Role of spinal cord glia in the central processing of peripheral pain perception.

BACKGROUND: The discovery that glial activation plays a critical role in the modulation of neuronal functions and affects the spinal processing of nociceptive signalling has brought new understanding on the mechanisms underlying central sensitization involved in chronic pain facilitation. Spinal glial activation is now considered an important component in the development and maintenance of allodynia and hyperalgesia in various models of chronic pain, including neuropathic pain and pain associated with peripheral inflammation. In addition, spinal glial activation is also involved in some forms of visceral hyperalgesia. PURPOSE: We discuss the signalling pathways engaged in central glial activation, including stress pathways, and the neuron-glia bidirectional relationships involved in the modulation of synaptic activity and pain facilitation. In this expanding field of research, the characterization of the mechanisms by which glia affect spinal neuro-transmission will increase our understanding of central pain facilitation, and has the potential for the development of new therapeutic agents for common chronic pain conditions.

Guanylate cyclase C-mediated antinociceptive effects of linaclotide in rodent models of visceral pain.

BACKGROUND Linaclotide is a novel, orally administered investigational drug currently in clinical development for the treatment of constipation-predominant irritable bowel syndrome (IBS-C) and chronic idiopathic constipation. Visceral hyperalgesia is a major pathophysiological mechanism in IBS-C. Therefore, we investigated the anti-nociceptive properties of linaclotide in rodent models of inflammatory and non-inflammatory visceral pain and determined whether these pharmacological effects are linked to the activation of guanylate cyclase C (GC-C). METHODS Orally administered linaclotide was evaluated in non-inflammatory acute partial restraint stress (PRS) and acute water avoidance stress (WAS) models in Wistar rats, and in a trinitrobenzene sulfonic acid (TNBS)-induced inflammatory model in Wistar rats and GC-C null mice. KEY RESULTS In TNBS-induced colonic allodynia, linaclotide significantly decreased the number of abdominal contractions in response to colorectal distension without affecting the colonic wall elasticity change in response to distending pressures after TNBS. However, linaclotide had no effect on visceral sensitivity under basal conditions. In addition, linaclotide significantly decreased colonic hypersensitivity in the PRS and WAS models. In wild type (wt) and GC-C null mice, the instillation of TNBS induced similar hyperalgesia and allodynia. However, in post-inflammatory conditions linaclotide significantly reduced hypersensitivity only in wt mice, but not in GC-C null mice. CONCLUSIONS & INFERENCES These findings indicate that linaclotide has potent anti-nociceptive effects in several mechanistically different rodent models of visceral hypersensitivity and that these pharmacological properties of linaclotide are exerted through the activation of the GC-C receptor. Therefore, linaclotide may be capable of decreasing abdominal pain in patients suffering from IBS-C.

PAR4: a new role in the modulation of visceral nociception.

Protease-activated receptors (PARs) are a family of G-protein-coupled receptors with a widespread distribution that are involved in various physiological functions including inflammation and nociception. In a recent study in Neurogastroenterology and Motility, Augé et al. describe for the first time the presence of PAR4 on visceral primary afferent neurons and its role in modulating colonic nociceptive responses, colonic hypersensitivity and primary afferent responses to PAR2 and Transient Receptor Potential Vanilloid-4 (TRPV4). Using the model of visceromotor response (VMR) to colorectal distension (CRD), they show that a PAR4 agonist delivered into the colon lumen decreases basal visceral response to CRD and reduces the exacerbated VMR to CRD induced by treatment with PAR2 or TRPV4 agonists. In isolated sensory neurons, they show that a PAR4 agonist inhibits calcium mobilization induced by PAR2 or TRPV4 agonists. Finally, they describe increased pain behaviour evoked by luminal application of mustard oil in PAR4 deficient mice compared to wild type controls. The newly discovered role of PAR4 in modulating visceral pain adds to our growing understanding of the contribution of colonic proteases and PARs to the mechanisms involved in colonic hypersensitivity and their potential role as therapeutic targets for irritable bowel syndrome.

Functional GI disorders: from animal models to drug development.

Despite considerable efforts by academic researchers and by the pharmaceutical industry, the development of novel pharmacological treatments for irritable bowel syndrome (IBS) and other functional gastrointestinal (GI) disorders has been slow and disappointing. The traditional approach to identifying and evaluating novel drugs for these symptom-based syndromes has relied on a fairly standard algorithm using animal models, experimental medicine models and clinical trials. In the current article, the empirical basis for this process is reviewed, focusing on the utility of the assessment of visceral hypersensitivity and GI transit, in both animals and humans, as well as the predictive validity of preclinical and clinical models of IBS for identifying successful treatments for IBS symptoms and IBS-related quality of life impairment. A review of published evidence suggests that abdominal pain, defecation-related symptoms (urgency, straining) and psychological factors all contribute to overall symptom severity and to health-related quality of life. Correlations between readouts obtained in preclinical and clinical models and respective symptoms are small, and the ability to predict drug effectiveness for specific as well as for global IBS symptoms is limited. One possible drug development algorithm is proposed which focuses on pharmacological imaging approaches in both preclinical and clinical models, with decreased emphasis on evaluating compounds in symptom-related animal models, and more rapid screening of promising candidate compounds in man.

Review article: modulation of the brain-gut axis as a therapeutic approach in gastrointestinal disease.

