An NTS-expressing inhibitory circuit from interpeduncular nucleus to dorsal raphe nucleus controls pain and comorbid depression in male mice

作者：Lingzhen Song, Ting Ge, Mengqiao Cui, Morou Zhang, Min Wu, Qize Li, Xiaomai Zhou, Sha Sha, Xin Yang, Junxia Yang, Ankang Hu, Jun‐Li Cao, Hongxing Zhang · 发表于：Cell Reports · 年份：2025 · DOI：10.1016/j.celrep.2025.116719 · 被引用次数：4 · 研究领域：Neuropeptides and Animal Physiology、Pain Mechanisms and Treatments、Neuroscience of respiration and sleep

Chronic pain often co-occurs with depression; however, the underlying neural mechanisms remain unclear. This study explored a specific inhibitory pathway—interpeduncular nucleus (IPN) neurotensin (NTS)-expressing neurons projecting to the dorsal raphe nucleus (DRN)—in mediating pain and depression comorbidity in male mice. We demonstrate that complete Freund's adjuvant (CFA) mice show increased IPN NTS neuronal activity. Optogenetically activating IPN NTS neurons or their projections to DRN in naive mice reliably induces pain- and depressive-like behaviors. Conversely, optogenetic inhibition of IPN NTS neurons or their DRN projections reverses CFA-induced pain behaviors and comorbid depression. Notably, this optogenetic activation evokes GABA and NTS co-release in DRN. Surprisingly, activating IPN NTS -DRN projection induced behavioral outcomes are prevented by intra-DRN infusion of GABA A receptor antagonist, whereas antagonizing DRN NTS receptors induces pain but does not affect depressive-like behaviors. Our findings indicate a neural mechanism by which IPN NTS neurons and their DRN projection regulate pain and depression comorbidity.