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  • Gefitinib hydrochloride Although differences in several noci


    Although, differences in several nociceptive tests have previously been described across strains (Mogil et al., 1999), it is the first time that pain sensitivity in response to chemical and thermal stimuli has been evaluated in B6,129CRHtklee mice. Our results showed no differences in pain sensitivity to chemical (visceral pain) and thermal stimuli (somatic pain) between CD1 and B6,129CRHtklee mice in the behavioral tests. In the current behavioral experiments, we showed that KO mice presented more number of writhes than WT and CD1 mice. However, there is no difference between KO and WT or CD1 mice in tail immersion test. The different results obtained in chemical and thermal stimulus could be due to the different mechanisms involved in these tests. Acetic Gefitinib hydrochloride is a widely used for the evaluation of peripheral antinociceptive activity and pain is generated indirectly via endogenous mediators, such as bradykinin, serotonin, histamine, substance P, and PGs, especially PGI2 as well as pro-inflammatory cytokines such as IL-1, IL-6, IL-8 and TNF-α, stimulating the peripheral nociceptor and sensitive neurons that were responsive to the inflammatory mediators (Le Bars et al., 2001). Whereas, tail flick used to evaluate central pain, is proposed to be mediated in large part by spinal mechanisms (Carsten, 2009). Our results suggesting that CRF1 receptor could not be implicated in the central pain induced by thermal stimulus are in agree with previous results demonstrating that CRF produces not effect on thermal nociception (tail flick assay) (Ayesta and Nikolarakis, 1989, Poree et al., 1989, Song and Takemori, 1991) and they are consistent with the failure of CRF overexpression to influence thermal hyperalgesia (van Gaalen et al., 2002). On the other hand, the deletion of CRF1 gen induces higher responses to inflammatory irritant modality, suggesting a role of CRF/CRF1 receptor in the inflammatory processes. In contrast to our data recently report demonstrated, in a rat visceral pain model, that subcutaneous injection of E2508, a selective CRF1 receptor antagonist, significantly decreased the number of abdominal muscle contractions induced by colonic distension, suggesting that this drug reduced visceral pain (Taguchi et al., 2017). In addition, CRF1 antagonist, CP-376395 to dampen the visceral hypersensitivity to colorectal distension in the wistar kyoto rats strain. (Su et al., 2014). However previous studies (Miguel and Nunes-de-Souza, 2011, Miguel et al., 2012) using a chemical stimulus (formalin test) demonstrated that NBI 27914 blocks the antinociceptive effects of CRF in Swiss mice. Altogether these data clearly indicate that the exact mechanisms by which the CRF and CRF1 receptor are involved in the pathophysiological processes of pain is not well known.
    Conflict of interest statement
    Acknowledgments This research was supported by grants from the Ministerio de Ciencia e Innovación (Grants SAF/FEDER 2010-17907; 2013-49076-P). Endowed Chair in Pain Management Universitat Autònoma de Barcelona, Parc de Salut MarMenarini, Barcelona, Sapin.
    Introduction Corticotropin-releasing factor (CRF) is a hypothalamic neurohormone, but also an extrahypothalamic neurotransmitter, that regulates the neuroendocrine, autonomic and behavioral stress reponses (Bale et al., 2002, Bale and Vale, 2004, Vale et al., 1981). The actions of CRF are mediated by two distinct G protein-coupled receptors, CRF receptor type 1 (CRF1) and CRF receptor type 2 (CRF2) (Chang et al., 1993, Lovenberg et al., 1995). CRF1 is expressed abundantly in the central nervous system (CNS), including the cerebral cortex, cerebellum and striatum (Van Pett et al., 2000). CRF2 is expressed predominantly in the periphery, and limited centrally to subcortical regions, such as the hypothalamus, hippocampus and amygdala (Van Pett et al., 2000). Originally, it was suggested that CRF1 and CRF2 mediate antagonistic effects in the CNS, since stimulation of CRF1 provoked activation of the HPA axis, anxiety and depression, and increase of locomotor activity (at least in a familial environment), whereas stimulation of CRF2 evoked anxiolytic and antidepressant effects, and decrease of locomotor activity (Bale et al., 2002, Bale and Vale, 2004, Vale et al., 1981). Recently, it was demonstrated that the role of CRF receptors in the stress responses is not a matter of simple dualism, but it depends upon the brain regions and neuron populations being activated (Henckens et al., 2016, Janssen and Kozicz, 2013).