BACKGROUND: The importance of bi-directional brain-gut interactions in gastrointestinal illness is increasingly being recognized, most prominently in the area of functional gastrointestinal disorders. Numerous current and emerging therapies aimed at normalizing brain-gut interactions are a focus of interest, particularly for irritable bowel syndrome and functional dyspepsia. METHODS: A literature search was completed for preclinical and clinical studies related to central modulation of gastrointestinal functions and published in English between 1980 and 2006. RESULTS: Existing data, while sparse, support the use of different classes of antidepressant drugs, including tricyclics, and selective and non-selective serotonin reuptake inhibitors in irritable bowel syndrome. Serotonin receptor agonists and antagonists with peripheral and possibly central effects are effective in treating specific subtypes of irritable bowel syndrome. Based largely on theoretical and preclinical evidence, several novel compounds that selectively target receptors at multiple levels within the brain-gut axis such as neurokinin, somatostatin and corticotropin-releasing factor receptor antagonists are promising. CONCLUSIONS: This review discusses the rationale for modulation of the brain-gut axis in the treatment of functional gastrointestinal disorders and highlights the most promising current and future therapeutic strategies.

The pathophysiology of irritable bowel syndrome.

Recent studies have provided evidence to suggest a possible role for mucosal immune activation in the pathophysiology of irritable bowel syndrome (IBS). On the other hand, novel findings using functional brain-imaging techniques support the concept that altered perception of visceral stimuli plays a key role in IBS symptom generation. These seemingly contradictory findings have revived the discussion about the relative contribution of peripheral versus central mechanisms in the symptom generation of IBS. In this review, we will provide evidence for the hypothesis that, in the absence of changes in visceral perception and alterations in endogenous pain modulation systems, chronic inflammatory mucosal changes in the gut are not a plausible mechanism to explain the presence of chronic abdominal pain, a clinical hallmark of IBS.

Acute and chronic stress differently affect visceral sensitivity to rectal distension in female rats.

Stressful life events are frequently associated with outward signs of irritable bowel syndrome (IBS). Increasing evidence suggests that acute and chronic stress stimuli implicate different physiological mechanisms and neuroendocrine responses. Therefore, we investigated the influence of acute and chronic stress on visceral nociception in female rats and the involvement of colonic mast cells in this effect. The effect of acute and chronic partial restraint stress (PRS) on visceral sensitivity to rectal distension (RD) was assessed by abdominal muscle electromyography. Colonic mast cell activation was determined by measuring histamine release after in vitro stimulation with substance P (SP) in colonic samples from rats experiencing RD vs. controls. Acute PRS significantly enhanced abdominal response to RD compared with sham PRS for all volumes of distension. In contrast, chronic PRS induced a hyperalgesic response for the highest volumes of distension (0.8 and 1.2 mL), but did not affect the number of abdominal contractions for the lowest volume (0.4 mL) compared with controls. Both acute and chronic PRS increased in vitro SP-induced histamine release without affecting mast cell numbers. RD induced similar in vitro histamine release from colonic samples from both acute and chronic PRS rats; this release, however, was significantly higher than that measured in sham-PRS rats. Acute and chronic PRS differently influence visceral sensitivity in response to RD in female rats. This difference, however, cannot be attributed to a different effect of either stress paradigm on mast cell histamine release.

Acute restraint stress activates functional NK1 receptor in the colon of female rats: involvement of steroids.

BACKGROUND AND AIMS: Psychological factors have been implicated in the aetiology of irritable bowel syndrome characterised by intestinal altered motility and visceral hypersensitivity. Similar disorders have been found in rats under stressful conditions. The role of tachykinins in bowel dysfunctions caused by stress is not fully documented. Therefore, we investigated the influence of stress on NK1 receptor activation at the colonic level in female rats. METHODS: The stress procedure used consisted of two hours of partial restraint. Histamine release was measured from colonic samples of control and stressed animals and the effect of SR140333, a NK1 receptor antagonist, on substance P induced histamine release was determined. Involvement of steroids has been evaluated in this response. RESULTS: NK1 receptor antagonist was found to inhibit substance P induced histamine release in samples from stressed female rats but not in samples from control animals. Previous treatment of female rats with RU 486 abolished this effect observed in stressed animals. Similarly, in samples from stressed female rats previously ovariectomised, SR140333 failed to inhibit substance P induced histamine release but previous treatment with both progesterone and oestrogen restored its effect. CONCLUSIONS: Stress induces NK1 receptor activation in the colon, and ovarian steroids are involved in this response.

Effect of ovarian hormones on intestinal mast cell reactivity to substance P.

Evidence exists to support the concept that ovarian hormones influence mast cell functioning and related events. Here, we evaluated the constitutive gender difference and the influence of ovarian status on rat mast cell (MC) distribution in jejunum and colon, histamine synthesis and/or its release elicited by Substance P (SP). Higher mast cell (MC) number and histamine release were found in female compared with male. In female rats, hormonal status did not affect the density of resident MC neither in the jejunum nor in the colon. Interestingly, histamine levels released after SP stimulation of jejunal segment was reduced in ovariectomized (OVX) compared with sham OVX rats, and restored in OVX female receiving progesterone. In the colon, OVX resulted in a significant increase in histamine levels released after SP stimulation and a treatment with progesterone did not restore basal histamine levels. Thus, ovarian steroid hormones do not affect jejunal and colonic mast cell number. However, the hormonal status differently influences jejunal and colonic MC sensitivity to SP.