1. ^*Department of Applied Pharmacology, Faculty of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical University, Sugitani, Toyama, Japan
2. ^†Department of Biochemistry, Tohoku University Graduate School of Medicine, Seiryo-machi, Aoba-ku, Miyagi, Japan
3. ^‡21st Century COE Program, Toyama Medical and Pharmaceutical University, Sugitani, Toyama, Japan

Correspondence: Yasushi Kuraishi, Department of Applied Pharmacology, Faculty of Pharmaceutical University, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama 9301-0194, Japan. Email: kuraisiy@ms.toyama-mpu.ac.jp

Received 25 December 2003; Revised 5 February 2004; Accepted 25 February 2004; Published online 30 June 2003.

Abstract

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 B₄ receptor antagonist ONO-4057 and azelastine, which inhibits the action and production of leukotriene B₄ 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 B₄. The results suggest that nociceptin acts on ORL1 receptor on the keratinocytes to produce leukotriene B₄, which induces itch-associated responses in mice.