Peripheral endothelin B receptor agonist-induced antinociception involves endogenous opioids in mice

Phuong N. Quang, Brian Schmidt

Research output: Contribution to journalArticle

Abstract

Endothelin-1 (ET-1) produced by various cancers is known to be responsible for inducing pain. While ET-1 binding to ETAR on peripheral nerves clearly mediates nociception, effects from binding to ETBR are less clear. The present study assessed the effects of ETBR activation and the role of endogenous opioid analgesia in carcinoma pain using an orthotopic cancer pain mouse model. mRNA expression analysis showed that ET-1 was nearly doubled while ETBR was significantly down-regulated in a human oral SCC cell line compared to normal oral keratinocytes (NOK). Squamous cell carcinoma (SCC) cell culture treated with an ETBR agonist (10-4 M, 10-5 M, and 10-6 M BQ-3020) significantly increased the production of β-endorphin without any effects on leu-enkephalin or dynorphin. Cancer inoculated in the hind paw of athymic mice with SCC induced significant pain, as indicated by reduction of paw withdrawal thresholds in response to mechanical stimulation, compared to sham-injected and NOK-injected groups. Intratumor administration of 3 mg/kg BQ-3020 attenuated cancer pain by approximately 50% up to 3 h post-injection compared to PBS-vehicle and contralateral injection, while intratumor ETBR antagonist BQ-788 treatment (100 and 300 μg/kg and 3 mg/kg) had no effects. Local naloxone methiodide (500 μg/kg) or selective μ-opioid receptor antagonist (CTOP, 500 μg/kg) injection reversed ETBR agonist-induced antinociception in cancer animals. We propose that these results demonstrate that peripheral ETBR agonism attenuates carcinoma pain by modulating β-endorphins released from the SCC to act on peripheral opioid receptors found in the cancer microenvironment.

Original languageEnglish (US)
Pages (from-to)254-262
Number of pages9
JournalPain
Volume149
Issue number2
DOIs
StatePublished - May 2010

Fingerprint

Endothelin B Receptors
Opioid Analgesics
Squamous Cell Carcinoma
Endothelin-1
Endorphins
Pain
Keratinocytes
Injections
Carcinoma
Leucine Enkephalin
Dynorphins
Neoplasms
Nociception
Tumor Microenvironment
Narcotic Antagonists
Opioid Receptors
Peripheral Nerves
Nude Mice
Analgesia
Cell Culture Techniques

Keywords

  • Cancer
  • Cancer mouse model
  • Endothelin
  • Opioids
  • Oral cancer
  • Pain

ASJC Scopus subject areas

  • Clinical Neurology
  • Anesthesiology and Pain Medicine
  • Neurology
  • Pharmacology

Cite this

Peripheral endothelin B receptor agonist-induced antinociception involves endogenous opioids in mice. / Quang, Phuong N.; Schmidt, Brian.

In: Pain, Vol. 149, No. 2, 05.2010, p. 254-262.

Research output: Contribution to journalArticle

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abstract = "Endothelin-1 (ET-1) produced by various cancers is known to be responsible for inducing pain. While ET-1 binding to ETAR on peripheral nerves clearly mediates nociception, effects from binding to ETBR are less clear. The present study assessed the effects of ETBR activation and the role of endogenous opioid analgesia in carcinoma pain using an orthotopic cancer pain mouse model. mRNA expression analysis showed that ET-1 was nearly doubled while ETBR was significantly down-regulated in a human oral SCC cell line compared to normal oral keratinocytes (NOK). Squamous cell carcinoma (SCC) cell culture treated with an ETBR agonist (10-4 M, 10-5 M, and 10-6 M BQ-3020) significantly increased the production of β-endorphin without any effects on leu-enkephalin or dynorphin. Cancer inoculated in the hind paw of athymic mice with SCC induced significant pain, as indicated by reduction of paw withdrawal thresholds in response to mechanical stimulation, compared to sham-injected and NOK-injected groups. Intratumor administration of 3 mg/kg BQ-3020 attenuated cancer pain by approximately 50{\%} up to 3 h post-injection compared to PBS-vehicle and contralateral injection, while intratumor ETBR antagonist BQ-788 treatment (100 and 300 μg/kg and 3 mg/kg) had no effects. Local naloxone methiodide (500 μg/kg) or selective μ-opioid receptor antagonist (CTOP, 500 μg/kg) injection reversed ETBR agonist-induced antinociception in cancer animals. We propose that these results demonstrate that peripheral ETBR agonism attenuates carcinoma pain by modulating β-endorphins released from the SCC to act on peripheral opioid receptors found in the cancer microenvironment.",
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