Blockade of peripheral endothelin receptors abolishes heat hyperalgesia and spontaneous nociceptive behavior in a rat model of facial cancer

Abstract Objective 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. Design 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 A /ET B endothelin receptors antagonist, bosentan (10 and 30 μg/50 μL), single or combined injections of peptidic ET A and ET B 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). Results Bosentan, lidocaine and morphine local treatment all attenuated tumor-induced heat hyperalgesia (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). Conclusion Endothelins, acting through peripheral ET A and ET B receptors, may play a significant role on the development of heat hyperalgesia and increased spontaneous grooming associated to facial cancer in rats.