55: Mechanism of Medial Ventral Tegmental Area to the Lateral Habenula in Chronic Pain Comorbidity

Topic: Basic Science
Subtopic: Pain category (ICD-11), Chronic neuropathic pain, , , , , , , , , , Neurocircuit modulation (could include opto, DREADDs)

Background and Aims: The mechanisms underlying chronic pain comorbid with anxiety and depression remain elusive, posing substantial clinical challenges. This study aims to investigate the role of ventral tegmental area (VTA) glutamate (Glu)/GABA co-releasing neurons and their projections to the lateral habenula (LHb) in the pathogenesis of chronic pain–anxiety/depression comorbidity, and to provide a theoretical basis for developing synergistic intervention strategies.

Methods: The spared nerve injury (SNI) mouse model was employed to induce chronic pain with anxiety and depression. Chemogenetic and optogenetic approaches were employed to modulate the excitability of the VTA–LHb pathway, followed by behavioral assessments of pain thresholds and affective behaviors. Fiber photometry was used to record calcium signals in VTA neurons projecting to the LHb, and neurotransmitter biosensors were applied to monitor Glu/GABA release in the LHb. Neuropharmacological validation of target function was performed. We characterized the excitability changes and neurotransmitter release patterns in the VTA–LHb pathway and their role in the development of chronic pain–anxiety/depression comorbidity.

Results: Chemogenetic inhibition of VTA excitatory neurons alleviated neuropathic pain and affective comorbidities in SNI mice. VTA–LHb pathway activation reduced pain thresholds in controls, while its inhibition alleviated pain and affective comorbidities in SNI mice. These neurons were activated by acute noxious stimuli and became hyperexcitable in the comorbid state. Acute pain increased both Glu and GABA signals in LHb, but comorbid mice showed elevated Glu with relatively reduced GABA. LHb co-administration of Glu antagonist and GABA agonist synergistically alleviated pain and affective comorbidities.

Conclusions: Pathological hyperexcitability of VTA–LHb Glu/GABA co-releasing neurons and the consequent Glu/GABA neurotransmitter imbalance in the LHb represent a critical neural circuit mechanism driving chronic pain–anxiety/depression comorbidity. These findings provide a theoretical basis for developing synergistic intervention strategies targeting this pathway and highlight its potential clinical translatability.

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Presenting Author: Wangyuan Zou
Submitting Author: Wangyuan Zou

Senior Author: Wangyuan Zou

IASP 2026 Global Year theme of Neuropathic Pain: Yes