Endothelin Signaling Contributes to Modulation of Nociception in Early-stage Tongue Cancer in Rats

Background: Patients with early stage tongue cancer do not frequently complain of tongue pain. Endothelin-1 signaling is upregulated in the cancerous tongue at the early stage. We tested the hypothesis that endothelin-1 signaling contributes to the modulation of tongue nociception. Methods: Squamous cell carcinoma cells were inoculated into the tongue under general anesthesia. Lingual mechanical sensitivity under light anesthesia using forceps from days 1 to 21 (n = 8) and the amounts of endothelin-1 and beta-endorphin in the tongue on days 6, 14, and 21 (n = 5 to 7) were examined after the inoculation. The effect of endothelin-A or mu-opioid receptor antagonism on the mechanical sensitivity was examined (n = 5 to 7). Results: Lingual mechanical sensitivity did not change at the early stage (days 5 to 6) but increased at the late stage (days 13 to 14). The amount of endothelin-1 increased (25.4 +/- 4.8 pg/ml vs. 15.0 +/- 5.2 pg/ml; P = 0.008), and endothelin-A receptor antagonism in the tongue induced mechanical hypersensitivity at the early stage (51 +/- 9 g vs. 81 +/- 6 g; P = 0.0001). The mu-opioid receptor antagonism enhanced mechanical hypersensitivity (39 +/- 7 g vs. 81 +/- 6 g; P < 0.0001), and the amount of beta-endorphin increased at the early stage. Conclusions: beta-Endorphin released from the cancer cells via endothelin-1 signaling is involved in analgesic action in mechanical hypersensitivity at the early stage.