B. Greenwood-Van Meerveld

Hyperexcitability of convergent colon and bladder dorsal root ganglion neurons after colonic inflammation: mechanism for pelvic organ cross‐talk

Abstract  Clinical studies reveal concomitant occurrence of several gastrointestinal and urologic disorders, including irritable bowel syndrome and interstitial cystitis. The purpose of this study was to determine the mechanisms underlying cross‐organ sensitization at the level of dorsal root ganglion (DRG) after acute and subsided gastrointestinal inflammation. DiI (1,1′‐dioctadecyl‐3,3,3′,3′‐tetramethylindocarbocyanine perchlorate) and Fast Blue were injected into the distal colon and urinary bladder of male rats, respectively. Convergent DRG neurons were found in L1‐L3 and L6‐S2 ganglia with an average distribution of 14% ± 2%. The resting membrane potential (RMP) of cells isolated from upper lumbar (UL) ganglia was −59.8 ± 2.7 mV, whereas lumbosacral (LS) neurons were more depolarized (RMP = −49.4 ± 2.1 mV, P ≤ 0.05) under control conditions. Acute trinitrobenzene sulfonic acid (TNBS) colitis (3 days) decreased voltage and current thresholds for action potential firing in LS but not UL convergent capsaicin‐sensitive neurons. This effect persisted for 30 days in the absence of overt colonic inflammation. The current threshold for action potential (AP) firing in UL cells was also decreased from 165.0 ± 24.5 pA (control) to 85.0 ± 19.1 pA at 30 days (P ≤ 0.05), indicating increased excitability. The presence of a subpopulation of colon‐bladder convergent DRG neurons and their persistent hyperexcitability after colonic inflammation provides a basis for pelvic organ cross‐sensitization.

Corticotropin‐releasing factor 1 receptor‐mediated mechanisms inhibit colonic hypersensitivity in rats

Abstract  The potential relationship between stress and irritable bowel syndrome (IBS) symptomatology suggests a possible role for stress‐mediating hormones, such as corticotropin‐releasing factor (CRF), in the altered perception of stimuli in IBS patients. In previous studies, Wistar–Kyoto (WKY) rats with genetic indices of high anxiety demonstrated colonic hypersensitivity coupled with a high basal level of CRF within the central nervous system. In the current study we tested the hypothesis that a selective, non‐peptide CRF1 receptor antagonist, antalarmin, would inhibit hypersensitivity in the WKY rat colon. Colonic sensitivity was determined by monitoring a visceromotor behavioural response during innocuous levels of colorectal distention (30 mmHg). In high anxiety WKY rats we found that antalarmin (20 mg kg−1, i.p.) significantly decreased the visceromotor response induced by colorectal distention. In a second study central administration (i.c.v.) of CRF was used to induce colonic hypersensitivity in lower anxiety Fischer 344 (F‐344) rats, and in this model, antalarmin significantly inhibited the CRF‐induced colonic hypersensitivity. In summary, a selective CRF1 receptor antagonist, antalarmin, inhibits colonic hypersensitivity apparent in WKY rats or in F‐344 rats given a central administration of CRF. Our findings suggest that CRF1 receptor antagonism may represent a novel therapeutic approach for the treatment of IBS.

Preclinical studies of opioids and opioid antagonists on gastrointestinal function

