Optogenetic activation of claustral glutamatergic neurons ameliorates pain hypersensitivity in a rat model of infraorbital nerve injury

Trigeminal neuropathic pain (TNP) is characterized by sensory hypersensitivity following trigeminal nerve injury and dysregulated cortical pain processing. The claustrum projects to the anterior cingulate cortex (ACC), a key region for sensory and affective pain responses, yet the role of this circuitry in TNP remains undefined. To address this gap, claustral glutamatergic neurons were optogenetically activated to determine whether enhancing claustral output modulates ACC activity and reduces orofacial pain hypersensitivity in a chronic constriction injury of the infraorbital nerve (CCI-ION) rat model.

Adult female Sprague–Dawley rats underwent CCI-ION or sham surgery, and AAV2-CaMKIIα-hChR2-EYFP or AAV2-CaMKIIα-EYFP was delivered into the claustrum. TNP hypersensitivity and anxiety-like behavior were assessed using electronic von Frey, cold acetone, and elevated plus maze tests. In vivo single-unit recordings were obtained from the ACC and ventral posteromedial (VPM) thalamus.

Optogenetic activation of CLAglu neurons attenuated trigeminal pain hypersensitivity and anxiety-like behavior. Electrophysiological analyses revealed that CLAglu stimulation suppressed ipsilateral ACC firing, with minimal contralateral changes, and reduced VPM activity. These findings demonstrate that enhancing claustral excitatory output suppresses ACC and VPM hyperactivity and alleviates orofacial pain hypersensitivity in TNP.

Therefore, claustrum-ACC circuitry represents a modulator of cortical pain processing and potential target for circuit-based interventions in TNP. Calcium/calmodulin-dependent protein kinase II alpha Chronic constriction injury of the infraorbital nerve Ventral posteromedial nucleus (of the thalamus) This work was supported by the National Research Foundation of Korea (NRF2023R1A2C1008079). Program in Neuroscience, College of Medicine, Chungbuk National University, Cheongju-si, Chungbuk, 28644, Republic of Korea Muhammad Ali, Jaisan Islam, Mahdi Hasan, Humaira Abbas, Yongjae Lee & Young Seok Park Department of Neurosurgery, Chungbuk National University Hospital, 776, 1 Sunhwanro, Seowon-gu, Cheongju-si, 28644, Republic of Korea All experiments and animal management were performed in accordance with the ethical guidelines of the International Association for the Study of Pain, approved by Chungbuk National University's Animal Care and Use Committee (IACUC) (CBNUA-25-0011-02).

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