Intradermal nociceptin elicits itch-associated responses through leukotriene B(4) in mice

Nociceptin, the endogenous peptide ligand for opioid receptor like-1 (ORL1) receptor, has been implicated in the inflammation and pain in the skin. We examined whether nociceptin is a pruritogen in mice. Intradermal injections of nociceptin (1-100 nmol per site) concentration dependently increased scratching in ICR mice; the effect started within 1 min, peaked at 10-20 min, and almost subsided by 30 min. The nociceptin action was absent in ORL1 receptor-deficient (ORL1(-/-)) mice. Systemic, but not local, treatment with naloxone significantly inhibited scratching induced by nociceptin. The action of nociceptin was inhibited by the leukotriene B(4) receptor antagonist ONO-4057 and azelastine, which inhibits the action and production of leukotriene B(4) in the skin. Prepronociceptin and ORL1 receptor mRNAs were substantially expressed in the skin, whereas their expression levels were very low in the dorsal root ganglia. In the skin, nociceptin- and ORL1 receptor-like immunoreactivities were localized in the epidermis. Administration of nociceptin to primary cultures of keratinocytes from ICR and C57BL/6 (ORL1(+/+)) mice, but not ORL1(-/-) mice, produced leukotriene B(4). The results suggest that nociceptin acts on ORL1 receptor on the keratinocytes to produce leukotriene B(4), which induces itch-associated responses in mice.