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  • Introduction Pain is frequently the


    Introduction Pain is frequently the first clinical symptom of head and neck carcinoma. Indeed, pain is the initial reason leading ∼70% of cancer patients 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 recommendation 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 pathophysiology 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 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 associated 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; 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-induced sensory changes associated with cancer CGP 53353 receptor 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 endothelin receptor antagonist potentiated morphine-induced antinociception, indicating that endothelin receptor blockade may represent 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 endothelin receptors in tumor-induced facial heat hyperalgesia, increased spontaneous grooming, as well as ongoing nociception.
    Material and methods
    Discussion This study showed the ability of peripheral blockade of both ETA and ETB endothelin receptors in controlling the facial heat hyperalgesia and increased facial grooming behavior in a model of facial cancer in rats. On the other hand, the current data demonstrate that peripheral dual blockade of both ETA and ETB receptors failed to modify tumor-induced ongoing facial nociception. These data suggest that peripheral ETA and ETB receptors mediate responses related to evoked nociception and increased grooming induced by facial cancer. We recently demonstrated that systemic treatment with the dual endothelin ETA and ETB receptor antagonist bosentan abolished tumor-induced heat hyperalgesia, increased spontaneous grooming and ongoing nociception in the same facial cancer model used in the present study (Kopruszinski et al., 2018). However, the contribution of peripheral endothelins was not investigated. Herein, it was shown that local treatment with bosentan blocked facial heat hyperalgesia and increased facial grooming in tumor-bearing rats. This effectiveness was similar to that promoted by local treatment with morphine and lidocaine, used as control drugs in this study. On the other hand, local treatments with the peptidic endothelin receptors antagonists BQ-123 and BQ-788, alone or in association, were unable to reduce the facial heat hyperalgesia or increased facial grooming of tumor-bearing rats. This ineffectiveness might be a result of increased synthesis and release of proteases by the tumor cells, resulting in the hydrolysis, and consequently, the degradation of the BQ molecules prior to receptor binding (Hardt, Lam, Dolan, & Schmidt, 2011; Schmidt, 2014). Thus, these data suggest that local both receptors contribute to the development of facial heat hyperalgesia associated to facial cancer and that dual endothelin receptor blockade with a non-peptidic drug was effective to control tumor-induced heat hyperalgesia.