Alfred Bayati

CRF2 receptor activation prevents colorectal distension induced visceral pain and spinal ERK1/2 phosphorylation in rats

Background and aims: Activation of corticotropin releasing factor 1 (CRF1) receptors is involved in stress related responses and visceral pain, while activation of CRF2 receptors dampens the endocrine and some behavioural stress responses. We hypothesised that CRF2 receptor activation may influence visceral pain induced by colorectal distension (CRD) in conscious rats, and assessed the possible sites and mechanisms of action. Methods: Male Sprague-Dawley rats were exposed to CRDs (60 mm Hg, 10 minutes twice, with a 10 minute rest interval). Visceromotor responses (VMR) were measured by electromyography or visual observation. Spinal (L6–S1) extracellular signal regulated kinase 1/2 (ERK 1/2) activation following in vivo CRD and CRF2 receptor gene expression in the T13–S1 dorsal root ganglia (DRG) and spinal cord were determined. Inferior splanchnic afferent (ISA) activity to CRD (0.4 ml, 20 seconds) was assessed by electrophysiological recording in an in vitro ISA nerve-inferior mesenteric artery (intra-arterial)-colorectal preparation. Results: In controls, VMR to the second CRD was mean 31 (SEM 4)% higher than that of the first (p<0.05). The selective CRF2 agonist, human urocortin 2 (hUcn 2, at 10 and 20 μg/kg), injected intravenous after the first distension, prevented sensitisation and reduced the second response by 8 (1)% and 30 (5)% (p<0.05) compared with the first response, respectively. RT-PCR detected CRF2 receptor gene expression in the DRG and spinal cord. CRD (60 mm Hg for 10 minutes) induced phosphorylation of ERK 1/2 in neurones of lumbosacral laminae I and IIo and the response was dampened by intravenous hUcn 2. CRD, in vitro, induced robust ISA spike activity that was dose dependently blunted by hUcn 2 (1–3 μg, intra-arterially). The CRF2 receptor antagonist, astressin2-B (200 μg/kg subcutaneously or 20 μg intra-arterially) blocked the hUcn 2 inhibitory effects in vivo and in vitro. Conclusions: Peripheral injection of hUcn 2 blunts CRD induced visceral pain, colonic afferent, and spinal L6-S1 ERK 1/2 activity through CRF2 receptor activation in rats.

Gastrointestinal-specific anxiety : an important factor for severity of GI symptoms and quality of life in IBS

Background  Gastrointestinal (GI)‐specific anxiety (GSA) has been proposed to influence symptom severity and quality of life (QOL) in patients with irritable bowel syndrome (IBS). The Visceral Sensitivity Index (VSI) is a recently developed, reliable and valid measure of GSA. Our aim was to evaluate the association between GSA, GI symptom severity, and QOL in IBS patients.

Vagal dysfunction in irritable bowel syndrome assessed by rectal distension and baroreceptor sensitivity

Abstract  Autonomic nervous system dysfunction has been implicated in the pathophysiology of irritable bowel syndrome (IBS). This study characterized the autonomic response to rectal distension in IBS using baroreceptor sensitivity (BRS), a measure of autonomic function. Rectal bag pressure, discomfort, pain, ECG, blood pressure and BRS were continuously measured before, during and after rectal distension in 98 healthy volunteers (34 ± 12 years old, 52 females) and 39 IBS patients (39 ± 11 years old, 35 females). In comparison with the healthy volunteers, IBS patients experienced significantly more discomfort (69 ± 2.2% vs 56 ± 3.6%; P < 0.05), but not pain (9 ± 1.4% vs 6 ± 2.4%; ns) with rectal distension despite similar distension pressures (51 ± 1.4 vs 54 ± 2.4 mmHg; ns) and volumes (394 ± 10.9 vs 398 ± 21.5 mL; ns). With rectal distension, heart rate increased in both healthy volunteers (66 ± 1 to 71 ± 1 bpm; P < 0.05) and IBS patients (66 ± 2 to 74 ± 3 bpm; P < 0.05). Systolic blood pressure also increased in both healthy volunteers (121 ± 2 to 143 ± 2 mmHg; P < 0.05) and patients (126 ± 3 to 153 ± 4 mmHg (P < 0.05) as did diastolic blood pressure, 66 ± 2 to 80 ± 2 mmHg (P < 0.05), compared with 68 ± 3 to 84 ± 3 mmHg (P < 0.05) in IBS patients. The systolic blood pressure increase observed in IBS patients was greater than that seen in healthy volunteers and remained elevated in the post distension period (139 ± 3 mmHg vs 129 ± 2 mmHg; P < 0.05). IBS patients had lower BRS (7.85 ± 0.4 ms mmHg−1) compared with healthy volunteers (9.4 ± 0.3; P < 0.05) at rest and throughout rectal distension. Greater systolic blood pressure response to rectal distension and associated diminished BRS suggests a compromise of the autonomic nervous system in IBS patients.

