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Exp. Mol. Med., Apr 10 2025, | https://doi.org/10.1038/s12276-025-01435-y Increased mGluR5 in somatostatin-positive interneurons mediates deactivation of the mPFC in a mouse model of neuropathic pain

Mirae Jang ^1,2, Jaegeon Lee ^1,2,3, Seung Ha Kim^1,2, Sang Ho Yoon ^1,2,3, Myoung-Hwan Kim ^1,2,3, Yong-Seok Lee ^1,2,3, Sun Kwang Kim ^4,5, Geehoon Chung ^6,* and Sang Jeong Kim ^1,2,3,*

¹Department of Physiology, Seoul National University College of Medicine, Seoul, Republic of Korea.
²Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea.
³Memory Network Medical Research Center, Neuroscience Research Institute, Wide River Institute of Immunology, Seoul National University College of Medicine, Seoul, Republic of Korea.
⁴Department of Physiology, College of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea.
⁵Department of Science in Korean Medicine, Graduate School, Kyung Hee University, Seoul, Republic of Korea.
⁶Department of Physiology, College of medicine, Chungbuk National University, Cheongju, Republic of Korea.

^*Corresponding authors: correspondence to Geehoon Chung or Sang Jeong Kim

Abstract

Understanding the neurobiological alterations associated with neuropathic pain is crucial for treatment interventions, but the underlying mechanisms remain unclear. We focused on the medial prefrontal cortex (mPFC), which undergoes various processes of plasticity during the development of neuropathic pain. In particular, in the neuropathic pain state, the pyramidal neuron activity is decreased and metabotropic glutamate receptor 5 (mGluR5) activity is increased in the mPFC. Here we investigated whether mGluR5 inactivation restores neuropathic pain in mice and, if so, how this inactivation affects local circuits in the mPFC. First, we confirmed the analgesic effect of mGluR5 inactivation in the mPFC using a pharmacological approach. Then, via electrophysiological recordings, we showed that the spontaneous inhibitory postsynaptic current (sIPSC) frequency in pyramidal neurons increased during the neuropathic pain state and that this change was attenuated by applying a mGluR5 antagonist. Also, the application of a mGluR5 agonist increased the sIPSC to layer 5 pyramidal neurons in naive mice, consistent with the findings in neuropathic pain conditions. Furthermore, somatostatin (SST)-expressing interneurons in the neuropathic pain group were more depolarized than those in the sham group through mGluR5 activation. Optogenetic inactivation of SST interneurons reversed the increase in sIPSC frequency of pyramidal neurons in the neuropathic pain group. Conversely, mGluR5 overexpression in SST interneurons in the mPFC of naive mice resulted in mechanical allodynia, a representative symptom of neuropathic pain. These results demonstrate that increased mGluR5 activity in SST interneurons contributes to neuropathic pain and that cell-type-specific modulation can provide new avenues for treating neuropathic pain.

논문정보

형식Research article
게재일2025년 04월 (BRIC 등록일 2025-04-15)
연구진국내 연구진
분야 의약학 > 신경의학

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