Crohn's Disease.

BACKGROUND: Abdominal pain and opioid analgesic use are common in Crohn's disease (CD). AIMS: We sought to identify factors associated with abdominal pain in CD and evaluate the impact of opioid analgesics on pain and quality-of-life scores in this setting. METHODS: We performed a longitudinal cohort study using a prospective, consented IBD natural history registry from a single academic center between 2009 and 2013. Consecutive CD patients were followed for at least 1 year after an index visit. Data were abstracted regarding pain experience (from validated surveys), inflammatory activity (using endoscopic/histologic findings), laboratory studies, coexistent psychiatric disorders, medical therapy, opioid analgesic, and tobacco use. RESULTS: Of 542 CD patients (56.6% women), 232 (42.8%) described abdominal pain. Individuals with pain were more likely to undergo surgery and were more frequently prescribed analgesics and/or antidepressants/anxiolytics. Elevated ESR (OR 1.79; 95%CI 1.11-2.87), coexistent anxiety/depression (OR 1.87; 95%CI 1.13-3.09), smoking (OR 2.08; 95%CI 1.27-3.40), and opioid use (OR 2.46; 95%CI 1.33-4.57) were independently associated with abdominal pain. Eighty patients (14.8%) were prescribed opioids, while 31 began taking them at or after the index visit. Patients started on opioids demonstrated no improvement in abdominal pain or quality-of-life scores on follow-up compared to patients not taking opioids. CONCLUSIONS: Abdominal pain is common in CD and is associated with significant opioid analgesic utilization and increased incidence of anxiety/depression, smoking, and elevated inflammatory markers. Importantly, opioid use in CD was not associated with improvement in pain or quality-of-life scores. These findings reinforce the limitations of currently available analgesics in IBD and support exploration of alternative therapies.

Systematic review and meta-analysis: Gastric electrical stimulation for gastroparesis.

BACKGROUND: Controlled trials of gastric electrical stimulation (GES) for gastroparesis reported no significant improvement in symptoms, while open label studies suggested substantial clinical benefits. AIM: To determine if GES is effective in reducing symptoms in patients with gastroparesis. METHODS: We searched PubMed and Embase for articles published in English (1990-2014) using "gastroparesis" as a search term restricted to "clinical trial". We included studies describing repeated patient-based symptom ratings before and during standardized treatments of at least one week duration. RESULTS: Five studies randomly allocated patients to periods with or without GES. Total symptom severity (TSS) scores did not differ between these periods (0.17 [95% confidence interval: -0.06 to 0.4]; P=0.15). However, sixteen open label studies of GES showed a significant TSS decrease (2.68 [2.04-3.32]; Q=39.0; P<0.001). Other treatment modalities similarly improved TSS by 1.97 [1.5-2.44] for medical therapy (MED), by 1.52 [0.9-2.15] for placebo arms (PLA), and by 2.32 [1.56-3.06] for botulinum toxin (BTx). There were significant differences in baseline TSS ratings among these studies (GES: 6.28 [6.28-7.42]; MED: 4.76 [4.09-5.42]; PLA: 4.59 [3.77-5.42]; BTx: 6.02 [5.3-6.74]; Q=35.1; P<0.001). Meta-regression analysis showed these baseline differences to significantly impact TSS ratings during treatment (Q=71.8; P<0.001). CONCLUSION: Independent of the treatment modality, baseline symptom severity impacts treatment results in gastroparesis. Considering the skewed population with refractory symptoms, regression to the mean likely contributes to the substantial discrepancies between the reported results of controlled and open label GES studies, raising questions about the use of GES outside of defined clinical trials.

Colectomy for constipation: time trends and impact based on the US Nationwide Inpatient Sample, 1998-2011.

