Department of Pharmacology, Biological Sciences Section, Federal University of Parana, Curitiba, Brazil.
Department of Pharmacology, Biological Sciences Section, Federal University of Parana, Curitiba, Brazil.
Arch Oral Biol. 2019 Jan;97:231-237. doi: 10.1016/j.archoralbio.2018.10.038. Epub 2018 Nov 2.
To improve understanding of the pathophysiology of cancer-induced facial nociception, by evaluating the contribution of peripheral endothelin receptors in tumor-induced facial heat hyperalgesia, increased spontaneous grooming, as well as ongoing nociception in a rat model of facial cancer.
The study was conducted using 396 rats. Facial cancer was induced by inoculating a suspension of Walker-256 cells into the rats' right vibrissal pad. Facial heat hyperalgesia and spontaneous grooming were assessed on day 6, while the conditioned place preference (CPP) test was performed on days 3-6 after tumor cells inoculation. Rats received local injections of the non-peptidic dual ET/ET endothelin receptors antagonist, bosentan (10 and 30 μg/50 μL), single or combined injections of peptidic ET and ET endothelin receptors antagonists (BQ-123 and BQ-788, at 20 ug/50 μL, each), or of lidocaine (1 mg/50 μl) and morphine (30 μg/50 μL).
Bosentan, lidocaine and morphine local treatment all attenuated tumor-induced heat hyperalgesia (p < 0.05) and spontaneous facial grooming (p < 0.05). However, BQ-123 and BQ-788 did not modify tumor-induced heat hyperalgesia or the spontaneous facial grooming (p > 0.05). Whether this difference in effectiveness is due to receptor affinity or to pharmacokinetic factors still needs to be explored. Local injection of bosentan, lidocaine or morphine failed to control ongoing nociception, as evidenced by the absence of CPP in tumor-bearing rats (p > 0.05).
Endothelins, acting through peripheral ET and ET receptors, may play a significant role on the development of heat hyperalgesia and increased spontaneous grooming associated to facial cancer in rats.
通过评估肿瘤诱导的面部热痛觉过敏、自发梳理增加以及面部癌症大鼠模型中持续性疼痛的外周内皮素受体在癌性面部疼痛的发病机制中的作用，来提高对其的认识。
本研究共纳入 396 只大鼠，通过将 Walker-256 细胞混悬液接种于大鼠右侧触须垫来诱导面部癌症。在接种肿瘤细胞后第 6 天评估面部热痛觉过敏和自发梳理，第 3-6 天进行条件性位置偏爱（CPP）测试。大鼠接受非肽类双重内皮素/内皮素受体拮抗剂博森坦（10 和 30μg/50μL）的局部注射，或肽类内皮素和内皮素受体拮抗剂（BQ-123 和 BQ-788，各 20μg/50μL）的单一或联合注射，或利多卡因（1mg/50μl）和吗啡（30μg/50μL）的局部注射。
博森坦、利多卡因和吗啡局部治疗均能减轻肿瘤诱导的热痛觉过敏（p<0.05）和自发的面部梳理（p<0.05）。然而，BQ-123 和 BQ-788 对肿瘤诱导的热痛觉过敏或自发的面部梳理没有影响（p>0.05）。这种疗效差异是由于受体亲和力还是由于药代动力学因素仍需要进一步研究。博森坦、利多卡因或吗啡局部注射均不能控制持续性疼痛，肿瘤大鼠缺乏 CPP（p>0.05）。
内皮素通过外周 ET 和 ET 受体发挥作用，可能在大鼠面部癌症相关的热痛觉过敏和自发梳理增加的发展中发挥重要作用。
