The conventional medical therapy for IBD

The conventional medical therapy for IBD consists in reducing the inflammatory response using various strategies that exert severe side-effects, a strategy that also decreases the risk of colon carcinoma [13], [14]. During the last decade, the activation of the cholinergic system has been proposed for the treatment of IBD patients according to its potential anti-inflammatory effect on immune cells [15], [16], [17], [18]. This effect is mediated by the release of 2825 (Ach), which activates the α7 nicotinic Ach receptor (α7nAchR) expressed in macrophages [19]. However Ach is also the ligand of the prototypical muscarinic receptor (mAchR), which is expressed together with α7nAchR on epithelial cells. Colon epithelial cells express mAchR subtypes 1 and 3. M3 mAchR, which is expressed in cancer cells [20], [21] is considered as a strong intestinal tumor promoter [22]. Previously, we found that Ach-induced activation of mAchR results in the modulation of cell adhesion properties correlating with the acquisition of invasive potential, whereas activation of α7nAchR exerts a protective role on epithelium integrity [23]. Using different in vivo models, Raufman et al., showed that M3 mAchR gene ablation decreases both colon tumor number, size and the degree of dysplasia [24], [25]. It has also been proposed that psychological stress-induced barrier dysfunction is dependent on the release of Ach by enteric nerves following CRF activation [26], [27].
Materials and methods
Results
Discussion Emerging evidence suggests that mAchR and ligands participate in regulating cellular proliferation and cancer progression, in particular in colon cancer (for review [48]). These effects have been sometimes attributed to mAchR-induced transactivation of EGF receptors. The main finding presented here is that Ach-mediated activation of mAchR can regulate CRF2 signaling. The latter occurs through the synthesis and release of Ucn3. Activation of these two GPRC converges on common Src/Erk/FAK and RhoA signaling pathways that result in the remodeling of cell adhesion complexes and actin cytoskeleton that stimulates cell migration and a protease dependent-mode of invasion. The proposed scheme for muscarinic and CRF receptors crosstalk is presented in Fig. 8.
Competing interests
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Acknowledgements The authors would like to thank Ms. Rebecca Powel for her careful language assistance. This work was supported by grants from Association pour la Recherche sur le Cancer, Ligue Nationale contre le Cancer, GEFLUC and ESPOIR. M. Pelissier-Rota was the recipient of a fellowship from the Ministère de la Recherche et de l\'Enseignement Supérieur.
Introduction Human and animal models demonstrate that stress can induce hyperalgesia (Imbe et al., 2006). In rats, the stress of a cold forced swim enhances thermal nociception measured using the hot plate assay (Quintero et al., 2000; Suarez-Roca et al., 2006a, 2006b), chemical nociception measured using the formalin test (Imbe et al., 2010; Quintero et al., 2011, 2003; Suarez-Roca et al., 2008), and musculoskeletal nociception measured using the grip force assay (Okamoto et al., 2012; Suarez-Roca et al., 2006a). Consistent with this, cold swim also increases neuronal activity in the spinal cord as indicated by increases in c-Fos (Quintero et al., 2003; Suarez-Roca et al., 2008). The mechanism(s) that produce acute stress-induced hyperalgesia remain unclear and must be elucidated if we are to eventually understand the even more important influence of chronic stress on musculoskeletal pain. A variety of models to induce stress or anxiety have been previously examined. One potential contributor to anxiety-induced hyperalgesia is cholecystokinin (CCK) which works in a pro-nociceptive fashion by inhibiting a descending antinociceptive pathway involving the periaqueductal gray (PAG) (reviewed by Lovick (2008)). GABA activity in the spinal cord appears to be essential for novelty stress-induced hyperalgesia (Vidal and Jacob, 1986) whereas noradrenaline is essential to acute anxiety-induced hyperalgesia (Jorum, 1988). Forced swim-induced hyperalgesia in rats lasts up to 9 days and is postulated to result from activity in the rostral ventromedial medulla (RVM) (Imbe et al., 2010), or decreased release of GABA in the spinal cord resulting in increased N-methyl-d-aspartate (NMDA) activity in the cord (Quintero et al., 2011). In addition to these events, one may reasonably posit that stress influences pain by the release of stress hormones. Consistent with this, corticotropin-releasing factor (CRF), the primary mediator of mammalian neuroendocrine stress responses, and its analogs, urocortin I, II and III, are not only distributed along the hypothalamic–pituitary–adrenal (HPA) axis, but also in pain-relevant sites in the central nervous system (CNS) (Fekete and Zorrilla, 2007; Korosi et al., 2007; Lariviere and Melzack, 2000). Together the CRF1 and CRF2 receptors have been found to shape behavioral and neurochemical responses to stress and frequently have opposite effects (reviewed by Coste et al. (2001) and Reul and Holsboer (2002)). CRF influences nociception (reviewed by Lariviere and Melzack (2000)), presumably by interacting with CRF receptors. Another model of hyperalgesia has demonstrated that an increase in footshock-induced urinary bladder hypersensitivity was attenuated by a CRF2 receptor antagonist at the spinal level in rats (Robbins and Ness, 2008). Thus, it would be of interest to determine whether these receptors also contribute to the stress-induced modulation of musculoskeletal nociception.