Potentiation of the lateral habenula-ventral tegmental area pathway underlines the susceptibility to depression in mice with chronic pain.

Chronic pain often develops severe mood changes such as depression. However, how chronic pain leads to depression remains elusive and the mechanisms determining individuals' responses to depression are largely unexplored. Here we found that depression-like behaviors could only be observed in 67.9% of mice with chronic neuropathic pain, leaving 32.1% of mice with depression resilience. We determined that the spike discharges of the ventral tegmental area (VTA)-projecting lateral habenula (LHb) glutamatergic (Glu) neurons were sequentially increased in sham, resilient and susceptible mice, which consequently inhibited VTA dopaminergic (DA) neurons through a LHbGlu-VTAGABA-VTADA circuit. Furthermore, the LHbGlu-VTADA excitatory inputs were dampened via GABAB receptors in a pre-synaptic manner. Regulation of LHb-VTA pathway largely affected the development of depressive symptoms caused by chronic pain. Our study thus identifies a pivotal role of the LHb-VTA pathway in coupling chronic pain with depression and highlights the activity-dependent contribution of LHbGlu-to-VTADA inhibition in depressive behavioral regulation.

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.