An NTS-CeA projection modulates depression-like behaviors in a mouse model of chronic pain.

Depressive symptoms comorbid with chronic pain are a common health problem, but the underlying neural circuit mechanisms remain elusive. Here, we identify a glutamatergic projection from the nucleus of the solitary tract (NTS) to the central nucleus of the amygdala (CeA) that mediates depression-like behaviors in a chemotherapy-induced neuropathic pain model. Inhibition or ablation of the glutamatergic NTS neurons alleviates depressive but not hypersensitive behaviors in these mice. The projected neurons form excitatory synapses with somatostatin-expressing neurons in the CeA. Silencing the NTS-CeA projection alleviates depressive but not hypersensitive behaviors, whereas activating the proection promotes depressive behaviors. In addition, in naïve mice, activation of the NTS-CeA projection induces obvious depressive behaviors that can be blocked by silencing the CeA somatostatin-expressing neurons. Together, we reveal a modulatory role of the NTS and its glutamatergic projection to the CeA circuit in modulating depression-like behaviors comorbid to chronic pain.

Somatostatin Neurons from Periaqueductal Gray to Medulla Facilitate Neuropathic Pain in Male Mice.

Projections from the periaqueductal gray (PAG) to the rostral ventromedial medulla (RVM) are known to engage in descending pain modulation, but how the neural substrates of the PAG-RVM projections contribute to neuropathic pain remains largely unknown. In this study, we showed somatostatin-expressing glutamatergic neurons in the lateral/ventrolateral PAG that facilitate mechanical and thermal hypersensitivity in a mouse model of chemotherapy-induced neuropathic pain. We found that these neurons form direct excitatory connections with neurons in the RVM region. Inhibition of this PAG-RVM projection alleviates mechanical and thermal hypersensitivity associated with neuropathy, whereas its activation enhances hypersensitivity in the mice. Thus, our findings revealed that somatostatin neurons within the PAG-RVM axial are crucial for descending pain facilitation and can potentially be exploited as a useful therapeutic target for neuropathic pain. PERSPECTIVE: We report the profound contribution of somatostatin neurons within the PAG-RVM projections to descending pain facilitation underlying neuropathic pain. These results may help to develop central therapeutic strategies for neuropathic pain.