Heightened central affective response to visceral sensations of pain and discomfort in IBS

Background  Typically, conventional functional imaging methods involve repeated exposures to sensory stimulation. In rectal distension (RD) studies that involve multiple distensions, however, it is difficult to disambiguate the central response to RD from pathological alterations in peripheral neural responses associated with relaxation and accommodation of the rectum.

Rapid initial gastric emptying and hypersensitivity to gastric filling in functional dyspepsia: effects of duodenal lipids.

Objective. Impaired distension-induced gastric accommodation and hypersensitivity to distension have been demonstrated by gastric barostat in patients with functional dyspepsia (FD). In this study we investigated distension-induced responses to gastric filling with water in healthy volunteers and FD patients, using non-invasive ultrasonography. Material and methods. Eighteen healthy volunteers and 18 FD patients were given infusions of 10 ml saline or lipid (3 kcal/ml) through a nasoduodenal tube. After tube retraction, the stomach was filled with 1000 ml water during 10 min. Intragastric volume was monitored by 3D ultrasonography, and fullness, pain and nausea were assessed. Results. Compared with healthy volunteers, patients with FD had faster gastric emptying at 5 min (p=0.0008) and reported more fullness (p=0.006) during gastric filling with water. Prior duodenal lipid exposure reduced initial gastric emptying rate in FD patients to the level seen in healthy volunteers. However, despite similar gastric volumes, the patients still reported greater fullness (p=0.002) and nausea (p=0.01). Conclusions. Patients with FD had abnormally rapid initial gastric emptying of water and hypersensitivity to gastric filling. Though normalizing gastric emptying rate and volumes, duodenal lipid exposure did not improve hypersensitivity. Rapid initial gastric emptying of water might be a sign of impaired distension-induced gastric accommodation.

Peripheral injection of sauvagine prevents repeated colorectal distension-induced visceral pain in female rats.

We investigated the effects of peripheral injection of sauvagine, a CRF2>CRF1 receptor (corticotropin-releasing factor) agonist compared with CRF, on two sets of tonic colorectal distension (CRDs 30, 40, 50 mmHg, 3-min on/off)-induced visceromotor response (VMR) measured as area under the curve (AUC) of abdominal muscle contraction in conscious female rats. Sauvagine (10 or 20 microg/kg, s.c.) abolished the 226.7+/-64.3% and 90.4+/-38.1% increase in AUC to the 2nd CRD compared with the 1st CRD (performed 30 min before) in female Fisher and Sprague-Dawley (SD) rats, respectively. CRF had no effect while the CRF1 antagonist, antalarmin (20 mg/kg, s.c.), alone or with sauvagine, blocked the enhanced response to the 2nd CRD, performed 60 min after the 1st CRD, and reduced further the AUC by 33.5+/-23.3% and 63.5+/-7.2%, respectively in Fisher rats. These data suggest that peripheral CRF2 receptor activation exerts antinociceptive effects on CRD-induced visceral pain, whereas CRF1 contributes to visceral sensitization.

Wistar Kyoto rats have impaired gastric accommodation compared to Sprague Dawley rats due to increased gastric vagal cholinergic tone

Objective. Gastric balloon distension shows that, in comparison with Sprague Dawley (SD) rats, Wistar Kyoto (WKY) rats have a decreased volume response owing to a lower accommodation rate. The aim of this study was to compare the role of the vagal cholinergic and nitrergic pathways in the accommodation reflex in these rat strains. Material and methods. The volume response to ramp-tonic gastric balloon distension was pharmacologically manipulated by using L-NAME 25 mg/kg i.v., molsidomine 20 mg/kg i.p., atropine 1 mg/kg i.v. and clonidine 0.7 mg/kg s.c. Results. Following L-NAME, the maximal volume response to distension was significantly decreased in WKY rats (0.74±0.11 ml versus 1.18±0.13 ml) whereas only a tendency to such a decrease was seen in SD rats. The NO donor molsidomine significantly increased the volume in SD rats (4.91±0.46 ml versus 1.81±0.50 ml) but only weakly in WKY rats. Atropine significantly increased the gastric volume in WKY rats (2.78±0.29 ml versus 1.00±0.17 ml) but not in SD rats. Clonidine increased the accommodation rate in the WKY rat, resulting in increased maximal volume (1.69±0.26 ml versus 0.65±0.11 ml) indicating a reduction in acetylcholine release as a consequence of stimulated presynaptic adrenergic receptors on cholinergic neurons. Conclusions. The results indicate that WKY rats may have an increased gastric vagal cholinergic drive, which, during distension, masks the relaxing effect of NO-releasing neurons. The findings in WKY rats could be of relevance for functional dyspeptic patients with impaired gastric accommodation to meals.

