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  • Previous studies from our laboratory in CD mice using

    2021-07-21

    Previous studies from our laboratory in CD1 mice using the incisional postoperative pain model have shown that the incision induces significant mechanical postoperative hyperalgesia lasting between 7 and 10days, with peak effect between 4h-2days (Cabañero et al., 2009a, Cabañero et al., 2009b, Campillo et al., 2010, Célérier et al., 2006). The present study confirms previous data obtained in CD1 mice and also demonstrate the development of hyperalgesia in B6,129CRHtklee mice (WT and KO), similar to that described in CD1 mice, at 4h after surgery and on postoperative day 2. According to previous data (Campillo et al., 2010), the pain hypersensitivity disappeared in CD1 mice, as demonstrated by the return of the mechanical threshold to the baseline values on postoperative day 20. However, present results demonstrate, for the first time, that postoperative mechanical hyperalgesia was significantly prolonged in mice with B6,129CRHtklee Tryptone indicating significant differences between strains of mice. The prolongation of hyperalgesia observed in B6,129CRHtklee mice could be due to a sustained and prolonged activity of the pro-nociceptive system. Previous studies from our laboratory using CD1 mice, have demonstrated that surgery plus remifentanil anaesthesia produces long lasting neuroplastic changes that could be involved in develop latent pain sensitization (Campillo et al., 2011). This long-lasting pain vulnerability was demonstrated in our study by the precipitated hyperalgesia induced after naloxone in CD1 and also in B6, 129CRHtklee (WT and KO) mice. This response has been explained by an increase in endogenous opioid peptides and/or increased signaling activity at the opioid receptor (Célèrier et al., 2001, Corder et al., 2013). According to a previous study (Campillo et al., 2011) hyperalgesia was observed after opioid antagonist administration 21days after surgery in CD1 mice suggesting that latent sensitization is mediated by endogenous opioid system. These results provide further evidence of opioid-mediated latent sensitization and suggest that impairment of the protective endogenous opioid system may play a relevant role in the development of persistent post-surgical pain. In accordance with recent finding in animal studies it has been demonstrated persistent postsurgical pain in humans (Werner and Bischoff, 2014) and patent sensitization mediated by opioid system (Pereira et al., 2015). According to these data the long-term therapeutic goal of future research is to alleviate persistent pain by either: a) facilitating endogenous opioid analgesia, thus restricting latent pain sensitization within a state of remission; or b) extinguishing or suppress latent sensitization (Taylor and Corder, 2014). In order to contribute to the development of new therapeutic our goal has been to investigate the role of CRF/CRF1 receptor in the latent pain sensitization. Our results demonstrated similar mechanical hyperalgesia in WT or KO mice after saline injection. However, the hyperalgesia observed in KO mice after naloxone administration was higher than that observed in WT and CD1 mice suggesting that the opioid antagonist reveals a potential interaction between opioid and CRF/CRF1 receptor pathways in long lasting pain sensitization. Conversely, a role for CRF-induced antinociception has been suggested on the basis of anatomical studies that found co-localization of CRF and dynorphin terminal within central nervous system (Marchant et al., 2007, Kravets et al., 2013, Retson and Van Bockstaele, 2013). Multiple studies have shown increased thresholds to nociceptive behaviors in nonstressed animals after exogenous administration of CRF activating CRF1 receptor, such as: increased mechanical and thermal withdrawal thresholds in Fischer and Lewis rats (Vit et al., 2006). These finding were confirmed by showing that CRF1 receptor antagonists such as NBI-27914, MPZP or R121919 exert antinociceptive effect to mechanical stimulation in a model of arthritis pain and attenuated mechanical hypersensitivity in the acute dependence model (Baiamonte et al., 2014, Cohen et al., 2013, Edawards et al., 2012, Ji et al., 2013, Park et al., 2015). However, it has been clear that CRF may cause a decrease in somatic pain sensitivity (analgesic effect) in animals (Lariviere and Melzack, 2000, Vit et al., 2006) and human (Likar et al., 2007, Mattered et al., 2005). Thus, the CRF1 receptor antagonists NBI-35965 fails to attenuate swim-induced hyperalgesia in Swiss mice (Abdelhamid et al., 2013). These discrepancies could be due to the different models used. There are substantial differences between post-incisional and other models such as inflammatory and neuropathic pain (Biddlestone et al., 2007, Honore et al., 2006). In addition, it is well documented that CRF1 and CRF2 receptors located within the amygdala are involved in somatic pain regulation in rats (Rouwette et al., 2012, Yarushkina et al., 2016). In this regard, it has been proposed that initial activation of CRF1 receptor produces a clear hyperalgesia that it necessary to protect the organism against further tissue damage. Simultaneously, activation of CRF1 receptor results in transport of CRF2 receptor toward the plasma membrane where it will bind CRF2 receptor ligands such as the urocortins released in the central nervous system. This second phase of CRF receptor activation produces an analgesic effect important for the termination of pain (Rouwette et al., 2012). This concept implicates that balanced and proper sequential recruitment of CRF receptors is crucial for successful management of the pain response. Consequently, the deletion of CRF1 receptor could produce an imbalance in this process could result in an enhanced of the hyperalgesia observed after naloxone in our study.