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

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 four 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 endothelin-A receptor attenuates carcinoma pain by modulating release of endogenous opioids to act on opioid receptors in the cancer microenvironment.

Analgesia Targeting IB4-Positive Neurons in Cancer-Induced Mechanical Hypersensitivity

“…We injected cancer supernatant containing a complex mixture of algogenic chemicals; therefore, cross activation or sensitization by chemical mediators on the two subsets of neurons is likely to occur. In addition to endothelin, NGF, proteases, IL-6, and TNF-α, as we have previously reported 29, 44, 45, 61 , OSCC releases neurturin which might activate IB4 (+) neurons. Since GDNF acts on IB4 (+) neurons to produce mechanical allodynia 25 , we investigated whether cancer supernatant contains a high level of GDNF.…”

A Study on the Mechanism of Cinobufagin in the Treatment of Paw Cancer Pain by Modulating Localβ-Endorphin ExpressionIn Vivo

“…Mechanical hyperalgesia was measured by IITC Von Frey 2390 in a quiet environment (room temperature 22 ± 1°C) [17, 18]. The mice were placed on a special glass grid, adapted to the quiet environment, and the experiment was performed.…”

New perspectives on the endothelin axis in pain

“…enhanced both spontaneous and palpation-induced guarding, although without altering the flinching behavior in osteolytic sarcoma-bearing mice [30]. Intra-tumor injection of the ET B receptor agonist BQ-3020 in mice inoculated with squamous cell carcinoma (SCC) attenuated tactile allodynia by approximately 50% for up to 3 hours post injection, while μ-opioid receptor antagonist injection transiently reversed ET B receptor agonist-induced antinociception [101]. In addition, oral SCC cells in culture were shown to significantly increase β-endorphin production upon ET B receptor agonist treatment [101].…”