A 83-01 br C M Kopruszinski et al br Fig
C.M. Kopruszinski et al.
Fig. 3. Eﬀect of local administration of lidocaine, morphine and endothelin receptor antagonists on tumor-induced facial grooming. A. Tumor inoculation increased facial grooming behavior on day 6 post inoculation. Local treatment with lidocaine or morphine reduced the facial grooming in tumor-bearing rats (**p < 0.01 versus Sham-Vehicle and #p < 0.05 versus Tumor-Vehicle, n=11-14). B. Local administration of BQ-123 and BQ-788 alone or associated failed to modify tumor-induced facial grooming (*p < 0.05 and **p < 0.01 versus Sham-Vehicle, n=8-18). C. Local treatment with bosentan reduced the facial grooming in tumor-bearing rats only at the highest dose (***p < 0.001 versus Sham-Vehicle and ###p < 0.001 versus Tumor-Vehicle, n=11-22). Results are presented as mean ± S.E.M. and statistical analysis was assessed by two-way ANOVA followed by Tukey test. Archives of Oral Biology 97 (2019) 231–237
Eﬀect of local administration of lidocaine, morphine or dual ETA/ETB en-dothelin receptor antagonist bosentan on tumor-induced ongoing/tonic noci-ception. Local treatment with lidocaine, morphine or bosentan failed to induce CPP on the test day (day 6 post tumor cell inoculation), as attested by absence of significant increases in the time spent in seconds in the drug-paired chamber in a CPP paradigm, when compared to pre-conditioning (baseline) scores measures (p > 0.05 versus BL, n = 10–12). Results are presented as mean ± SEM and statistical analysis was assessed by two-way ANOVA fol-lowed by Tukey test.
Time spent in drug-paired chamber (seconds)
Group Baseline Test
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.
The contribution of local ETA and ETB receptors towards heat hy-peralgesia induced by inoculation of XC tumor A 83-01 in the paw of mice has been demonstrated by Baamonde and colleagues (Baamonde et al., 2004). Furthermore, using neuropathic and inflammatory nociception models, several studies have shown a significant eﬀect of local injection of ETA or ETB receptor antagonists in controlling heat hyperalgesia (Baamonde et al., 2004; Fattori et al., 2017; Khodorova, Montmayeur,
& Strichartz, 2009; Werner et al., 2010). More specifically in the or-ofacial region, previous reports also demonstrated the participation of peripheral ETA and ETB receptors in the development of heat hyper-algesia in a model of trigeminal neuropathic pain (Chichorro et al., 2009). Likewise, herein we demonstrated that peripheral ETA and ETB endothelin receptors also seem to be involved in tumor-induced facial heat hyperalgesia. Thus, heat hyperalgesia in conditions such as neu-ropathy and cancer appears to be mediated by peripheral ETA and ETB receptors. These findings raise another possibility for the lack of eﬃ-cacy for the selective ETA and ETB receptor antagonists in contrast to the antinociceptive eﬀect achieved with the dual ETA/ETB endothelin receptors antagonist, bosentan. In accordance to this hypothesis, it would be necessary the blockade of both endothelin receptors to in-terfere with heat hyperalgesia an spontaneous grooming associated with facial cancer. In line with this idea, the co-administration of BQ-123 with BQ788 results in a tendency to decrease the facial grooming. However, this question deserves further investigation, since most of the mechanisms related to endothelin nociceptive eﬀects are unknown. However, it has been shown that activation of ETA receptors expressed in trigeminal peripheral sensory fibers cause sensitization of TRPV1 receptors resulting in heat hyperalgesia (Plant, Zollner, Mousa, & Oksche, 2006, 2007). Likewise, ETB receptors have been shown to be expressed by non-peptidergic C fibers and satellite glia cells of the tri-geminal system, but the mechanisms underlying their hyperalgesic ef-fects are currently unknown (Brandli et al., 1996; Chichorro et al., 2009, 2010; Kitano et al., 1998).
In addition to these hypotheses, other factors related to the phar-macokinetics of BQs and bosentan, such as their distribution profile, or related to the receptor binding aﬃnity may account to the diﬀerence in eﬀectiveness, but these aspects remain to be investigated.
The inoculation of tumor cells in the facial region of rats also in-creases spontaneous facial grooming behavior, which is suggestive of spontaneous nociception in rodents (Akiyama, Carstens, & Carstens, 2010; Hidaka et al., 2011; Kopruszinski et al., 2018; Ono et al., 2009; Sago et al., 2012; Spradley, Davoodi, Carstens, & Carstens, 2012). In-terestingly, there are preclinical and clinical indicatives of the im-portance of endothelin-1 for the promotion and maintenance of spon-taneous nociception (Gokin et al., 2001; Hans, Schmidt, & Strichartz,