BACKGROUND: Current guidelines include subtotal colectomy as treatment for refractory slow transit constipation. AIM: To use the US Nationwide Inpatient Sample (NIS) (1998-2011) and longitudinal data from the State Inpatient Database (2005-2011), comparable to NIS, to examine colectomy rates, in-hospital morbidity and emergency department (ED) visits or readmissions among patients treated for constipation. METHODS: Colectomies for any reason were identified based on the primary procedural code (ICD-9-CM 45.8x). Index hospitalisations were defined by the primary diagnosis of constipation (ICD-9-CM 564.x) associated with the primary procedural code for colectomy (ICD-9-CM45.8x) after exclusion of other diseases associated with colectomy. Demographic variables, comorbidities, complications and adverse events during the hospitalisation were captured, and ED visits and admissions were recorded for periods before and after colectomy. RESULTS: Nationally, colectomies for constipation rose from 104 procedures in 1998 (1.2% of annual colectomies) to 311 in 2011 (2.4% of annual colectomies). While there were no perioperative deaths, perioperative complications occurred in 42.7% of patients during the index hospitalisation. Longitudinal data were analysed for 181 patients, with similar perioperative complications and a readmission rate of 28.9% within the first 30 days after the index hospitalisation. Resource utilisation was tracked for a median time of 630 (0-2386) before and 463 (0-2204) days after colectomy with unchanged ED visits (median: 2 vs. 2, P = 0.21), but increased hospitalisations (median: 1 vs. 2, P = 0.003). CONCLUSIONS: Colectomy rates for constipation are rising, are associated with significant morbidity and do not decrease resource utilisation, raising questions about the true benefit of surgery for slow transit constipation.

Adult cyclical vomiting syndrome: a disorder of allostatic regulation?

Cyclic vomiting syndrome (CVS) is an idiopathic illness characterized by stereotypic and sudden-onset episodes of intense retching and repetitive vomiting that are often accompanied by severe abdominal pain. Many associated factors that predict CVS attacks, such as prolonged periods of fasting, sleep deprivation, physical and emotional stress, or acute anxiety, implicate sympathetic nervous system activation as a mechanism that may contribute to CVS pathogenesis. Furthermore, adult patients with CVS tend to have a history of early adverse life events, mood disorders, chronic stress, and drug abuse-all associations that may potentiate sympathetic neural activity. In this review, we set forth a conceptual model in which CVS is viewed as a brain disorder involving maladaptive plasticity within central neural circuits important for allostatic regulation of the sympathetic nervous system. This model not only can account for the varied clinical observations that are linked with CVS, but also has implications for potential therapeutic interventions. Thus, it is likely that cognitive behavioral therapy, stress management ("mind-body") interventions, regular exercise, improved sleep, and avoidance of cannabis and opiate use could have positive influences on the clinical course for patients with CVS.

Factors influencing admission and outcomes in gastroparesis.

BACKGROUND: Current data suggest that gastroparesis is associated with an increased mortality, with reported rates ranging from 4% to nearly 40%. Considering this variability, the goal of this study was to determine mortality rates and risk factors for adverse outcomes in gastroparesis. METHODS: Using the diagnosis code for gastroparesis, admission rates, duration of hospitalizations, discharge status, and inpatient mortality were determined for emergency department encounters and admissions compiled in the Nationwide Emergency Department Sample and Nationwide Inpatient Sample of the Agency for Healthcare Research and Quality. Comorbid conditions, procedural evaluations, age cohort, and gender distribution were examined as potential risk factors. KEY RESULTS: More than 50% of the emergency encounters for gastroparesis resulted in admission with age, cardiovascular, renal, and infectious disorders, but not diabetes mellitus being associated with higher admission rates. Inpatient mortality was 1.2 ± 0.1%, was not negatively affected by diabetes mellitus as comorbidity, and increased with coexisting infections and with more aggressive therapy. Discharge status was similarly affected by comorbidities, treatment complications, and more aggressive therapy. CONCLUSIONS & INFERENCES: These results demonstrate that gastroparesis does not come with a high mortality risk, with most deaths being due to comorbid conditions. Although gastrostomies and/or nutritional support were used in only a minority of admissions, the associated increase in morbidity and mortality highlights the need to carefully select the right candidates for such interventions and to discuss the common occurrence of adverse outcomes with patients.

