Therapeutic strategies for pain signaling via endothelin receptor: endothelin A receptor antagonists as novel analgesic adjuncts

Owing to improvements of medical technology, cancer has become a treatable disease. While the number of cancer survivors is gradually increasing year by year, many patients are suffering from pain as side–effects or after–effects of cancer treatment. Opioids are used as medical narcotics for the treatment of cancer pain. In the United States, opioid prescriptions that prioritize pain relief have led in many cases to opioid addiction and abuse, and many patients have lost their lives due to overdoses of opioid analgesics. There is an urgent need to develop new methods to reduce the use of opioids and novel effective treatments with fewer side–effects to overcome this situation. Endothelin, known as a vasoconstrictor, has been shown to be involved in pain through its specific receptor, the endothelin A receptor. In addition, endothelin A receptor antagonists are also known to potentiate the effects of opioids and relieve opioid tolerance, although the mechanisms are yet to be elucidated. Here, we present a review based on previous reports on the relationship between endothelin–associated pain signaling and opioids. Furthermore, we show that heterodimerized endothelin A and μ–opioid receptors are involved in endothelin A receptor–mediated pain. We also show that a novel endothelin A receptor antagonist with a higher selectivity for the endo thelin A receptor than existing endothelin A receptor antagonists, potentiates opioid effects ; this endothelin A antagonist would potentially be a novel analgesic adjuvant.