In this study, we evaluated the importance of PACAP/PAC1 receptor signaling in itch-like behaviors in mice.
　Both intradermal (i.d.) and intrathecal (i.t.) injection of PACAP (1 pmol–1 nmol) dose-dependently elicited scratching/biting behaviors, and these behaviors were inhibited by pretreatment with the μ-opioid receptor antagonist naltrexone (1 mg/kg, s.c.). The scratching/biting behaviors induced by i.d. and i.t. PACAP were inhibited by i.d. and i.t. co-injection of one of novel small-molecule PAC1 receptor antagonists (PA-8, PA-9 or their derivatives, 0.01-1 nmol), respectively. We further found that i.t., but not i.d., pretreatment of PAC1 receptor antagonists (1 nmol) attenuated chloroquine-, compound 48/80- and 5-HT-induced scratching/biting behaviors. Single oral administration of the PAC1 receptor antagonists (3-30 mg/kg) dose-dependently suppressed itch-associated behaviors in dry skin, DNFB-induced atopic dermatitis and imiquimod-induced psoriasis-like model mice. In addition, the development of 5-HT and DNFB-induced itch-like behaviors was markedly depressed in mice lacking PACAP.
　These results suggest that PACAP-PAC1 receptor signaling in the spinal cord (and possibly in the skin) is involved in an important mechanism underlying the itch-like behaviors, and blocking PAC1 receptor system may be a new strategy to manage itch sensation in skin diseases.