Gastroparesis on the rise: incidence vs awareness?

BACKGROUND: Recent reports provide a conflicting picture with a stable prevalence of gastroparesis (GP) in a population-based study, but a more than doubling in hospitalizations for gastroparesis within the last 10 years. We hypothesized that this apparent discrepancy is due to changes in disease recognition and coding rather than prevalence. METHODS: Using data from the Nationwide Inpatient Sample, Healthcare cost and utilization project, Agency for Healthcare Research and Quality, we examined time trends of resource utilization for GP and related disorders. KEY RESULTS: Between 1994 and 2009, annual hospitalizations for gastroparesis as primary diagnosis increased more than 18-fold from 918 to 16,736. In the same time frame, hospitalizations for not otherwise specified functional disorders of the stomach decreased by nearly 50% from 13,430 to 6480 per year. CONCLUSIONS & INFERENCES: Although hospitalizations rates and emergency encounters for gastroparesis have increased dramatically within the last 2 decades, there was a concomitant decrease in resource utilization for other functional disorders of the stomach, suggesting that increased awareness contributed to this trend, which represents a shift in diagnoses rather than a true difference in the incidence and/or prevalence of these illnesses.

The rising tide of cholecystectomy for biliary dyskinesia.

BACKGROUND: Expert consensus defines biliary dyskinesia as a rare disorder of the gall-bladder characterised by pain and impaired gall-bladder function. AIM: To determine trends in cholecystectomy rates for biliary dyskinesia in the United States. METHODS: As biliary dyskinesia does not have a distinct diagnosis code, the narrative diagnoses for patients were reviewed and abstracted for 200 patients treated for the most commonly used diagnosis codes for biliary dyskinesia (validation sample). Time trends in cholecystectomies and hospitalisations for biliary diseases were assessed using the Nationwide Inpatient Sample (Agency for Healthcare Research and Quality) based on codes for cholecystectomy and diagnosis codes for different biliary disorders. RESULTS: In the validation sample, biliary dyskinesia accounted for 81% of the patients with ICD-9 code 575.8 (gall-bladder disease not elsewhere specified). Between 1997 and 2010, admissions for acute cholecystitis and complications of gallstone disease decreased slightly, whereas admissions with the primary diagnosis code ICD-9 575.8 tripled. This rise was most pronounced in the paediatric population (700% increase), with biliary dyskinesia accounting for more than 10% of cholecystectomies. Compared with acute biliary diseases, significantly more of the elective hospitalisations were covered by private insurances. CONCLUSIONS: Practice patterns differ from expert opinion, with biliary dyskinesia accounting for an increasing fraction of cholecystectomies. The rise in these elective interventions is associated with a shift to a younger, low risk and predominantly privately insured population. Considering the benign nature of biliary dyskinesia, it is time to reassess the need for operative interventions, which have never been compared with active conservative therapy.

Wireless ambulatory pH studies: manometric or endoscopic guidance?

