Endothelin B receptors exert antipruritic effects via peripheral κ-opioid receptors

Endothelin B receptor agonists exert antipruritic effects on itching induced via endothelin-1 (ET-1) and compound 48/80. Peripheral µ- and κ-opioid receptors (MORs and KORs, respectively) are reported to be involved in the anti-nociceptive properties triggered by ET(B) agonists. Therefore, we investigated the role of peripheral opioid receptors in the scratching response induced by ET-1. ET(A) and ET(B) antagonists and non-selective and selective opioid receptor antagonists were co-injected with ET-1 in the neck of mice and the number of scratching bouts was counted. Pretreatment with systemically administered naloxone significantly reduced the number of scratches, while co-injection of naloxone substantially augmented the effect of ET-1. Co-injection of nor-Binaltorphimine (nor-BNI), a KOR antagonist, significantly increased the number of scratches induced by ET-1. However, CTOP (a MOR antagonist) and naltrindole [a δ-opioid receptor (DOR) antagonist] did not alter the scratching response elicited by ET-1. These results indicate that peripheral KORs mediate the antipruritic effect of endothelin B receptor activation.