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

Abstract

ObjectiveTo 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. DesignThe 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 ETA/ETB endothelin receptors antagonist, bosentan (10 and 30 μg/50 μL), single or combined injections of peptidic ETA and ETB 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). ResultsBosentan, 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). ConclusionEndothelins, acting through peripheral ETA and ETB receptors, may play a significant role on the development of heat hyperalgesia and increased spontaneous grooming associated to facial cancer in rats.