Wireless pH studies are widely used to assess the presence and severity of gastroesophageal reflux disease. We hypothesized that sedation or air insufflation during a preceding endoscopy may systematically alter results. A retrospective review of ambulatory pH studies completed between January 2008 and April 2010 was performed. The pH capsule was placed 6 cm above the endoscopically determined location of the squamocolumnar junction or 5 cm above the manometrically localized upper border of the lower esophageal sphincter (LES). A total of 356 patients (65% women) underwent pH studies using the BRAVO system (GIVEN Imaging, Yoqneam, Israel). In 186 patients (E-P), the capsule was placed during endoscopy. In 170 patients (M-P), capsule placement was based on manometric determination of LES boundaries using pharyngeal anesthesia only. Endoscopic placement was successful in all cases, whereas two patients could not tolerate capsule insertion with topical anesthesia only. The mean recording time did not differ between the two groups (E-P: 2468 ± 38 min; M-P: 2415 ± 40 min). The number of patients with abnormal findings on day 1 but normal results for day 2 was similar with 15% for E-P compared with 11% for M-P. However, there was a significant difference in total acid exposure times between days 1 and 2 for endoscopically (day 1: 7.3 ± 1.2; day 2: 4.8 ± 0.5; P < 0.01), but not manometrically based placement (day 1: 7.7 ± 0.7; day 2: 7.2 ± 0.6). There was no difference in the number of symptoms between days or groups (E-P day 1:13.4 ± 1.3; E-P day 2: 16.0 ± 1.6; M-P day 1: 14.1 ± 2.1; M-P day 2: 15.7 ± 2.0). Similarly, the symptom sensitivity index did not differ significantly between days and groups (E-P: day 1: 4.1 ± 0.5; day 2: 5.9 ± 0.8; M-P: day 5.3 ± 0.8; day 2: 5.7 ± 0.8). The majority of patients tolerate insertion of a wireless pH monitoring capsule without sedation. Unsedated placement did not negatively affect total recording times. Although endoscopy resulted in higher acid exposure on day one it did not significantly increase the overall fraction of abnormal tests. If confirmed in prospective studies, the more consistent findings and a potential to lower cost favor manometrically guided capsule placement.

An innovative sphincter preserving pull-through technique with en bloc colon and small bowel transplantation.

This report describes a new innovative pull-through technique of hindgut reconstruction with en bloc small bowel and colon transplantation in a Crohn's disease patient with irreversible intestinal failure. The approach was intersphincteric and the anastomosis was established between the allograft colon and the recipient anal verge with achievement of full nutritional autonomy and anal continence.

Deletion of P2X3 receptors blunts gastro-oesophageal sensation in mice.

Prior studies have demonstrated P2X receptor expression in the majority of nodose neurons. Immunoreactivity for P2X receptors has also been seen in putative gastric mechanoreceptors, the intraganglionic laminar endings. We therefore hypothesized that deletion of P2X3 receptors will blunt responses to gastric distension in vagal sensory neurons. Using wildtype and P2X3(-/-) mice, we examined responses to purinergic agonists in retrogradely labelled gastric sensory neurons with patch-clamp techniques. Activation of gastro-oesophageal neurons by fluid distension was studied with intracellular electrodes. Distension-evoked ATP release into the gastric lumen was determined with the luciferase assay and intake and gastric emptying of a solid meal was assessed. ATP triggered inward currents in 80% of gastric nodose neurons. In P2X3(-/-) mice, the peak current density was lower compared to controls. Ten of 14 controls but none of 30 neurons from P2X3(-/-) mice responded to alpha,beta-metATP. Gastro-oesophageal sensory neurons of P2X3(-/-) mice showed a blunted response to fluid distension of oesophagus and stomach. This difference was not explained by differences in distension-evoked ATP release, which did not differ between knockout mice and controls. Food intake during a 3-h period was lower in P2X3(-/-) mice. Gastric emptying of a solid meal was slightly faster in knockout mice after 1.5 h, but did not differ between groups at 3 h. Our data support a role of purinergic signalling in gastric vagal afferents. Considering the role of vagal input in sensations of fullness or nausea, P2X receptors may be interesting treatment targets for dyspeptic symptoms.

Luminal stimuli acutely sensitize visceromotor responses to distension of the rat stomach.

Inflammation can enhance responses to different stimuli consistent with the development of hypersensitivity. To determine whether sequentially applied stimuli interact, we determined visceromotor responses (VMR) to gastric distension, measured at baseline and 60 min after instillation of saline, glycocholic acid (GCA) or ethanol through a gastrostomy in controls and rats with gastric ulcers. In another series of experiments, chemicals were administered before and 60 min after repeated distension of the stomach. Ethanol, but not saline or GCA, increased VMR in controls with a more significant rise in rats with gastric ulcerations. GCA increased responses to gastric distension in controls, whereas GCA and ethanol enhanced responses to gastric distensions in rats with gastric ulcers. Responses to saline, GCA, or ethanol were not affected by repeated noxious distension of the stomach. Luminal stimuli can trigger visceromotor responses and sensitize gastric afferents to mechanical stimulation, thus potentially contributing to dyspeptic symptoms.

