Muscarinic acetylcholine receptor M2 in the anterior cingulate cortex mediates central sensitization after peripheral nerve injury
TL;DR
Results indicate that the activity of mAChRs M2 in ACC pyramidal neurons is necessary for GluA1-dependent synaptic strengthening and pain sensitization, and targeting this receptor may represent a viable strategy for alleviating ACC-mediated chronic pain.
Abstract
The activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor subunit glutamate A1 (GluA1) in anterior cingulate cortex (ACC) has been implicated mechanical sensitization after peripheral nerve injury. Separately, muscarinic acetylcholine receptor (mAChR) activation is known to initiate downstream signaling cascades that regulate glutamate receptor expression, trafficking, and upregulation. To investigate the role of mAChR in the ACC under neuropathic pain conditions, we employed chronic constriction injury (CCI) modeling combined with mechanical allodynia tests, in vitro whole-cell patch-clamp recordings, western blotting, immunofluorescence staining, and RNA interference techniques in this study. Our results demonstrated that CCI led to increased amplitude and frequency of miniature excitatory postsynaptic currents, along with elevated GluA1 protein levels in the ACC. Notably, expression of mAChR M2 in the ACC was not significantly altered following nerve injury. However, conditional knockdown of mAChR M2 in ACC excitatory neurons significantly reduced GluA1 expression and attenuated neuropathic pain development in mice. These results indicate that the activity of mAChRs M2 in ACC pyramidal neurons is necessary for GluA1-dependent synaptic strengthening and pain sensitization. Thus, targeting this receptor may represent a viable strategy for alleviating ACC-mediated chronic pain.