PAC1受容体拮抗薬PA-81004はオキサリプラチン誘発性冷的アロディニアに対し優れた予防効果を示す

• Published in: 日本薬理学会年会要旨集 p. 2-B-P-126
• Main Authors: 斎藤, 弘樹, 宮田, 篤郎, 髙﨑, 一朗, 足原, 佑弥, 栗原, 崇
• Format: Journal Article
• Language: Japanese
• Published: 公益社団法人 日本薬理学会 2022
• Subjects: antagonist; pain; receptor
• ISSN: 2435-4953
• DOI: 10.1254/jpssuppl.96.0_2-B-P-126

Oxaliplatin (OXA), a third-generation platinum-based anticancer agent, is widely used for colorectal cancer. However, OXA causes acute peripheral neuropathy in approximately 80-90% patients. The most common symptom is cold allodynia in the hands and feet. At present, there are few drugs that can prevent OXA-induced peripheral neuropathy. Previously, we demonstrated that pituitary adenylate cyclase-activating polypeptide (PACAP) and its receptor PAC1 are important role for the chronic pain, and developed a small-molecule antagonist of PAC1 receptor (PA-81004, Takasaki et al., JPET, 2018; Eur J Med Chem, 2022). In this study, we investigated whether PA-81004 has a preventive effect on oxaliplatin-induced cold allodynia. Cold allodynia developed 1 day after single injection of OXA (5 mg/kg, i.p.), peaked at 4 days, and lasted for 6 days. The administration of OXA also caused transient weight loss. Repetitive administration of PA-81004 (0.1-30 mg/kg) showed a dose-dependent inhibitory effect, but weight loss was observed, possibly due to repetitive administration. A single intraperitoneal dose (0.1-3 mg/kg) administered 30 min prior to OXA administration showed no weight loss and an anti-allodynic effect. Intravenous administration of PA-81004 was more potent than intraperitoneal administration in preventing the onset of cold allodynia and also in inhibiting weight loss. The present results suggest that PAC1 receptors are involved in OXA-induced cold allodynia and that PA-81004 may become a preventive agent against OXA-induced peripheral neuropathy.