Upregulation of Beta4 subunit of BK_Ca channels in the anterior cingulate cortex contributes to mechanical allodynia associated anxiety-like behaviors.

The anterior cingulate cortex (ACC) serves as a critical hub for the anxiety and pain perception. The large-conductance Ca²⁺-activated potassium channels, or BK_Ca channels, are ubiquitously expressed throughout the central nervous system including the cingulate cortex. However, what changes of cortical BK_Ca channels undergo in the ACC remains unknown in pain-related anxiety. In the present study, a significant upregulation of synaptic and non-synaptic BK_Ca channel accessory β4 subunits in the ACC was accompanied with pain-associated anxiety-like behaviors in the chronic compression of multiple dorsal root ganglia (mCCD) of the rat. NS1619, an opener of BK_Ca channels, significantly rescued the alteration of fAHP and AP duration of ACC pyramidal neurons in mCCD rats. The mRNA expression of BK_Ca β4 subunits was extremely upregulated in the ACC after mCCD with the increased amount of both synaptic and non-synaptic BK_Ca β4 subunit protein. Meanwhile, NS1619 reversed the enhanced AMPA receptor-mediated spontaneous excitatory postsynaptic current (sEPSC) frequency and the attenuated PPR of ACC neurons in mCCD rats. Local activation of BK_Ca channels in the ACC reversed mechanical allodynia and anxiety-like behaviors. These results suggest that the upregulation of postsynaptic and presynaptic BK_Ca β4 subunit may contribute to neuronal hyperexcitability and the enhanced synaptic transmission in the ACC in neuropathic pain state, and then may result in anxiety-like behavior induced by neuropathic pain.

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