117: Involvement of the trigeminal spinal subnucleus oralis in orofacial neuropathic pain development

Topic: Basic Science
Subtopic: Pain category (ICD-11), Chronic primary orofacial pain, , , , Electrophysiology, Neurocircuit modulation (could include opto, DREADDs), Behavioral studies, , , , ,

Background and Aims: Recent studies have shown that a significant number of nociceptive neurons are located in the trigeminal spinal subnucleus oralis (Vo), suggesting that the Vo functions as a orofacial pain perception. We hypothesized that Vo noceptive neurons contribute to the development of persistent orofacial pain following trigeminal nerve injury. However, the contribution of these neurons projecting from the trigeminal ganglion (TG) to the Vo (TG-Vo neurons) to persistent orofacial pain remains unclear. Therefore, we investigated the role of the TG–Vo pathway in the development of orofacial neuropathic pain using a rat model of partial infraorbital nerve ligation (PNL).

Methods: The mechanical head withdrawal threshold (MHWT) was measured by von Frey filaments to the whisker pad skin, as well as by the occurrence of freezing behavior induced by optogenetic activation of the TG-Vo pathway in naive rats. Two different tracers were used to determine whether TG-Vo afferents have axon collaterals projecting to Vc. The extracellular recordings of Vo neuronal activity, complemented by Ca2+ imaging analysis of TG-Vo neurons, and the effect of a TRPA1 antagonist on Vo neuronal activity. Immunohistochemical analyses of CGRP, IB4, and TRPA1 were conducted in TG-Vo neurons in PNL rats.

Results: PNL rats exhibited a significant reduction in MHWT; notably, chemical lesioning of the Vo significantly reversed this mechanical hypersensitivity. Optogenetic activation of the TG–Vo pathway in naive rats induced a significant reduction in MHWT. The excitability of Vo wide-dynamic-range (WDR) neurons was significantly enhanced in PNL rats. Immunohistochemical analysis showed increased expression of CGRP and TRPA1 in TG–Vo neurons following PNL. Ca2+ imaging demonstrated that Ca2+ influx induced by the TRPA1 agonist AITC was significantly more prominent in PNL rats. Peripheral administration of the TRPA1 blocker HC-030031 significantly attenuated the enhanced mechanical responses of Vo WDR neurons in PNL rats.

Conclusions: These findings strongly suggest that the TG–Vo pathway plays a critical role in the development and maintenance of orofacial neuropathic pain through a CGRP-TRPA1- dependent mechanism.

References: 1. Chiang CY, Hu B, Hu JW, Dostrovsky JO, Sessle BJ. Central sensitization of nociceptive neurons in trigeminal subnucleus oralis depends on integrity of subnucleus caudalis. J Neurophysiol 2002;88(1):256-264.
2. Terayama R, Tsuji K, Furugen H, Minh DNP, Nakatani A, Uchibe K. Effects of Peripheral Nerve Injury on the Induction of c-Fos and Phosphorylated ERK in the Brainstem Trigeminal Sensory Nuclear Complex. Ann Neurosci 2023;30(3):177-187.
3. Yurika Ide, Koichi Iwata, Yoshinori Hayashi, Suzuro Hitomi, Zhou Yue, Yuka Nakaya, Shiori Kawasaki, Masayuki Kobayashi, Barry J Sessle, Toshimitsu Iinuma, and Masamichi Shinoda. Trigeminal ganglion-trigeminal spinal subnucleus oralis pathway contributes to orofacial neuropathic pain. PAIN 2026 in press.

Presenting Author: Koichi Iwata
Submitting Author: Koichi Iwata

Senior Author: Koichi Iwata

IASP 2026 Global Year theme of Neuropathic Pain: No

• Koichi Iwata: Professor - Nihn University
• Yurika Ide: PhD student - Nihon University
• Yoshinori Hayashi: Associate Prof. - NIhon University
• Suzuro Hitomi: Associate Prof. - Nihon University
• Yue Zhou: PhD student - Nihon University
• Yuka Nakaya: Assistent Prof. - Nihon University
• Masayuki Kobayashi: Professor - Nihon University
• Barry J Sessle: Professor - University of Toronto
• Masamichi Shinoda: Professor - Nihon University