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C.M. Kopruszinski et al.
2009; Pickering et al., 2007, 2008; Smith, Haymond, Smith, & Sweitzer, 2014). In addition, preclinical studies using diﬀerent cancer models reported elevated endothelin levels in animals that demonstrate evoked hypersensitivity or signs of spontaneous nociception, highlighting the contribution of endothelin receptors to the development of these as-pects of cancer pain (Awano, Dawson, Hunter, Turner, & Usmani, 2006; Kandalaft, Facciabene, Buckanovich, & Coukos, 2009; Mankapure, Barpande, Bhavthankar, & Mandale, 2015; McKenzie et al., 2014; Pickering et al., 2008; Schmidt et al., 2007). In line with these ob-servations, our group has shown that systemic treatments with bo-sentan and morphine markedly reduced the incidence of spontaneous grooming associated with the facial tumor (Kopruszinski et al., 2018). The present study evidenced the eﬀectiveness of local bosentan treat-ment in controlling tumor-induced increased spontaneous grooming. Thus, processing of spontaneous pain-like behavior appears to be mediated by peripheral (local) ETA and ETB receptors.
In order to further explore the role of peripheral endothelins on spontaneous nociception, we also evaluated the eﬀect of local treatment with bosentan, lidocaine and morphine in tumor-induced ongoing no-ciception, through the induction of conditioned place preference (CPP). Our data failed to reveal the occurrence of CPP induction in tumor-bearing rats after local treatments. On the other hand, previous studies have already revealed the eﬃcacy of systemic treatment with bosentan (Kopruszinski et al., 2018) and morphine (Kopruszinski et al., 2018; Remeniuk et al., 2015) in controlling tumor-induced ongoing nocicep-tion, observed by significant CPP for the drug-paired chamber. We speculate that the tumor-induced increased spontaneous grooming might represent a phasic pain component of spontaneous nociception, whereas tumor-induced ongoing pain may constitute a tonic component of spontaneous nociception. These diﬀerent components of pain also indicate distinct mechanisms. The results of the current study might suggest that the Dexmedetomidine of peripheral sensitization by locally injected drugs is not suﬃcient to control tumor-induced ongoing nociception, which require additional central mechanisms. Corroborating this hy-pothesis, some authors suggested that the mechanism related to the relief of ongoing nociception in the CPP test is through the activation of the corticolimbic system (Navratilova, Xie, King, & Porreca, 2013; Porreca & Navratilova, 2017). Moreover, Sago et al. (2012) suggested the existence of a microglia-dependent activation pathway for the de-velopment of ongoing nociception induced by the tumor (Sago et al., 2012). Additionally, preclinical studies demonstrate that some tumors can promote nerve sprouting and neuronal reorganization, which seems to contribute directly to the emergence and maintenance of changes related to ongoing nociception (Jimenez Andrade & Mantyh, 2010; Mantyh, Clohisy, Koltzenburg, & Hunt, 2002, 2010).
Altogether, the results of this study demonstrate that peripheral blockade of both ETA and ETB receptors reduces tumor-induced facial heat hyperalgesia and increased spontaneous grooming, without mod-ifying ongoing nociception. It is possible to suggest that bosentan is acting upon both receptors present in primary sensory aﬀerents, or is causing the blockade of ETA, and mainly ETB receptors, present in tumor cells, promoting the blockade of endothelin-1 release from these cells, which in both cases will prevent peripheral nociceptor sensitiza-tion (Barr, Kam, Khodorova, Montmayeur, & Strichartz, 2011; Khodorova et al., 2009; Schmidt, Hamamoto, Simone, & Wilcox, 2010; Schmidt, 2014; Smith et al., 2014).
The current findings contribute to the knowledge of the pathophy-siology of cancer-induced facial pain and may facilitate the clinical exploration of the benefits of endothelin receptor blockade as a useful adjuvant strategy for facial cancer pain management.
This study was supported by National Council for Scientific and Technological Development (CNPq), grant #477679/2012-9. The first author received PhD. scholarship by Coordination for the Improvement Archives of Oral Biology 97 (2019) 231–237
of Higher Education Personnel (CAPES) during the study development.
Conflict of interest
The authors declare no conflicts of interest.
The group is grateful to CNPq and CAPES for their funding support. We thank Dr. Sandra Coccuzzo Sampaio (Butantan Institute, Sao Paulo, Brazil) for kindly donating the Walker-256B tumor cells. We also thank Dr. Alexandra Acco, M.Sc. Eder Gambeta and M.Sc. Larissa Galuppo for technical support.
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