Dual mechanisms of angiotensin-induced activation of mouse sympathetic neurones.

Ang II directly activates neurones in sympathetic ganglia. Our goal was to define the electrophysiological basis of this activation. Neurones from mouse aortic-renal and coeliac ganglia were identified as either 'tonic' or 'phasic'. With injections of depolarizing currents, action potentials (APs) were abundant and sustained in tonic neurones (TNs) and scarce or absent in phasic neurones (PNs). Resting membrane potentials were equivalent in TNs (-48 +/- 2 mV, n = 18) and PNs (-48 +/- 1 mV, n = 23) while membrane resistance was significantly higher in TNs. Ang II depolarized and increased membrane resistance equally in both TNs (n = 8) and PNs (n = 8) but it induced APs only in TNs, and enhanced current-evoked APs much more markedly in TNs (P < 0.05). The AT1 receptor antagonist losartan (2 microm, n = 6) abolished all responses to Ang II, whereas the AT2 receptor blocker PD123,319 had no effect. The transient K+ current (IA), which was more than twice as large in TNs as in PNs, was significantly inhibited by Ang II in TNs only whereas the delayed sustained K+ current (IK), which was comparable in both TNs and PNs, was not inhibited. M currents were more prominent in PNs and were inhibited by Ang II. The IA channel blocker 4-aminopyridine triggered AP generation in TNs and prevented the Ang II-induced APs but not the depolarization. Blockade of M currents by oxotremorine M or linopirdine prevented the depolarizing action of Ang II. The protein kinase C (PKC) inhibitor H7 (10 microm, n = 9) also prevented the Ang II-induced inhibition of IA and the generation APs but not the depolarization nor the inhibition of M currents. Conversely, the PKC agonist phorbol 12-myristate 13-acetate mimicked the Ang II effects by triggering APs. The results indicate that Ang II may increase AP generation in sympathetic neurones by inducing a PKC-dependent inhibition of IA currents, and a PKC-independent depolarization through inhibition of M currents. The differential expression of various K+ channels and their sensitivity to phosphorylation by PKC may determine the degree of activation of sympathetic neurones and hence may influence the severity of the hypertensive response.

Basic and clinical aspects of visceral sensation: transmission in the CNS.

Pain and discomfort are the leading cause for consultative visits to gastroenterologists. Acute pain should be considered a symptom of an underlying disease, thereby serving a physiologically important function. However, many patients experience chronic pain in the absence of potentially harmful stimuli or disorders, turning pain into the primary problem rather than a symptom. Vagal and spinal afferents both contribute to the sensory component of the gut-brain axis. Current evidence suggests that they convey different elements of the complex sensory experience. Spinal afferents play a key role in the discriminatory dimension, while vagal input primarily affects the strong emotional and autonomic reactions to noxious visceral stimuli. Drugs, surgical and non-pharmacological treatments can target these pathways and provide therapeutic options for patients with chronic visceral pain syndromes.

Experimentally induced ulcers and gastric sensory-motor function in rats.

Prior studies have demonstrated that inflammation can sensitize visceral afferent neurons, contributing to the development of hyperalgesia. We hypothesized that both afferent and efferent pathways are affected, resulting in changes in motor and sensory function. Kissing ulcers (KU) were induced in the distal stomach by injecting 60% acetic acid for 45 s into a clamped area of the stomach. In controls, saline was injected into the stomach. A balloon catheter was surgically placed into the stomach, and electromyographic responses to gastric distension were recorded from the acromiotrapezius muscle at various times after ulcer induction. The accommodation reflex was assessed by slowly infusing saline into the distally occluded stomach. Gastric pressure changes in response to vagal stimulation were measured in anesthetized rats. Contractile function of circular muscle strips was examined in vitro using force-displacement transducers. KU caused gastric hypersensitivity that persisted for at least 14 days. Fluid distension of the stomach led to a rapid pressure increase in KU but not in control animals, consistent with an impaired accommodation reflex. Gastric ulcers enhanced the contractile response to vagal stimulation, whereas the effect of cholinergic stimulation on smooth muscle in vitro was not changed. These data suggest that inflammation directly alters gastric sensory and motor function. Increased activation of afferents will trigger vagovagal reflexes, thereby further changing motility and indirectly activating sensory neurons. Thus afferent and efferent pathways both contribute to the development of dyspeptic symptoms.

