Neonatal maternal separation alters stress-induced responses to viscerosomatic nociceptive stimuli in rat. Am J Physiol Gastrointest Liver Physiol 282: G307-G316, 2002. First published October 3, 2001 10.1152/ajpgi.00240.2001.-This study investigated the combined effect of neonatal maternal separation and acute psychological stress on pain responses in adult rats. Long-Evans dams and their male pups were reared under two conditions: 1) 180 min daily maternal separation (MS180) on postnatal days 2-14 or 2) no handling or separation (NH). At 2 mo of age, visceromotor responses to graded intensities of phasic colorectal distension (10-80 mmHg) at baseline as well as following acute 60 min water avoidance stress (WA) were significantly higher in MS180 rats. Both groups showed similar stress-induced visceral hyperalgesia in the presence of naloxone (20 mg/kg ip). MS180 rats had smaller stress-induced cutaneous analgesia in the tail-flick test compared with NH rats, with a residual naloxone-resistant component. MS180 rats showed an enhanced fecal pellet output following WA or exposure to a novel environment. These data suggest that early life events predispose adult Long-Evans rats to develop visceral hyperalgesia, reduced somatic analgesia, and increased colonic motility in response to an acute psychological stressor, mimicking the cardinal features of irritable bowel syndrome. irritable bowel syndrome; stress; analgesia; naloxone IRRITABLE BOWEL SYNDROME (IBS) is a disorder characterized by chronic abdominal pain and discomfort associated with alterations in bowel habits in the absence of a demonstrable pathology (67). Although IBS is likely a heterogeneous disorder in terms of etiology and pathophysiology, alterations in bowel habits are likely related to alterations in autonomic regulation of the gut, whereas symptoms of abdominal pain and discomfort are thought to involve additional changes in the perception of visceral events, in the form of visceral hyperalgesia or allodynia (46, 48). Additionally, in IBS patients without a concurrent diagnosis of fibromyalgia, visceral hypersensitivity is associated with a normal or diminished somatic pain sensitivity to noxious stimuli (13).Progress in the development of more effective therapies has been hampered due to the lack of animal models that mimic the key features of IBS, in particular the enhanced perception of visceral events. Many investigations have utilized acute inflammatory insults to the gut using agents such as glycerol, mustard oil, acetic acid, or zymosan to produce acute visceral hypersensitivity, thereby mimicking inflammatory bowel disorders. However, IBS is a chronic disorder characterized by the absence of inflammatory changes in the gut mucosa. More recently, several potential IBS models have been reported, all of which mimic certain aspects of the human syndrome (2, 15, 62, 72). They include an early life colon irritation model (2), an adult stress sensitization model (62), and an adult postinfection model in the rat (15) and in the mouse (72). Alt...

Gastrointestinal-specific anxiety seems to be an important factor for GI symptom severity and QOL in patients with IBS.

Background and aims: Activation of corticotropin releasing factor 1 (CRF 1 ) receptors is involved in stress related responses and visceral pain, while activation of CRF 2 receptors dampens the endocrine and some behavioural stress responses. We hypothesised that CRF 2 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 CRF 2 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 CRF 2 agonist, human urocortin 2 (hUcn 2, at 10 and 20 mg/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 CRF 2 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 mg, intraarterially). The CRF 2 receptor antagonist, astressin 2 -B (200 mg/kg subcutaneously or 20 mg intraarterially) 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 CRF 2 receptor activation in rats.

In the current study, colorectal distension (CRD) was performed in conscious mice, in order to study visceral (colon) sensitivity. Electrodes were chronically implanted into the external oblique muscle to obtain the electromyographic (EMG) response to CRD. CRD was performed using a computerized system, which inflated the balloon with air to the desired pressures. An increasing (10-80 mmHg) and a repeated (12 x 55 mmHg) phasic paradigm with distensions lasting 10 s and with 5-min intervals were used. The EMG recordings were linearly correlated to intracolonic pressures between 10 and 80 mmHg, which are characteristic of the visceromotor response (VMR). Repeated phasic distensions at 55 mmHg resulted in a stable VMR in female mice, but an increasing VMR in male mice. Interestingly, the duration of the VMR was about 5 s, which is shorter than the actual duration of the distension. U-69593 and fentanyl (selective kappa and mu opioid receptor agonists) significantly reduced the VMR at subcutaneous doses of 0.5 and 0.05 mg x kg-1, respectively. In conclusion, a CRD model for repetitive quantitative studies of colorectal sensitivity and evaluation of pharmacological modulation of visceral sensitivity in conscious mice is presented.

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. METHODS This study addressed potential confounders found in previous imaging studies by collecting functional magnetic resonance imaging studies (fMRI) data during a single slow ramp-tonic distension paradigm and analysing fMRI signal changes using independent component analysis. KEY RESULTS Compared with controls, IBS participants showed increased activation of the anterior cingulate cortices, insula and ventral medial prefrontal regions suggesting heightened affective responses to painful visceral stimuli. In addition, the failure by IBS patients to down-regulate activity within ventral medial prefrontal and the posterior cingulate/precuneus regions was suggestive of reduced sensitivity to somatic changes and delayed shifts away from rest in ;default network' activity patterns. Controls showed heightened activation of the thalamus, striatal regions and dorsolateral prefrontal cortex suggesting greater arousal and salience-driven sustained attention reactions and greater modulation of affective responses to discomfort and pain. CONCLUSION&INFERENCES This work points to alterations in the central response to visceral pain and discomfort in IBS, highlighting diminished modulation and heightened internalization of affective reactions.