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  • EP receptor is known to


    EP4 receptor is known to mediate the protective effect of PGE2 on the respiratory, gastrointestinal and glomerular epithelial lining (Aoudjit et al, 2006, Kabashima et al, 2002, Schmidt et al, 2011). In this study, the expression of asEP4 in the gills was limited to the epithelial lining suggesting that the EP4 receptor may mediate a similar protective role. In contrast, the expression in the pyloric caeca was limited to the intraepithelial leukocytes and no expression was detected in the epithelium. Our results are in agreement with the finding of Hult et al. who found that the expression of EP4 protein in human intestine is limited to the lamina propria and the intestinal crypts (Hult et al., 2011). In humans and mice, different patterns of expression are seen across the gastrointestinal tract (Lejeune et al, 2010, Morimoto et al, 1997). Hence, the presence of EP4 in other parts of the gastrointestinal tract in Atlantic salmon should be further investigated. The expression of EP4 receptor in the skin has previously been investigated in mice (Lee et al, 2005, Tober et al, 2007). While it is well established that the EP4 receptor can be detected by RT-PCR (Lee et al, 2005, Rundhaug et al, 2011), contradictory findings have been reported regarding the expression of EP4 proteins by immunohistochemistry. One study reported that EP4 is undetectable (Lee et al., 2005) while another one showed that it can be detected in skin epidermal keratinocytes and dermal leukocytes (Tober et al., 2007). In the current study, asEP4 expression was detected in Atlantic salmon skin both by RT-PCR and immunohistochemistry. The expression of asEP4 proteins was found to be exclusive to the E7080 in the examined fish but with different levels and patterns. The reason behind different levels and patterns of expression observed remains unclear. It was reported previously that the expression of EP4 receptor in the colon and other EP receptors in the skin become more intense and diffused when it is inflamed or upon exposure to chronic radiation respectively (Lee et al, 2005, Lejeune et al, 2010). Since intense and diffuse staining of some mitotic figures and lymphocytes in some areas in skins were present, one possible explanation is that the different patterns of expression observed are due to some ongoing E7080 inflammatory process although normal physiological differences cannot be excluded.
    Acknowledgement This research was funded by the Research Council of Norway, SFI-Sea Lice Research Centre, grant number 203513.
    Introduction Sensitization of nociceptive dorsal root ganglion (DRG) neurons plays an essential role in the development of pathological pain state. Sensitized neurons lower the activation threshold to both noxious and innocuous stimuli, thus contributing to the generation of hyperalgesia and allodynia, respectively. Various pro-inflammatory mediators released from inflammatory cells in injured tissues enable to excite nerve endings of nociceptive DRG neurons (nociceptors) to induce peripheral sensitization. Prostaglandin E2 (PGE2), a well-characterized pain mediator in damaged or inflamed tissue, is known to sensitize nociceptors through its four EP receptors (EP1–4) expressed in DRG neurons (Oida et al., 1995, Lin et al., 2006, Ma et al., 2010). PGE2 directly excites nociceptors by increasing membrane Ca++ currents (Gold et al., 1996b) and tetrodotoxin-resistant voltage-gated Na+ currents (Gold et al., 1996a, Rush and Waxman, 2004). It also potentiates sensitizing effects exerted by other pain mediators such as ATP, bradykinin and capsaicin (Vanegas and Schaible, 2001, Moriyama et al., 2005, Wang et al., 2007, Zhang et al., 2008). Moreover, PGE2 directly stimulates the release of pain-related peptides substance P (SP) and calcitonin gene-related peptide (CGRP) from nociceptors (Hingtgen et al., 1995, Vasko, 1995) and indirectly potentiates the release of SP and CGRP evoked by other pain mediators (Vasko et al., 1994). EP4 receptor subtype was shown to be involved in PGE2-induced peptide release (Southall and Vasko, 2001). In addition to the sensitizing nociceptors at the functional levels, PGE2 was shown by us and others to stimulate the synthesis of SP, CGRP (Ma and Eisenach, 2003, Ma, 2010, Ma et al., 2010), Nav1.8 channel (Villarreal et al., 2005), interleukin-6 (IL-6) (St-Jacques and Ma, 2011) and brain-derived neurotrophic factor (BDNF) (Cruz Duarte et al., 2012) in DRG neurons at both gene and protein levels during inflammatory and neuropathic pain. These data indicate that PGE2 is central for the establishment of the network of pain mediators. And EP4 receptor plays a pivotal role in mediating these effects of PGE2 (Ma, 2010, St-Jacques and Ma, 2011, Cruz Duarte et al., 2012, Villarreal et al., 2013).