Selective PAC1 Receptor Antagonist, PA-810-04 Attenuates Oxaliplatin-Induced Hyperexcitability and Coordinated Firing in Cultured Dorsal Root Ganglion Neurons

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.