Involvement of κ-opioid receptors in visceral nociception in mice

Abstract  It has been shown that the behavioural responses to chemically evoked visceral nociception are increased in transgenic mice lacking the κ‐opioid receptor (KOR). The aim of the present study was to evaluate the contribution of KOR in mechanically evoked visceral pain by performing colorectal distension (CRD) and monitoring the subsequent visceromotor response (VMR) in control mice (KOR+/+) and in mice lacking KOR (KOR−/−). Pseudo‐affective visceral pain responses were evoked in conscious mice using increasing (10–80 mmHg) and repeated (12 × 55 mmHg) phasic CRD paradigms. The resulting VMR was determined by monitoring the electromyographic activity of the abdominal muscle. The increasing and repeated CRD paradigms, respectively, evoked similar responses in both KOR+/+ and KOR−/− mice. The selective KOR‐agonists U‐69593 (5 and 25 mg kg−1, s.c.) and asimadoline (25 mg kg−1, s.c.) significantly decreased the VMR in KOR+/+ mice, while having no effect in KOR−/− mice. In contrast, the selective μ‐opioid receptor agonist fentanyl significantly reduced the VMR in both types of mice and appeared more efficacious in KOR−/− mice. The opioid receptor antagonist naloxone (0.3–30 mg kg−1 s.c.) did not affect the response to CRD in C57BL/6 mice at any dose tested. In conclusion, the data confirm that the KOR agonists used in this study inhibit the VMR to CRD in mice by acting via KOR receptors. In addition, the data suggest that the endogenous opioid system is not likely to modulate the VMR to mechanically evoked visceral pain in mice.

Pressure-induced gastric accommodation studied with a new distension paradigm. Abnormally low accommodation rate in patients with functional dyspepsia.

Objective. A new distension paradigm, by which the gastric volume response to ramp-tonic distension can be analysed in detail, has been developed. The aim of this study was to investigate the applicability of this new paradigm in man, and to compare pressure-induced gastric accommodation in healthy volunteers (HV) and patients with functional dyspepsia (FD). Material and methods. Ten HV, and 11 FD patients were examined twice; once in the fasting state and once postprandially. Intragastric bag pressure was raised from 1 to 12 mmHg in 4 min (ramp phase) and then kept constant for 5 min (tonic phase). Results. Compared to HV, fasting FD patients had lower gastric accommodation rates (0.9±0.2 versus 2.5±0.4 ml/s, p=0.002), lower maximum volume (239±39 versus 428±64 ml, p=0.01) and a longer accommodation time (157±26 versus 92±15 s, p=0.03). A test meal prior to distension tended to normalize the response in FD patients. Conclusions. This new barostat paradigm allowed detailed analysis of short-term pressure-induced accommodation in man. Impaired gastric distension-induced accommodation is a novel abnormality in FD.

Altered neuroendocrine response and gastric dysmotility in the Flinders Sensitive Line rat

Abstract  In the search for animal models that can replicate some features of functional dyspepsia (FD) patients, we turned our interest to the Flinders Sensitive Line (FSL) rat. Gastric motility disturbances prevalent in FD patients as well as urine corticosterone and plasma prolactin were measured following buspirone challenge. Flinders Resistant Line (FRL) rat was used as control. The results show that the FSL rats have a disturbed gastric motility, reflected as both an increased gastric accommodation rate and gastric volume during gastric distension as well as a delayed gastric emptying, the latter possibly as a consequence of the former. Lipid administration resulted in a significant increase in maximal gastric volume only in the FRL rats. Both the corticosterone response to buspirone and the 24‐h urinary output of corticosterone were normal in FSL rats. Similar to FD patients, the FSL rat showed supersensitivity to buspirone in the increase in prolactin release. Although FSL rats show some features similar to a subset of FD patients, the increased gastric accommodation contrasts to the reduced accommodation often seen in FD patients. Further studies are warranted to determine the relevance of this rat strain as a model for FD.