Endothelin-A receptor antagonism attenuates carcinoma-induced pain through opioids in mice.
We previously reported that endothelin A (ET-A) receptor antagonism attenuates carcinoma-induced pain in a cancer pain mouse model. In this study, we investigated the mechanism of ET-A receptor-mediated antinociception and evaluated the role of endogenous opioid analgesia. Squamous cell carcinoma (SCC) cell culture treated with the ET-A receptor antagonist (BQ-123) at 10(-6) M and 10(-5) M significantly increased production and secretion of beta-endorphin and leu-enkephalin, respectively. Behavioral studies were performed by inducing tumors in the hind paw of female nude mice with local injection of cells derived from a human oral SCC. Significant pain, as indicated by reduction in withdrawal thresholds in response to mechanical stimulation, began at 4 days after SCC inoculation and lasted to 18 days, the last day of measurement. Local administration of either naloxone methiodide (500 microg/kg), selective antagonists for mu-opioid receptor (CTOP, 500 microg/kg), or delta-opioid receptor (naltrindole, 11 mg/kg) but not kappa-opioid receptor (nor-BNI, 2.5 mg/kg) significantly reversed antinociception observed from ET-A receptor antagonism (BQ-123, 92 mg/kg) in cancer animals. These results demonstrate that antagonism of peripheral ET-A receptor attenuates carcinoma pain by modulating release of endogenous opioids to act on opioid receptors in the cancer microenvironment.


CONCLUSIONS
This article proposes a novel mechanism for ET-A receptor antagonist drugs in managing cancer-induced pain. An improved understanding of the role of innate opioid analgesia in ET-A receptor-mediated antinociception might provide novel alternatives to morphine therapy for the treatment of cancer pain.
Quang
Phuong N
PN
UCSF School of Dentistry, Oral and Craniofacial Sciences Graduate Program, University of California, San Francisco, San Francisco, CA 94143-0440, USA.
Schmidt
Brian L
BL
D000700:Analgesics / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology / Q000627:therapeutic use; D002294:Carcinoma, Squamous Cell / Q000150:complications* / Q000378:metabolism / Q000503:physiopathology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D065130:Endothelin A Receptor Antagonists; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009292:Narcotic Antagonists; D009368:Neoplasm Transplantation / Q000379:methods; D009374:Neoplasms, Experimental / Q000150:complications / Q000378:metabolism / Q000503:physiopathology; D018847:Opioid Peptides / Q000819:agonists* / Q000378:metabolism; D010148:Intractable Pain / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D010456:Peptides, Cyclic / Q000494:pharmacology / Q000627:therapeutic use; D011957:Receptors, Opioid / Q000819:agonists* / Q000378:metabolism; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured
D000700:Analgesics; D000959:Antihypertensive Agents; D065130:Endothelin A Receptor Antagonists; D009292:Narcotic Antagonists; D018847:Opioid Peptides; D010456:Peptides, Cyclic; D011957:Receptors, Opioid; C072247:cyclo(Trp-Asp-Pro-Val-Leu)