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  • Introduction It has been well stablished the role of CRF

    2021-07-21

    Introduction It has been well stablished the role of CRF in somatic pain regulation (Yarushkina et al., 2011, Yarushkina et al., 2016). However, the effects of CRF in pain relief are controversial and it has been described anti- and pronociceptive effects (Ji et al., 1995, Larauche et al., 2009, Nijsen et al., 2005). CRF action is mediated through CRF receptors of type 1 and 2 (CRF1 and CRF2) distributed in central and peripheral nervous system (Perrin and Vale, 1999, Stengel and Taché, 2009). CRF1 and CRF2 receptors located within the amygdala are involved in somatic pain regulation and may mediate opposite effects (Rouwette et al., 2012). Pronociceptive effect of intra-amygdala CRF administration has been shown to be mediated by CRF1 receptors, while the antinociceptive effect of CRF is mediated by CRF2 receptors (Ji and Neugebauer, 2008, Rouwette et al., 2012). Brain CRF administration enhances colorectal distension-induced visceral pain in rats through CRF1 receptors (Martinez and Taché, 2006). In KPT-335 with this result, it has been demonstrated that intra-dorsal periaqueductal gray matter (PAGM) administration of CRF1 receptor antagonist NBI 27914 prevents CRF-induced analgesic effect on tonic pain induced by formalin injection, suggesting the involvement of CRF1 receptors in the analgesia. However, PAGM administration of the CRF2 receptor antagonist antisauvagine 30 did not influence in the analgesic effect (Miguel and Nunes-de-Souza, 2011). There is evidence that peripheral injection of CRF induces visceral hypersensitivity to colorectal distention, an effect reproduced by the intraperitoneal administration of the selective CRF1 agonist, cortagine in rats and mice (Larauche et al., 2009). Pretreatment with Astressin, a nonselective CRF antagonism, blocked this CRF-induced sensitization, but Astressin 2-B, a selective CRF2 antagonist did not affect it suggesting that peripheral CRF1 signaling induced visceral sensitization were modulated by peripheral CRF2 signaling (Nozu et al., 2014). On the other hand, CRF is a major mediator of the endocrine arm of the stress response by centrally stimulating the hypothalamic-pituitary-adrenal (HPA) axis. Briefly the hypothalamus releases CRF, which binds to CRF1 receptors localized on corticotroph cells in the anterior pituitary, then induces the secretion of adrenocorticotropin hormone (ACTH) which stimulates glucocorticoid secretion from the adrenal glands; glucocorticoid is a tonic anti-inflammatory mediator (Lightman, 2008). In the inflammatory processes the role of CRF and its receptors also remain controversial; some reports showed pro-inflammatory effects while some others indicated anti-inflammatory effects (for review see Im, 2015, Zhu et al., 2011). The local application of CRF in the brain and spinal cord has been shown to produce antinociceptive effects against inflammatory pain, and this action may be mediated by CRF receptors (Mousa et al., 2004). Thus, intracerebral injections of CRF inhibited stress-induced aggravation of trinitrobenzene-colitis, while central injection of the CRF1 and CRF2-antagonist, Astressin worsened colitis (Million et al., 1999). Taken together these results indicate that CRF can exert both pro-and anti-inflammatory functions depending on the type of receptors, the tissues, the route of administration and the disease phases. Therefore, it would be of interest to determine the possible implication of CRF/CRF1 receptor in the modulation of pain. In this study we have used a mouse model of post-incisional pain that closely mimics the surgical procedure in humans in order to evaluate the role of CRF/CRF1 receptors in the pro-nociceptive and inflammatory response to injury (incision), using genetically engineered mice lacking functional CRF1 receptor. In addition, phenotypic nociceptive behavior responses were evaluated in healthy B6,129CRHtklee wild type (WT) and CRF1 receptor known (KO) mice, using chemical and thermal nociceptive stimuli. Swiss CD1 was used as reference strain.