UCSF

Cancer pain is a frequent and disabling consequence for many patients yet the mechanism of cancer pain remains unknown largely due to its complex etiology. The objective of this thesis work was to investigate the potential of a peptide produced by carcinoma cells, endothelin, as a novel target for cancer pain management. This study provided evidence in support of Hypothesis 1: Oral squamous carcinoma cells produce endogenous opioids in response to changes in endothelin-1 signaling. Effects of endothelin-1 (ET-1) signaling on secretion of opioids by oral squamous cell carcinoma (SCC) were studied in vitro. Oral SCC cell line HSC-3 produces abundant ET-1 that can act in both an autocrine or paracrine manner. In the untreated oral SCC cells, endogenous opioids were detected in both cultured media and cell lysates. When treated with Endothelin-A receptor antagonist, secreted levels of &beta-endorphin and leu-enkephalin were increased; whereas treatment with Endothelin-B receptor agonist increased production of only &beta-endorphin. This apparent regulation of endogenous opioid levels by endothelin receptor drugs in vitro procured evidence suggesting that Hypothesis 2: Endothelin-A receptor antagonist and Endothelin-B receptor agonist attenuate carcinoma-induced nociception in cancer animals through regulation of endogenous opioids. Endothelin-A (ET-AR) antagonism has been demonstrated previously to attenuate carcinoma-mediated hyperalgesia in an orthotopic cancer pain mouse model. In this study, effects of ET-BR agonist in vivo were evaluated and determined to also result in significant increase in paw withdrawal thresholds, indicating attenuation of cancer-induced nociception. When peripheral &mu- or &delta-opioid receptor antagonists were administered following ET-AR antagonism, nociceptive attenuation was completely reversed. Attenuation from ET-BR agonism was likewise reversed upon administration of &mu-opioid receptor antagonist. Combined results demonstrate that endogenous opioids are the likely mediators responsible for attenuation of carcinoma-induced nociception with either ET-AR antagonist or ET-BR agonist.

These novel findings suggest that there exist innate modulation of pain by SCCs involving endogenous opioids that can be exploited through manipulation of endothelin activity in the cancer micro-environment. Regulation of ET-AR or ET-BR signaling may be targets for future innovations for cancer pain management.