Opioid receptors in the gastrointestinal (GI) tract mediate the effects of endogenous opioid peptides and exogenously administered opioid analgesics, on a variety of physiological functions associated with motility, secretion and visceral pain. The studies reviewed or reported here describe a range of in vivo activities of opioid receptor antagonists upon GI function in rodents, focusing on µ receptors. Naloxone, and the peripherally acting µ‐opioid receptor antagonists alvimopan and methylnaltrexone, reverse morphine‐induced inhibition of GI transit in mice and rats, and morphine‐ or loperamide‐induced inhibition of castor oil‐induced diarrhoea in mice. At doses producing maximal reversal of morphine‐induced effects upon GI transit, only the central nervous system (CNS) penetrant antagonist naloxone was able to reverse morphine‐induced analgesia. Both central and peripheral opioid antagonists may affect GI function and/or visceromotor sensitivity in the absence of exogenous opioid analgesics, suggesting a constitutive role for endogenous opioid peptides in the control of GI physiology. Furthermore, in contrast to naloxone, alvimopan does not produce hypersensitivity to the visceromotor response induced by nociceptive levels of colorectal distension in a rodent model of postinflammatory colonic hypersensitivity, suggesting that in the periphery endogenous μ‐opioid receptor‐mediated mechanisms do not regulate colonic sensitivity. The data support the hypothesis that peripherally acting opioid antagonists may be able to selectively block opioid receptors in the GI tract, thereby preserving normal GI physiology, while not blocking the effects of endogenous opioid peptides or exogenous opioid analgesics in the CNS. These findings suggest that the primary sites of action of µ‐opioid agonists with respect to inhibition of GI function are in the periphery, whereas analgesic activity resides primarily in the CNS.

Long-term colonic hypersensitivity in adult rats induced by neonatal unpredictable vs predictable shock

Abstract  Our goal was to examine the relationship between early life trauma and the development of visceral hypersensitivity in later life in irritable bowel syndrome (IBS). Rat pups underwent neonatal conditioning: (i) paired odour‐shock, where odour is a predictable shock signal, (ii) unpaired odour‐shock, where odour is an unpredictable shock signal or (iii) control odour‐only with odour presentations and handling without shock. At maturity, colorectal sensitivity was measured as a visceromotor behavioural response. In adulthood, colorectal distension (CRD) induced a pressure‐dependent increase in the number of abdominal muscle contractions all three experimental groups. However, compared to animals that had received control odour‐only presentations in infancy, there was an attenuated response to CRD in animals previously exposed to neonatal predictable shock pups and an exaggerated response in the animals previously exposed to neonatal unpredictable shock. Adult responses to CRD were altered by infant experience with shock trauma. However, depending on the context of that early life trauma, there are major differences between the long‐term effects of that early life trauma on colonic sensitivity compared to controls. These results strengthen the link between early life trauma and adult IBS, and suggest that unpredictable trauma is a critical factor for later life disorders.

Activation of peripheral 5-HT4 receptors attenuates colonic sensitivity to intraluminal distension

Abstract  Tegaserod is a 5‐HT4 receptor partial agonist approved for the treatment of irritable bowel syndrome in women with constipation and in both men and women with chronic constipation. The efficacy of tegaserod is based on the importance of 5‐HT4 receptors regulating intestinal peristalsis and secretion, and possibly visceral sensory pathways. Our aim was to investigate the effect of tegaserod on colorectal sensitivity using models of normal and exaggerated responsiveness to colorectal distension (CRD). The visceromotor responses (VMR) to CRD at graded pressures (0–60 mmHg) were measured by the number of reflex abdominal contractions. Acute colorectal hypersensitivity was induced by intracolonic infusion of dilute acetic acid. Chronic hypersensitivity was observed in rats following spontaneous resolution of trinitrobenzenesulfonic acid‐induced colitis. Rats with normosensitive colons served as controls. Tegaserod (0.1–10 mg kg−1) caused dose‐dependent reduction of the VMR to CRD in control rats and in those with colonic hypersensitivity. 5‐HT4 antagonists reversed the effects of tegaserod in rats with normosensitive colons, and partially inhibited effects in rats with colonic hypersensitivity. Central administration of tegaserod had no inhibitory effect. These results support the assumption that colonic hypersensitivity could be normalized by tegaserod acting, at least in part, through peripheral 5‐HT4 receptors.

