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 β-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 µ-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 µ-opioid receptor antagonism enhanced mechanical hypersensitivity (39 ± 7 g vs. 81 ± 6 g; P < 0.0001), and the amount of β-endorphin increased at the early stage. Conclusions β-Endorphin released from the cancer cells via endothelin-1 signaling is involved in analgesic action in mechanical hypersensitivity at the early stage.