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
beta-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 3mg/kg
BQ-3020 attenuated
cancer pain by approximately 50% up to 3h post-injection compared to PBS-vehicle and contralateral injection, while intratumor ETBR antagonist
BQ-788 treatment (100 and 300microg/kg and 3mg/kg) had no effects. Local
naloxone methiodide (500microg/kg) or selective
mu-opioid receptor antagonist (
CTOP, 500microg/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 beta-
endorphins released from the SCC to act on peripheral
opioid receptors found in the cancer microenvironment.