13: Satellite Glial Activation Induces Excitation of Ganglion Neurons to Cause Hyperalgesia in Rats

Topic: Basic Science
Subtopic: Non-specific to any diagnosis (including studies in healthy animals), Electrophysiology, Neurocircuit modulation (could include opto, DREADDs), Behavioral studies

Background and Aims: Satellite glial cells (SGCs) in peripheral sensory ganglia are activated by signals transmitted from ganglion neurons. Activated SGCs are thought to induce abnormal excitation in ganglion neurons by transferring neurotransmitters and cytokines, resulting in hyperalgesia. However, it has not been demonstrated that neuronal excitability changes immediately following SGCs activation. In this study, we aimed to evaluate whether neuronal excitability changes after SGCs activation by ATP released from abnormally excited neurons in trigeminal ganglia (TG) and to clarify the mechanism involved. Furthermore, we aimed to clarify whether SGCs activation causes pain-related behavior/hyperalgesia in rats.

Methods: To assess immediate communication with neurotransmitters between neurons and SGCs in TG, we employed patch-clamp recording from neurons in whole-mount or sliced TG preparations from SD rats, where interactions between neurons and SGCs seemed to be well preserved as in their physiological conditions. We analyzed the excitatory changes in TG neurons within 30 min following SGC activation. We also examined calcium imaging and transmitter analysis with cultivated SGCs, and immunohistochemical analysis. To further elucidate the effects of SGC activation, we employed optogenetic techniques to selectively activate SGCs and performed the analysis of neuronal excitatory changes and nociceptive behavioral test.

Results: The activation of SGCs by an ATP analogue, BzATP, increased TG neuronal excitability, and this was suppressed by application of a hemichannel blocker or metabotropic glutamate receptor 5 (mGluR5) antagonist. BzATP application also increased calcium influx into the cultivated SCGs and caused the glutamate release from them. Purinergic P2X7 receptors were exclusively expressed in SGCs, while mGluR5 was mainly expressed in small-sized nociceptive TG neurons. Optogenetic activation of SGCs also elevated the excitability of TG neurons. Repetitive optogenetic activation of SGCs caused sustained decrease of mechanical withdrawal threshold in masseter muscle in rats, demonstrating the development of mechanical hyperalgesia.

Conclusions: This study revealed that BzATP binding to P2X7 receptors on SGCs increased intracellular Ca²⁺, thereby activating SGCs. This led to glutamate release from SGCs via hemichannels, which activated mGluR5 expressed on TG neurons and increased neuronal excitability. This series of changes was induced within 30 min after SGCs activation. Analysis of action potential duration suggested that this neuronal excitability increase was induced by dysfunction in voltage-gated potassium channels. Furthermore, results from optogenetic experiments clearly demonstrated that SGC activation induced increase neuronal excitability and hyperalgesia.

References: Shinoda, M., Kubo, A., Hayashi, Y., et al. (2019). Peripheral and central mechanisms of persistent orofacial pain. Front Neurosci, 13, 1227. doi:10.3389/fnins.2019.01227.
Warwick, R. A., & Hanani, M. (2013). The contribution of satellite glial cells to chemotherapy-induced neuropathic pain. Eur J Pain, 17(4), 571-580. doi:10.1002/j.1532-2149.2012.00219.x.
Kubo, A., Iwata, K., Shinoda, M., et al. (2026). Purinergic receptor- and metabotropic glutamate receptor 5-mediated interactions between satellite glial cells and neurons in rat trigeminal ganglia. Glia, 74(2):e70126. doi: 10.1002/glia.70126.

Presenting Author: Asako Kubo
Submitting Author: Asako Kubo

Senior Author: Asako Kubo

IASP 2026 Global Year theme of Neuropathic Pain: No

• Asako Kubo: PhD - Department of Acupuncture and Moxibustion, Faculty of Rehabilitation, Niigata University of Health and Welfare
• Sho Sawada: PhD - Department of Oral and Maxillofacial Surgery Ⅱ, Nihon University School of Dentistry
• Kenta Kobayashi: PhD - Section of Viral Vector Development, Center for Genetic Analysis of Behavior, National Institute for Physiological Sciences
• Koichi Iwata: PhD - Department of Physiology, Nihon University School of Dentistry
• Masamichi Shinoda: PhD - Department of Physiology, Nihon University School of Dentistry
• Toru Taguchi: PhD - Department of Physical Therapy, Faculty of Rehabilitation, Niigata University of Health and Welfare
• Kazue Mizumura: PhD - Department of Physiology, Nihon University School of Dentistry