Acta Dermato-Venereologica Issue 8, 2017 97-8CompleteContent | Page 11

928 INVESTIGATIVE REPORT Involvement of µ-opioid Receptors and κ-opioid Receptors in Itch- related Scratching Behaviour of Imiquimod-induced Psoriasis-like Dermatitis in Mice Nobuaki TAKAHASHI 1 , Mitsutoshi TOMINAGA 1 , Ryohei KOSAKA 1 , Yayoi KAMATA 1 , Yoshie UMEHARA 1 , Hironori MATSUDA 1 , Azumi SAKAGUCHI 1 , Hideoki OGAWA 1 and Kenji TAKAMORI 1,2 Institute for Environmental and Gender-Specific Medicine, Juntendo University Graduate School of Medicine, and 2 Department of Dermatology, Juntendo University Urayasu Hospital, Chiba, Japan 1 The pathogenesis of psoriatic itch is poorly under- stood. The aim of this study was to investigate the in- volvement of opioid receptors in scratching behaviour of imiquimod-induced psoriasis-like dermatitis model mice. Topical application of 5% imiquimod cream to the rostral back skin of mice induced antihistamine- resistant scratching behaviour. The expression of µ-opioid receptor (MOR) protein increased in the epi- dermis, dorsal root ganglia (DRG) and spinal cord of imiquimod-treated mice. In contrast, the expression of κ-opioid receptor (KOR) protein decreased in the DRG and spinal cord of imiquimod-treated mice, and was undetectable in the epidermis of both groups. Topical or intraperitoneal administration of the MOR antago- nist naloxone and oral administration of the centrally acting KOR agonist ICI-199,441 inhibited scratching behaviour, whereas oral administration of the peri­ pherally-selective KOR agonist asimadoline did not. These results suggest that peripheral and central MOR and central KOR may be involved in the modulation of scratching behaviour in imiquimod-treated mice. Key words: imiquimod; itch; opioid receptor; psoriasis. Accepted May 16, 2017; Epub ahead of print May 17, 2017 Acta Derm Venereol 2017; 97: 928–933. Corr: Kenji Takamori, Department of Dermatology, Juntendo University Urayasu Hospital, 2-1-1 Tomioka, Urayasu, Chiba 279-0021, Japan. E- mail: [email protected] P soriasis is a common chronic inflammatory skin disease, and most patients experience itch (1). Such itch also reduces the quality of life (QOL) of patients with psoriasis (2). Histamine is a major pruritogen, and histamine H 1 receptor (H 1 R) antagonists are widely used to treat pruri- tus. H 1 R antagonists, however, are frequently ineffective in treating psoriatic itch (3, 4). Although other possible pruritogens and mediators may evoke itch sensation in psoriasis patients, none has been clearly demonstrated to cause itching (3). Thus, few therapeutic options are available to reduce itch, and it is important to develop new antipruritic treatments for patients with psoriasis. Opioid receptors are classified into 4 types: µ-type (MOR), κ-type (KOR), δ-type (DOR) and nociceptin opioid (NOP)-type receptors (5, 6). These opioid re- doi: 10.2340/00015555-2704 Acta Derm Venereol 2017; 97: 928–933 ceptors and their ligands are generally involved in pain sensation (7, 8). In particular, morphine and other MOR agonists are frequently used to treat pain associated with cancer (9). However, MOR agonists can cause pruritus as a side-effect (7, 10). Moreover, studies in primates and rodents have shown that MOR agonists evoke itch, whereas MOR antagonists suppress itch (11–16). In contrast, KOR agonists have been found to suppress itch in primates and rodents, whereas KOR antagonists have been shown to evoke itch in rodents (7, 17–20). We previously reported that imbalances in the expression and/or activation of the µ- and κ-opioid systems, rather than epidermal hyperinnervation, may be involved in the pathogenesis of psoriatic itch (21). Furthermore, a recent study reported that imbalance of epidermal MOR and KOR may be involved in the pathogenesis of pso- riatic itch (22). Therefore, although the roles of opioid systems in the modulation of itch and pain sensations remain enigmatic (16, 23), these findings suggest that MOR and KOR may be promising therapeutic targets in patients with psoriatic itch. This study pharmacologically investigated the roles of MOR and KOR in scratching behaviour in a mouse model of imiquimod (IMQ)-induced psoriasis-like der- matitis (24–26). MATERIALS AND METHODS ( for complete details see Appendix S1 1 ) Mice Male C57BL/6J mice (8–9 weeks old; Oriental BioService, Kyoto, Japan) were maintained in the experimental animal facility of Juntendo University Graduate School of Medicine under a 12-h light:12-h dark cycle at a regulated temperature of 22–24°C, with food and tap water provided ad libitum. Care and handling of all animals conformed to the NIH guidelines for animal research, and all animal procedures were approved by the Institutional Animal Care and Use Committee of Juntendo University Graduate School of Medicine. Induction of psoriasis-like dermatitis Mice were anaesthetized with sevoflurane, and the rostral part of the back was clipped with an electric shaver at least 3 days https://www.medicaljournals.se/acta/content/abstract/10.2340/00015555-2704 1 This is an open access article under the CC BY-NC license. www.medicaljournals.se/acta Journal Compilation © 2017 Acta Dermato-Venereologica.