• Ichiro Takasaki, Ryota Nagashima, Takahiro Ueda, Yuya Ashihara, Tomoya Nakamachi, Takuya Okada, Naoki Toyooka, Atsuro Miyata, and Takashi Kurihara.
• Laboratory of Pharmacology, Faculty of Engineering, University of Toyama, Toyama 930-8555, Japan; Graduate School of Pharma-Medical Sciences, University of Toyama, Toyama 930-8555, Japan; Graduate School of Innovative Life Science, University of Toyama, Toyama 930-8555, Japan. Electronic address: takasaki@eng.u-toyama.ac.jp.
• J Pain. 2025 Feb 1; 27: 104751104751.

AbstractChemotherapy-induced peripheral neuropathy (CIPN) is a type of peripheral neuropathy that develops in patients treated with certain anticancer drugs. Oxaliplatin (OXA) causes CIPN in approximately 80-90 % of patients; thus, it is necessary to elucidate its underlying mechanism and develop effective treatments and prevention methods. The purpose of this study was to determine whether the pituitary adenylate cyclase-activating polypeptide (PACAP)/PAC1 receptor system in the spinal dorsal horn is involved in OXA-induced acute cold allodynia and examine the effect of a PAC1 receptor antagonist. Administration of OXA induced acute cold allodynia in wild-type mice, but not in PACAP-/- mice. In the dorsal root ganglia, OXA upregulated PACAP expression, particularly in small-sized neurons. OXA-induced cold allodynia was ameliorated by intrathecal (i.t.) injection of PACAP6-38 (peptide antagonist for PACAP receptor) and PA-8 (small-molecule antagonist specific for PAC1 receptor). I.t. PACAP, but not vasoactive intestinal polypeptide, resulted in cold allodynia, which was blocked by PA-8. OXA induced the activation of spinal astrocytes in a PAC1 receptor-dependent manner. The results suggest that spinal PACAP/PAC1 receptor systems are involved in OXA-induced acute cold allodynia through astrocyte activation. Furthermore, we demonstrated that the systemic administration of PA-8 resulted in therapeutic and preventative effects on OXA-induced acute cold allodynia. Because PA-8 did not affect the anticancer effects of OXA, we propose PAC1 receptor inhibition as a new strategy for the treatment and prevention of CIPN. PERSPECTIVE: Cold allodynia is a hallmark of OXA-induced peripheral neuropathy. This study demonstrated the involvement of spinal PACAP/PAC1 receptors in OXA-induced acute cold allodynia. We propose PAC1 receptor inhibition as a new strategy for the treatment and prevention of OXA-induced acute cold allodynia.Copyright © 2024 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.

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