Enhanced excitability and mechanical sensitivity in trigeminal Aβ-nociceptors contributes to oxaliplatin-induced orofacial mechanical allodynia
The 5th Annual MSC Emerging Science Contest for Early-Career Investigators took place on January 7, 2026. Below is a description of one of the presentations from the contest. (A recording of the event is available here).
Category: Pain
Runner up: Saurav Gupta, PhD, University of Alabama at Birmingham
Title: Enhanced excitability and mechanical sensitivity in trigeminal Aβ-nociceptors contributes to oxaliplatin-induced orofacial mechanical allodynia
Description: Patients treated with chemotherapy drugs like oxaliplatin often experience mechanical hypersensitivity and mechanical allodynia, a condition where even light touch to the face feels painful. We propose that this pain is driven by increased excitability and mechanical hypersensitivity in a specific type of neuronal cell, trigeminal Aβ-nociceptors, which may become hypersensitive due to the upregulation of two key ion channels: Nav1.8, which is involved in pain signaling, and Piezo2, which detects mechanical pressure. Most previous research has focused on other nerve fibers (C-fibers and Aδ-fibers) in chemotherapy-induced neuropathy. Our study is the first to show that Aβ-nociceptors in the trigeminal ganglion also play a major role in mechanical allodynia. We demonstrated that these neurons become hyperexcitable after oxaliplatin treatment, with increased activity of Nav1.8 and Piezo2. This provides a new mechanistic insight into why patients experience severe pain from light touch. We combined behavioral, electrophysiological, and molecular biology approaches, utilizing Nav1.8Cre/eYFP mice, a transgenic mouse line that allows for the identification of Aβ-nociceptors by measuring the speed of nerve fibers under a fluorescent microscope.
More specifically, oxaliplatin-treated mice exhibited mechanical hypersensitivity in behavioral tests, as determined by the von Frey test and the AI-based measurement of orbital tightening. We then harvested trigeminal ganglion (TG) neurons from these animals and conducted electrophysiological recordings from trigeminal Aβ-nociceptors (Nav1.8-positive Aβ TG neurons). We found that in the oxaliplatin-treated group, trigeminal Aβ-nociceptors exhibited a significant reduction in AP rheobase and more negative AP threshold, indicating increased excitability. Furthermore, voltage-clamp recordings revealed enhanced voltage-activated inward and outward currents, alongside increased action potential firing at 100 Hz and 500 Hz stimulation in the oxaliplatin-treated group, further supporting a hyperexcitable state following oxaliplatin treatment. We further found that TTX-resistant sodium currents were significantly elevated, as demonstrated by electrophysiological recordings and also by RT-PCR, implicating Nav1.8 upregulation as a mechanism for the hyperexcitability of these neurons. Moreover, we demonstrate in the oxaliplatin-treated group that mechanically activated currents were markedly increased in trigeminal Aβ-nociceptors, correlating with an upregulation of Piezo2 expression in the trigeminal Aβ-nociceptors.
Our findings suggest that nociceptive Aβ-afferent neurons may be key contributors to oxaliplatin-induced mechanical allodynia, providing novel mechanistic insights into the pathophysiology of chemotherapy-induced peripheral neuropathy. These results highlight potential therapeutic targets for mitigating chemotherapy-induced neuropathic pain.