Increased nerve growth factor expression triggers bladder overactivity.

UNLABELLED: Prior studies have demonstrated an association between visceral inflammation, an increase in nerve growth factor (NGF) expression, and development of hyperalgesia. Because multiple mediators are released during inflammatory processes, we examined the effect of NGF alone using viral gene transfer in vivo. Replication-deficient adenoviral vectors encoding for NGF or beta-galactosidase were injected into the bladder wall. NGF levels were determined with an enzyme-linked immunoabsorbance assay. Cystometrograms were obtained 3 and 5 days after gene transfer by using a surgically implanted bladder catheter in awake male rats. Although the treatment with a control virus did not change NGF levels compared with those of naive animals, the vector encoding for NGF increased NGF protein levels in the bladder 4-fold. Histologically, no evidence of inflammation was noted. Expression of NGF led to bladder overactivity, whereas beta-galactosidase expression was without effect. These data demonstrate that a transient increase in NGF expression without associated inflammation sensitizes visceral reflex pathways, leading to bladder overactivity. Treatment strategies targeting NGF signaling might be useful in disorders involving sensitization of peripheral nerves. PERSPECTIVE: Growth factors have been implicated in the pathogenesis of inflammatory pain. This study uses gene transfer to demonstrate that NGF sensitizes afferent pathways in the absence of inflammation, making it a potentially relevant treatment target.

Gastric ulcers reduce A-type potassium currents in rat gastric sensory ganglion neurons.

Voltage-dependent potassium currents are important contributors to neuron excitability and thus also to hypersensitivity after tissue insult. We hypothesized that gastric ulcers would alter K(+) current properties in primary sensory neurons. The rat stomach was surgically exposed, and a retrograde tracer (1,1'-dioctadecyl-3,3,3,3'-tetramethylindocarbocyanine methanesulfonate) was injected into multiple sites in the stomach wall. Inflammation and ulcers were produced by 10 injections of 20% acetic acid (HAc) in the gastric wall. Saline (Sal) injections served as control. Nodose or T9-10 dorsal root ganglia (DRG) cells were harvested and cultured 7 days later to record whole cell K(+) currents. Gastric sensory neurons expressed transient and sustained outward currents. Gastric inflammation significantly decreased the A-type K(+) current density in DRG and nodose neurons (Sal vs. HAc-DRG: 82.9 +/- 7.9 vs. 46.5 +/- 6.1 pA/pF; nodose: 149.2 +/- 10.9 vs. 71.4 +/- 11.8 pA/pF), whereas the sustained current was not altered. In addition, there was a significant shift in the steady-state inactivation to more hyperpolarized potentials in nodose neurons (Sal vs. HAc: -76.3 +/- 1.0 vs. -83.6 +/- 2.2 mV) associated with an acceleration of inactivation kinetics. These data suggest that a reduction in K(+) currents contributes, in part, to increased neuron excitability that may lead to development of dyspeptic symptoms.

Arylacetamide kappa-opioid receptor agonists produce a tonic- and use-dependent block of tetrodotoxin-sensitive and -resistant sodium currents in colon sensory neurons.

