Proanthocyanidins induce analgesic and anxiolytic effects in spared nerve injured mice by decreasing in vivo firing rate of pyramidal cells in the insular cortex.

Neuropathic pain is one of the most common symptoms of clinical pain that often accompanied by severe emotional changes such as anxiety. However, the treatment for comorbidity of chronic pain and anxiety is limited. Proanthocyanidins (PACs), a group of polyphenols enriched in plants and foods, have been reported to cause pain-alleviating effects. However, whether and how PACs induce analgesic and anxiolytic effects in the central nervous system remain obscure. In the present study, we observed that microinjection of PACs into the insular cortex (IC) inhibited mechanical and spontaneous pain sensitivity and anxiety-like behaviors in mice with spared nerve injury. Meanwhile, PACs application exclusively reduced the FOS expression in the pyramidal cells but not interneurons in the IC. In vivo electrophysiological recording of the IC further showed that PACS application inhibited the firing rate of spikes of pyramidal cells of IC in neuropathic pain mice. In summary, PACs induce analgesic and anxiolytic effects by inhibiting the spiking of pyramidal cells of the IC in mice with neuropathic pain, which should provide new evidence of PACs as the potential clinical treatment of chronic pain and anxiety comorbidity.

Glutamatergic synapses from the insular cortex to the basolateral amygdala encode observational pain.

Empathic pain has attracted the interest of a substantial number of researchers studying the social transfer of pain in the sociological, psychological, and neuroscience fields. However, the neural mechanism of empathic pain remains elusive. Here, we establish a long-term observational pain model in mice and find that glutamatergic projection from the insular cortex (IC) to the basolateral amygdala (BLA) is critical for the formation of observational pain. The selective activation or inhibition of the IC-BLA projection pathway strengthens or weakens the intensity of observational pain, respectively. The synaptic molecules are screened, and the upregulated synaptotagmin-2 and RIM3 are identified as key signals in controlling the increased synaptic glutamate transmission from the IC to the BLA. Together, these results reveal the molecular and synaptic mechanisms of a previously unidentified neural pathway that regulates observational pain in mice.

The increased in vivo firing of pyramidal cells but not interneurons in the anterior cingulate cortex after neuropathic pain.

Chronic pain damages the balance between excitation and inhibition in the sensory cortex. It has been confirmed that the activity of cortical glutamatergic pyramidal cells increases after chronic pain. However, whether the activity of inhibitory interneurons synchronized changed remains obscure, especially in in vivo conditions. In the present study, we checked the firing rate of pyramidal cells and interneurons in the anterior cingulate cortex, a main cortical area for the regulation of nociceptive information in mice with spared nerve injury by using in vivo multi-channel recording system. We found that the firing rate of pyramidal cells but not interneurons increased in the ACC, which was further confirmed by the increased FOS expression in pyramidal cells but not interneurons, in mice with neuropathic pain. Selectively high frequency stimulation of the ACC nociceptive afferent fibers only potentiated the activity of pyramidal cells either. Our results thus suggest that the increased activity of pyramidal cells contributes to the damaged E/I balance in the ACC and is important for the pain hypersensitivity in mice with neuropathic pain.