Advisor(s)
Jianguo Gu
Committee Member(s)
Jennifer Deberry
Robert Sorge
Saurabh Aggarwal
William Reed
Document Type
Dissertation
Date of Award
1-27-2026
Degree Name
Doctor of Philosophy (PhD)
School
Joint Health Sciences (Interdisciplinary)
Department
Neurobiology
Abstract
Chemotherapy-induced peripheral neuropathy (CIPN) remains a major clinical challenge, often manifesting as mechanical allodynia, tactile deficits, and orofacial pain. While much of the field has historically focused on C- and Aδ-fiber nociceptors, emerging evidence suggests that large-diameter nociceptive Aβ-afferent neurons may also contribute to pain signaling under pathological conditions. This dissertation investigates the functional, molecular, and behavioral roles of nociceptive Aβ neurons in CIPN, with a particular focus on oxaliplatin-induced neuropathies in the trigeminal system. Using a combination of behavioral assays, including a novel sheltering tube method and quantitative grimace scale (qGS) analysis, alongside patch-clamp electrophysiology and single-cell RT-PCR, this work demonstrates that Nav1.8-positive Aβ-afferents undergo significant functional reprogramming following chemotherapy. These neurons exhibit increased excitability, enhanced mechanically activated (MA) currents, and upregulation of Nav1.8 and Piezo2, contributing to mechanical hypersensitivity after oxaliplatin treatment. In contrast, Nav1.8-negative low-threshold mechanoreceptors (LTMRs) exhibited altered potassium channel function and reduced mechanosensitivity after vincristine exposure, helping to explain the clinical coexistence of numbness and pain in CIPN. Additionally, this dissertation identifies and characterizes a previously unstudied population of sinus-innervating trigeminal ganglion (TG) neurons, which express Nav1.9 and exhibit distinct electrophysiological and molecular features. These neurons demonstrate mechanosensitivity and Piezo2 expression, suggesting a specialized role in sinus-related pain and mechanotransduction. Together, these findings challenge the traditional dichotomy of touch and pain pathways and highlight the plasticity of Aβ-afferents in neuropathic conditions. By integrating molecular profiling with functional analysis, this work provides new insights into the mechanisms of chemotherapy-induced pain and identifies potential targets such as Nav1.8, Nav1.9, and Piezo2 for non-opioid therapeutic intervention. The study also establishes a foundation for future research into sinus pain mechanisms and the broader role of Aβ neurons in somatosensory disorders.
Keywords
Aβ-HTMRs/ Aβ-LTMRs;Aβ-nociceptors;CIPN;Mechanical allodynia;Nav1.8;Trigeminal Ganglion
ProQuest Publication Number
32282161
ProQuest ID
ISBN
9798273349698
Recommended Citation
Gupta, Saurav, "Orofacial Pain Behaviors And Underlying Ion Channel Mechanisms In Trigeminal Peripheral Neuropathy In Mice" (2026). ETDs from 2020-2029. 25.
https://digitalcommons.library.uab.edu/etd-2020s/25
