49: A neuronal mechanism underlying comorbid pain and depression in mice

Topic: Basic Science
Subtopic: Pain category (ICD-11), Chronic neuropathic pain, , , , , , , , ,

Background and Aims: Trigeminal neuropathic pain is a chronic, debilitating condition often accompanied by depressive symptoms; however, the mechanisms behind this comorbidity remain poorly understood. Here, we aimed to identify and test the function of injury-activated neurons in the parasubthalamic nucleus (PSTN) that modulate both pain and depression-like behaviors in a trigeminal neuropathic pain model.

Methods: We induced trigeminal neuropathic pain using chronic constriction injury of the infraorbital nerve (CCI-ION) in mice. Mechanical hypersensitivity was assessed with von Frey testing, and depression-like behaviors were assessed using the tail suspension and forced swim tests. Injury-activated neurons were captured using TRAP in Fos2A-iCreER (TRAP2) mice. We then used optogenetics to manipulate TRAPed PSTN neurons and immunostaining to determine the cell type. In parallel, CaMKII promoter–driven chemogenetics was used to selectively activate excitatory PSTN neurons and evaluate effects on pain and depression-like behaviors.

Results: CCI-ION reduced head withdrawal thresholds in the von Frey test and increased immobility in the tail suspension and forced swim tests. Using TRAP, we labeled a subset of PSTN neurons activated by trigeminal nerve injury. Optogenetic activation of these TRAPed PSTN neurons attenuated both pain hypersensitivity and depression-like behaviors, whereas silencing them further worsened both phenotypes. Immunostaining showed that most TRAPed PSTN neurons were glutamatergic, and consistent with this, chemogenetic activation of CaMKII-positive (excitatory) PSTN neurons alleviated trigeminal neuropathic pain and associated depression-like behaviors.

Conclusions: Injury-activated, predominantly glutamatergic PSTN neurons causally modulate both trigeminal neuropathic pain and depression-like behaviors in the CCI-ION model. These findings suggest that glutamatergic neurons in the PSTN are critical for the modulation of comorbid pain and depression in the CCI-ION mouse model, which could be targeted for treating this comorbidity condition.

References: Liu S, Crawford J, Maltezos H, Sun Y, Tao R, Tao F. A glutamatergic brain neural circuit is critical for modulating trigeminal
neuropathic pain. Pain. 2025 Nov 1;166(11):2529-2540. PubMed Central PMCID: PMC12354078.
This work was supported by the National Institutes of Health Grants R03DE031822 (S.L.), R01DE031255 (F.T.), and R01DE032061 (F.T.).

Presenting Author: Sufang Liu
Submitting Author: Sufang Liu

Senior Author: Feng Tao

IASP 2026 Global Year theme of Neuropathic Pain: Yes

• Nichole Jeong: B.S. - Texas A&M University College of Dentistry
• Feng Tao: MD, PhD - Texas A&M University College of Dentistry