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Discussion On the other hand, surgical patients have to some extent stress during pre- and/or post-operative period. It is well known that CRF/CRF1 receptor is involved in the activation of HPA during acute and chronic stress (Papadimitriou and Priftis, 2009, Zelena et al., 2005). CRF/CRF1 receptor stimulates ACTH and glucocorticoid release, which could be responsible of the analgesia describe in visceral and somatic pain models in response to potent and/or long-lasting stressors (Butler and Finn, 2009, Gui et al., 2004, Koolhaas et al., 2011, Larauche et al., 2012). In mice with CRF1 receptor gene Necrosulfonamide (KO) we have demonstrated an increased response in visceral pain without changes in somatic pain. These data are in agreement with a recent study demonstrating that mild social stress in mice, can induced analgesia in visceral but not in somatic pain models (Pitcher et al., 2017). The deletion of CRF1 receptor could cause long-lasting deficiency of stress-induced production of the CRF, ACTH and corticosterone. Thus, previous studies have demonstrated that the inhibition of CRF-induced corticosterone levels was accompanied by a disappearance of CRF-induced analgesia (Yarushkina et al., 2011). Together, these results and present data could indicate that the decreased activity of the HPA axis could be involved in surgery-induced latent pain sensitization observed in KO mice. In this study we also demonstrated that basal values of plasma extravasation obtained before surgery were lower in B6,129CRHtklee WT and KO mice versus CD1 mice demonstrating differences between strains. In addition, the plasma extravasation was increased two days after surgery in CD1 and B6,129CRHtklee KO confirming that inflammation together with nociceptive sensitization are the hallmarks of tissue surrounding surgical incisions. In addition, postsurgical plasma extravasation was higher in B6,129CRHtklee KO mice suggesting a relationship between CRF1 receptors and inflammation. It is known that multiple brain areas, inhibitory neurons within the dorsal horn of the spinal cord as well as immune cells that co-express CRF receptors and opioid peptides (Mousa et al., 2007). In addition, it is known that some inflammatory mediators produce proopiomelanocortin and proenkephalin under inflammatory conditions (Chadzinska et al., 2001, Mousa et al., 2004, Rittner and Brack, 2007) and during these conditions there is an increased expression of opioid receptors in peripheral neurons (Ballet et al., 2003, Ji et al., 1995). Moreover, it has been demonstrated that CRF or stress induced the release of opioid peptides in inflamed tissues (Labuz et al., 2009, Machelska, 2003, Stein and Fuller, 1990). Taken together these results suggest that a selective stimulation of immune cells by CRF led to opioid peptide-mediated activation of opioid receptors to participate in an intense localized inflammatory response. However, the exact mechanisms by which the CRF family and its receptors are involved in the pathophysiological processes of inflammation is not well known. Our study clearly demonstrated that the deletion of CRF1 receptor increase the inflammatory response after surgery incision suggesting that the CRF/CRF1 receptor could be implicated in the inflammatory response to tissue injury. In this regard, CRF reduced the nociceptive response induced by formalin injection into the hid paw in mice while NBI 2714, a selective CRF1 antagonist, completely blocked the antinociceptive effect of CRF; antisauvagine 30, a CRF2 receptor antagonist, did not alter the CRF effects (Miguel and Nunes-de-Souza, 2011). However, previous data have demonstrated that NBI 27914 and CP-154,526, selective CRF1 receptor antagonist, were effective at alleviating acute inflammatory hyperalgesia induced by carrageenan in rats (Hummel et al., 2010). These discrepancies suggest a need for further studies with different animal models of pain to better understand the role of CRF1 receptor in the neurobiology of pain modulation.