Selective PAC1 Receptor Antagonist, PA-810-04 Attenuates Oxaliplatin-Induced Hyperexcitability and Coordinated Firing in Cultured Dorsal Root Ganglion Neurons
5 affiliations
- 1Department of Clinical Pharmacy and Pharmacology, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan
- 2Department of Pharmacy, Kagoshima University Hospital, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan
- 3Department of Oral Anatomy and Cell Biology, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan
- 4Laboratory of Pharmacology, Graduate School of Pharma-Medical Sciences, University of Toyama, 3190 Gofuku, Toyama 930-8555, Japan
- 5Department of Pharmacology, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan
Abstract
Oxaliplatin-induced peripheral neuropathy (OIPN) is a major dose-limiting adverse effect of chemotherapy, and dorsal root ganglion (DRG) neurons are its principal targets. Although pituitary adenylate cyclase-activating polypeptide (PACAP)/PAC1 receptor signaling has been implicated in neuropathic pain, its contribution to the oxaliplatin-induced hyperexcitability of primary sensory neurons remains unknown. We used a dual-axis multi-electrode array (MEA) platform quantifying the total spike count (TSC) and synchronous spike ratio (SSR), indices of overall activity and coordinated firing. Short-term oxaliplatin exposure produced concentration-dependent increases in TSC and SSR in cultured DRG neurons, which were significantly attenuated by the selective PAC1 receptor antagonist, PA-810-04. Similarly, conditioned medium from oxaliplatin-treated satellite glial cell (SGC)-enriched cultures increased TSC and SSR in naïve DRG neurons, and these effects were suppressed by PA-810-04. Exogenous PACAP alone increased TSC concentration-dependently, with only a modest effect on SSR, as a positive control. These findings identify a PA-810-04-sensitive component of early oxaliplatin-induced hyperexcitability in primary sensory neurons, while the proposed neuron–glia mechanism remains hypothetical. They also provide a quantitative in vitro approach for investigating neuron–glia interactions in early OIPN and evaluating PAC1-targeted candidates.
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BibTeX
@article{arima2026selective,
title = {{Selective PAC1 Receptor Antagonist, PA-810-04 Attenuates Oxaliplatin-Induced Hyperexcitability and Coordinated Firing in Cultured Dorsal Root Ganglion Neurons}},
author = {Taiyo Arima and Kazuhiro Takahama and Kimitaka Suetsugu and Yukiko Kobae and Haruki Iwai and Ichiro Takasaki and Takashi Kurihara and Hideyuki Terazono},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = oct,
doi = {10.3390/ijms27219665},
url = {https://www.mdpi.com/1422-0067/27/21/9665},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Selective PAC1 Receptor Antagonist, PA-810-04 Attenuates Oxaliplatin-Induced Hyperexcitability and Coordinated Firing in Cultured Dorsal Root Ganglion Neurons
AU - Taiyo Arima
AU - Kazuhiro Takahama
AU - Kimitaka Suetsugu
AU - Yukiko Kobae
AU - Haruki Iwai
AU - Ichiro Takasaki
AU - Takashi Kurihara
AU - Hideyuki Terazono
PY - 2026
DA - 2026/10/28
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27219665
UR - https://www.mdpi.com/1422-0067/27/21/9665
AB - Oxaliplatin-induced peripheral neuropathy (OIPN) is a major dose-limiting adverse effect of chemotherapy, and dorsal root ganglion (DRG) neurons are its principal targets. Although pituitary adenylate cyclase-activating polypeptide (PACAP)/PAC1 receptor signaling has been implicated in neuropathic pain, its contribution to the oxaliplatin-induced hyperexcitability of primary sensory neurons remains unknown. We used a dual-axis multi-electrode array (MEA) platform quantifying the total spike count (TSC) and synchronous spike ratio (SSR), indices of overall activity and coordinated firing. Short-term oxaliplatin exposure produced concentration-dependent increases in TSC and SSR in cultured DRG neurons, which were significantly attenuated by the selective PAC1 receptor antagonist, PA-810-04. Similarly, conditioned medium from oxaliplatin-treated satellite glial cell (SGC)-enriched cultures increased TSC and SSR in naïve DRG neurons, and these effects were suppressed by PA-810-04. Exogenous PACAP alone increased TSC concentration-dependently, with only a modest effect on SSR, as a positive control. These findings identify a PA-810-04-sensitive component of early oxaliplatin-induced hyperexcitability in primary sensory neurons, while the proposed neuron–glia mechanism remains hypothetical. They also provide a quantitative in vitro approach for investigating neuron–glia interactions in early OIPN and evaluating PAC1-targeted candidates.
SN - 1422-0067
ER -