• Satomi Kobayashi, Hironobu Osaki, Shigeki Kato, Kazuto Kobayashi, and Masayuki Kobayashi.
• Department of Pharmacology, Nihon University School of Dentistry, Tokyo, Japan.
• Pain. 2025 Jan 21.

AbstractThe insular cortex (IC) processes various sensory information, including nociception, from the trigeminal region. Repetitive nociceptive inputs from the orofacial area induce plastic changes in the IC. Parvalbumin-immunopositive neurons (PVNs) project to excitatory neurons (pyramidal neurons [PNs]), whose inputs strongly suppress the activities of PNs. This study investigated how PVNs in the IC modulate pain-related behaviors using optogenetics. To evaluate the effect of PVN activation on pain-related behavior, we applied nociceptive heat stimulation to the whisker pads of PV-Cre rats that received an injection of adeno-associated virus-Flex-channelrhodopsin-2-mCherry into the IC. Exposure to nociceptive heat stimulation significantly increased the amount of pain-related escape behavior, and PVN activation by optogenetics did not significantly decrease pain-related behavior. We next examined the possibility that long-term potentiation (LTP) of PVN→PN synapses suppresses pain-related behaviors. We recorded light-evoked inhibitory postsynaptic currents (IPSCs) from PNs in the IC slice preparation to examine whether optogenetic activation of PVNs can induce LTP. Repetitive optogenetic stimulation (ROS) of PVNs in a manner analogous to theta burst stimulation increased the amplitude of IPSCs for at least 50 minutes. Long-term potentiation was induced by either the -45 or -60 mV membrane potential of PNs. Then, the IC received ROS to induce LTP of IPSCs from PVNs to PNs, and we evaluated pain-related behaviors. Compared to those before ROS, the pain-related behaviors were further reduced after ROS. These results suggest that LTP induction of PVN→PN synapses in the IC could be a possible treatment for abnormal pain in the orofacial area.Copyright © 2025 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association for the Study of Pain.

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