Activation of GABAergic neurons in anterior cingulate cortex and their impacts on pulpitis-induced pain

Abstract

Dental pulpitis, a highly prevalent condition associated with severe pain, often poses a challenge for conventional analgesics, which exhibit limited efficacy in providing effective relief. Previous researches have focused primarily on the dental pulp nerve fibers, trigeminal ganglion, and medullary dorsal horn. Over the past few years, GABAergic neurons have been validated as important regulators of pain. However, the central neural mechanisms, especially involving GABAergic neurons in higher brain centers, that modulate dental pulpitis pain remain largely unclear. In this study, we utilized various techniques, including immunofluorescence staining, transmission electron microscopy, multichannel electrophysiology, in vivo fiber photometry and chemogenetics to investigate functional and structural plasticity of GABAergic neurons and their subgroups in anterior cingulate cortex (ACC) during dental pulpitis. FOS staining results indicated activation of ACC GABAergic neurons in pulpitis mice. Electron microscopy revealed the changes of postsynaptic densities in ACC synapses. Mean firing rates and calcium signals of ACC GABAergic neurons were significantly increased. Additionally, chemogenetic activation of ACC GABAergic neurons reduced pulpitis pain. Specifically, activation of parvalbumin-positive (PV) neurons had no effect while activating somatostatin-positive (SST) neurons significantly relieved pulpitis pain. In summary, our study identified the ACC as an important central modulator of dental pulpitis pain, highlighting the involvement of GABAergic neurons, especially the SST neurons. Our findings may offer potential therapeutic targets for dental pulpitis pain management.