Dose PACAP-PAC1 signaling contribute to oxaliplatin-induced peripheral neuropathy?

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K16134
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 48030:Pharmacology-related
• Research Institution: Kagoshima University
• Principal Investigator: Saito Hiroki 鹿児島大学, 医歯学総合研究科, 客員研究員 (80747478)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: 下垂体アデニル酸シクラーゼ活性化ポリペプチド / PACAP / PAC1受容体 / PAC1受容体拮抗薬 / 非ペプチド性拮抗薬 / 化学療法誘発性末梢神経障害 / オキサリプラチン / 冷アロディニア

Outline of Final Research Achievements

In this study, we investigated the effect of a novel small-molecule PACAP-specific PAC1 receptor antagonist (PA-810-04) on the cold and mechanical allodynia in the mouse and common marmoset models of oxaliplatin (OXA)-induced peripheral neuropathy.
OXA-induced cold and mechanical allodynia were dose-dependently inhibited by single intraperitoneal (i.p.) and intravenous pretreatment of PA-810-04. Furthermore, i.p. pretreatment of PA-810-04 repeatedly exhibited anti-cold allodynic effect on OXA-treated mice, suggesting that PA-810-04 would not show significant analgesic tolerance. In addition, PA-810-04 also exhibited preemptive analgesic action in the non-human primate (common marmoset) model of OXA-induced cold allodynia.
These results suggest that PACAP/PAC1 signaling is involved in OXA-induced cold and mechanical allodynia and that PA-810-04 may become an analgesic agent against OXA-induced peripheral neuropathy.

Free Research Field

Pharmacology

Academic Significance and Societal Importance of the Research Achievements

成人の慢性疼痛保有率は世界的に近年増加傾向であり、疼痛領域の市場規模は世界医薬品市場においても、がん、糖尿病、免疫に続く第4位の市場規模 (2021年は約8兆円) となっている。世界的ながん、糖尿病患者数の増加、および人口の高齢化は、疼痛の中でも難治度の高い神経障害性疼痛保有率を増加させており、有害作用がなく、長期使用可能な鎮痛薬の開発が求められている。本研究成果は、疼痛発症予防に臨床的な有用性を一貫して示した鎮痛薬が未だ存在しない「がん化学療法に伴う末梢神経障害性疼痛 (CIPN)」に対するFirst-in-classの鎮痛薬開発の端緒となることが期待される。