そう痒における新規PACAP type 1受容体小分子拮抗薬の効果

• Published in: 日本薬理学会年会要旨集 p. 1-P-014
• Main Authors: 宮田, 篤郎, 加藤, 翔, 豊岡, 尚樹, 合田, 浩明, 髙﨑, 一朗, 村田, 万佑子, 栗原, 崇, 池田, 竜太, 岡田, 卓哉
• Format: Journal Article
• Language: Japanese
• Published: 公益社団法人 日本薬理学会 2020
• Subjects: antagonist; itching; skin; spinal cord
• ISSN: 2435-4953
• DOI: 10.1254/jpssuppl.93.0_1-P-014

The role of pituitary adenylate cyclase-activating polypeptide (PACAP) in pain transmission has been well documented, but its involvement in itch transmission is entirely unclear. We recently developed novel small-molecule antagonists of PACAP type 1 (PAC1) receptor including PA-8 by in silico screening. In this study, using PA-8, we investigated the possible involvement of PACAP/PAC1 receptor signaling in itch. 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 subcutaneous pretreatment with the μ-opioid receptor antagonist naltrexone (1 mg/kg). The scratching/biting behaviors induced by i.d. and i.t. PACAP were inhibited by i.d. and i.t. co-injection of PA-8 (0.1–10 nmol), respectively. The application of 5-HT (200 nmol in EtOH) to the skin elicited scratching behaviors, and they were suppressed by i.t., but not i.d., pretreatment of PA-8 (0.1–10 nmol). Next, we examine the effects of PA-8 on pruritic models. In the itch model induced by cutaneous application of acetone/ether and water (AEW, a dry skin model) or 2,4-dinitrofluorobenzene (DNFB, an atopic dermatitis model), single oral administration of PA-8 (3 – 30 mg/kg) dose-dependently suppressed the itch-associated behaviors. These results suggest that PACAP/PAC1 receptor signaling in the skin and/or spinal cord is involved in an itch sensation. The small-molecule PAC1 receptor antagonist may become an orally available antipruritic drug in the treatment of acute and chronic itch.