Corticotropin‐releasing factor receptor 1‐deficient mice show decreased anxiety and colonic sensitivity

Abstract  Corticotropin releasing factor (CRF) is an important mediator in the stress response. Previous studies in rodent models demonstrated that stress‐induced colonic hypersensitivity was inhibited by CRF1 receptor antagonism. As CRF1R‐deficient mice have an impaired stress response our goal was to further explore the importance of CRF1R in the development of colonic hypersensitivity. Using conscious CRF1R (+/+), CRF1R (+/−) and CRF1R (−/−) mice colonic sensitivity was assessed via a visceromotor behavioural response (VMR) induced by colorectal distension (CRD, 0–60 mmHg). In the CRF1R (+/+) mice there was a pressure‐dependent increase in the VMR to CRD that was moderately attenuated in the CRF1R (+/−) mice. However in the CRF1R (−/−) mice a VMR to CRD was only observed at the highest distension pressure (60 mmHg). A CRF1R antagonist, NBI 30775 (30 mg kg−1 i.p.) significantly decreased the VMR to CRD in CRF1R +/+ mice. An identical inhibitory effect of NBI 30775 was observed in 43% of the CRF1R +/− mice. This study provides pharmacological and genetic evidence for the importance of CRF1R in colonic sensitivity and suggests a link between stress and visceral perception.

Importance of 5-hydroxytryptamine receptors on intestinal afferents in the regulation of visceral sensitivity

Abstract  Serotonin (5‐HT) plays an important role as a signalling molecule in the gastrointestinal (GI) tract. The regulation of GI sensitivity via 5‐HT is mediated by specific 5‐HT receptor subytypes on intrinsic and extrinsic afferents. This review discusses visceral afferent hypersensitivity in irritable bowel syndrome (IBS) and the importance of 5HT3, 5HT4, and 5HT2B receptor‐mediated mechanisms in the regulation of visceral sensitivity.

Importance of Stress Receptor-Mediated Mechanisms in the Amygdala on Visceral Pain Perception in an Intrinsically Anxious Rat

Background  Stress worsens abdominal pain experienced by patients with irritable bowel syndrome (IBS), a chronic disorder of unknown origin with comorbid anxiety. Previously, we have demonstrated colonic hypersensitivity in Wistar–Kyoto rats (WKYs), a high‐anxiety strain, which models abdominal pain in IBS. In low‐anxiety rats, we have demonstrated that the central nucleus of the amygdala (CeA) regulates colonic hypersensitivity and anxiety induced by selective activation of either glucocorticoid receptors (GR) or mineralocorticoid receptors (MR), which is also mediated by the corticotropin releasing factor (CRF) Type‐1 receptor. The goal of the present study was to test the hypothesis that the CeA through GR, MR, and/or CRF‐1R regulates colonic hypersensitivity in WKYs.

Gender specific effects of neonatal limited nesting on viscerosomatic sensitivity and anxiety‐like behavior in adult rats

Evidence exists to suggest that early life stress (ELS), such as neglect or abuse has profound effects on the developing brain. The current study tests the hypothesis that ELS in the form of neonatal limited nesting (LN) may serve as a predisposing factor for the development of altered nociceptive processing and comorbid increases in anxiety‐like behavior in adulthood.

Enteroendocrine cells: a review of their role in brain–gut communication

Specialized endoderm‐derived epithelial cells, that is, enteroendocrine cells (EECs), are widely distributed throughout the gastrointestinal (GI) tract. Enteroendocrine cells form the largest endocrine organ in the body and play a key role in the control of GI secretion and motility, the regulation of food intake, postprandial glucose levels and metabolism. EECs sense luminal content and release signaling molecules that can enter the circulation to act as classic hormones on distant targets, act locally on neighboring cells and on distinct neuronal pathways including enteric and extrinsic neurons. Recent studies have shed light on EEC sensory transmission by showing direct connections between EECs and the nervous system via axon‐like processes that form a well‐defined neuroepithelial circuits through which EECs can directly communicate with the neurons innervating the GI tract to initiate appropriate functional responses.