Endothelin-A Receptor Antagonism Attenuates Carcinoma-Induced Pain Through Opioids in Mice

Phuong N. Quang, Brian Schmidt

Research output: Contribution to journalArticle

Abstract

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 β-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 μg/kg), selective antagonists for μ-opioid receptor (CTOP, 500 μg/kg), or δ-opioid receptor (naltrindole, 11 mg/kg) but not κ-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. Perspective: 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.

Original languageEnglish (US)
Pages (from-to)663-671
Number of pages9
JournalJournal of Pain
Volume11
Issue number7
DOIs
StatePublished - Jul 2010

Fingerprint

Endothelin A Receptors
Opioid Analgesics
Carcinoma
Opioid Receptors
Pain
Squamous Cell Carcinoma
naltrindole
Analgesia
Endorphins
Leucine Enkephalin
Tumor Microenvironment
Narcotic Antagonists
Nude Mice
Morphine
Neoplasms
Cell Culture Techniques
Injections
Therapeutics
Pharmaceutical Preparations
Cancer Pain

Keywords

  • cancer
  • cancer mouse model
  • Endothelin
  • oral cancer
  • pain

ASJC Scopus subject areas

  • Anesthesiology and Pain Medicine
  • Neurology
  • Clinical Neurology

Cite this

Endothelin-A Receptor Antagonism Attenuates Carcinoma-Induced Pain Through Opioids in Mice. / Quang, Phuong N.; Schmidt, Brian.

In: Journal of Pain, Vol. 11, No. 7, 07.2010, p. 663-671.

Research output: Contribution to journalArticle

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