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  • br Introduction br Pain is frequently the first clinical sym


    1. Introduction
    Pain is frequently the first clinical symptom of head and neck car-cinoma. Indeed, pain is the initial reason leading ∼70% of cancer pa-tients to seek professional assistance (Lam & Schmidt, 2011; Rettig & D’Souza, 2015; Schmidt, 2014). Clinically, cancer-induced facial pain can be evoked or occurs spontaneously and its intensity is characterized as moderate to severe (Lam & Schmidt, 2011; Viet & Schmidt, 2012). The current treatment protocols follow the analgesic ladder re-commendation of the World Health Organization (WHO) for cancer pain management (Mercadante & Fulfaro, 2005; Mercadante & Giarratano, 2013; Mercadante, 2010). However, studies demonstrated that a significant proportion of patients have unsatisfactory pain control and present many side effects that markedly reduce their quality of life
    (Dy et al., 2008; Foley, 2004). Thus, a better understanding of the pa-thophysiology of cancer-induced facial pain and the improvement of therapeutic strategies for pain control are clearly warranted (Lam & Schmidt, 2011; Schmidt, 2014, 2015).
    There is mounting evidence for the involvement of endothelins in A83-01 many processes related to facial cancer, including pain (McKenzie, Hinsley, Hunter, & Lambert, 2014; Pickering, Jay Gupta, Quang, Jordan, & Schmidt, 2008; Quang & Schmidt, 2010b; Russo et al., 2010). Increased serum levels of endothelin-1 (ET-1) have been detected in patients with facial cancer (Pickering, Jordan, & Schmidt, 2007), as well as in tumor-bearing animals, and these alterations have been as-sociated with tumor progression and the development of spontaneous and evoked nociception (Connelly & Schmidt, 2004; Fujita, Andoh, Saiki, & Kuraishi, 2008; Lam & Schmidt, 2011; Pickering et al., 2008;
    Corresponding author at: University of Arizona, College of Medicine, Department of Pharmacology, Tucson, AZ, USA.
    E-mail address: [email protected] (C.M. Kopruszinski). 1 Present address: University of Arizona, College of Medicine, Department of Pharmacology, Tucson, AZ, USA.
    C.M. Kopruszinski et al.
    Schmidt et al., 2007; Yan, Peng, & Huang, 2015). Moreover, preclinical studies in different cancer models have demonstrated the efficacy of endothelin receptor blockade on tumor-induced sensory changes. These studies highlight that the endothelin system is implicated in tumor-in-duced sensory changes associated with cancer A83-01 inoculation (Fujita et al., 2008; Hamamoto, Khasabov, Cain, & Simone, 2008; Quang & Schmidt, 2010a; Schmidt et al., 2007). We recently demonstrated that systemic blockade of endothelin ETA and ETB receptors abolished tumor-induced evoked and ongoing nociception in a rat model of facial carcinoma. It was also shown that systemic treatment with an en-dothelin receptor antagonist potentiated morphine-induced anti-nociception, indicating that endothelin receptor blockade may re-present an improved new treatment strategy for patients with head and neck cancer pain (Kopruszinski et al., 2018). However, the involvement of the peripheral endothelin system in evoked and ongoing nociception related to facial cancer has not yet been characterized. In light of these considerations, this study examined the contribution of peripheral en-dothelin receptors in tumor-induced facial heat hyperalgesia, increased spontaneous grooming, as well as ongoing nociception.
    2. Material and methods
    This study was conducted on male Wistar rats weighing 180–220 g. Animals were housed in a temperature-controlled room, under 12 h dark/light circadian cycle, with free access to chow and tap water. All experimental procedures were performed in accordance with the ARRIVE guidelines, with the ethical guidelines of the International Association for the Study of Pain regulations on animal welfare and the National Institutes of Health guide for the care and use of laboratory animals. The experiments were previously approved by Federal University of Parana - Institutional Committee on the Ethical Use of Animals (authorization # 645). This study used 396 rats total, 366 animals for all the behaviors experiments and 30 animals for in vivo maintenance of the tumor cells. To determine the sample size is a re-quirement of the Committee on the Ethical Use of Animals of our in-stitution before the approval of the experimental Protocols. We have determined the sample size by using the GPower 3.1 software, which, considering a significance level of 5%, estimated a minimum of 5 rats for experiments assessing thermal hyperalgesia, 11 rats for the condi-tioned place preference evaluation and 17 for the analysis of facial grooming. All efforts were made to diminish the number of animals used and their suffering along the study. r>