We have previously reported that U50,488 [(trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]benzeneacetamide] enantiomers contribute to visceral antinociception by a nonopioid receptor-mediated blockade of sodium currents in colon sensory neurons. The present experiments were undertaken to examine the effect of arylacetamide kappa-opioid receptor agonists (kappa-ORAs) U50,488 and EMD 61,753 [(N-methyl-N-[1S)-1-phenyl)-2-(13S))-3-hydroxypyrrolidine-1-yl)-ethyl]-2,2-diphenylacetamide HCl] on tetrodotoxin-sensitive (TTX-S) and -resistant (TTX-R) sodium currents, and the mechanism of their sodium channel-blocking actions. Whole cell patch-clamp experiments were performed on colon sensory neurons from the S1 dorsal root ganglion identified by content of retrograde tracer 1.1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine metanesulfonate. The concentration-response curves of U50,488 and EMD 61,753, for tonic inhibition of total, TTX-S, and TTX-R sodium currents were similar (EC50 values for U50,488 and EMD 61,753 were 8.4 +/- 1.69 and 1.2 +/- 1.78 microM, respectively). In contrast, the peptide kappa-ORA dynorphin was without effect in these experiments. U50,488 (10 microM) shifted the voltage dependence of steady-state inactivation curves for total, TTX-S, and TTX-R currents to more negative potentials. Inhibition was present at holding potentials of -100 to -20 mV. After the tonic block elicited by 10 microM U50,488, repetitive stimulation with 5-ms depolarizing pulses at a frequency of 3 Hz further enhanced the inhibition of total, TTX-R, and TTX-S currents by 43.8 +/- 4.9, 46.2 +/- 4.9, and 40 +/- 3.2%, respectively. These results demonstrate that arylacetamide kappa-ORAs nonselectively inhibit voltage-evoked sodium currents in a manner similar to local anesthetics, by enhancing closed-state inactivation and induction of use-dependent block.

Nerve growth factor and gastric hyperalgesia in the rat.

We recently demonstrated an association between the development of hyperalgesia and an increase in nerve growth factor (NGF) during gastric inflammation. We hypothesized that block of NGF signalling will blunt injury-induced hyperalgesia. Male Sprague-Dawley rats (300-400 g) were anaesthetized, the stomach was exposed and placed in a circular clamp. Acetic acid (60%) or saline (control) was injected into this area and aspirated 45 s later, resulting in kissing ulcers. A balloon was surgically placed into the stomach and electromyographic responses to gastric distension (GD) were recorded from the acromiotrapezius muscle. Animals received a daily injection of neutralizing NGF antibody or control serum for 5 days. NGF in the stomach wall was measured with an ELISA. The severity of gastric injury was assessed macroscopically and by determination of myeloperoxidase (MPO) activity. Gastric injury enhanced the visceromotor response to GD and increased NGF content. Anti-NGF significantly blunted the development of hyperalgesia and led to a decrease in gastric wall thickness and MPO activity. Increases in NGF contribute to the development of hyperalgesia after gastric injury. This may be partly mediated by direct effects on afferent nerves and indirectly by modulatory effects on the inflammatory response.

Role of nerve growth factor in modulation of gastric afferent neurons in the rat.

Recent studies demonstrated that experimental ulcers are associated with changes in the properties of voltage-sensitive sodium currents in sensory neurons. We hypothesized that nerve growth factor (NGF) contributes to these changes. Gastric ulcers were induced by acetic acid injection into the wall of the rat stomach. NGF expression was determined by ELISA and immunohistochemically. Sensory neurons were labeled by injection of a retrograde tracer into the gastric wall. Sodium currents were recorded in gastric sensory neurons from nodose and dorsal root ganglia cultured for 24 h in the presence of NGF or a neutralizing NGF antibody, respectively. Gastric ulcer formation caused a rise in NGF concentration within the gastric wall and an increase in NGF immunoreactivity. Exposure to NGF caused a significant increase in the TTX-resistant sodium current, whereas the TTX-sensitive sodium current remained unchanged. This was associated with an acceleration of the recovery from inactivation in spinal sensory neurons. Production and release of NGF in the gastric wall may contribute to sensitization of primary afferent neurons during gastric inflammation.