The pPVTglu- CeAGABA circuit is involved in regulating hyperalgesia in the chronic NTG mouse model in males

Chronic migraine imposes a large disease burden; however, its underlying mechanisms remain poorly understood. The paraventricular thalamus (PVT), traditionally linked to arousal, has recently been shown to regulate pain and negative emotions. However, the role of the PVT and its related neural circuits in migraine remains insufficiently investigated. The neglect of the PVT could be due to its high basal neuronal activity under physiological conditions, complicating the isolation of disease-specific changes. A mouse model of chronic migraine was established by repeated intraperitoneal injection of nitroglycerin (NTG) i.p. The mechanical hyperalgesia, anxiety, and depression-like behaviors of the mice were evaluated using the von Frey test, open field test, elevated plus maze test, and tail suspension test. The activation status of the posterior PVT (pPVT) was determined via the FosTRAP strategy, and behavioral tests were performed after its neurons were inhibited chemogenetically. Neural circuits potentially involved in regulation were subsequently identified by combining anterograde tracing with activity mapping in downstream regions. Finally, chemogenetic manipulation was employed to further verify the role of the circuit in NTG-induced chronic migraine. Mice with chronic migraine exhibited mechanical hyperalgesia and anxiety-like behavior, whereas depression-like behavior was not observed. Compared with the control group, the model group showed increased activation in the pPVT, as indicated by the results of the FosTRAP strategy. Chemogenetic inhibition of pPVT glutamatergic neurons can alleviate mechanical hyperalgesia in model mice without affecting anxiety-like behaviors. Projections from the pPVT innervate multiple regions, including the central amygdala (CeA). The model group showed increased activation in the CeA and its afferent input from the pPVT (pPVTglu- CeA). Chemogenetic inhibition of CeA GABAergic neurons alleviated both mechanical hyperalgesia and anxiety-like behavior in model mice. However, chemogenetic inhibition of both pPVTglu- CeA and CeA GABAergic neurons receiving input from the pPVT (pPVT- CeAGABA) can ameliorate mechanical hyperalgesia in model mice without affecting anxiety-like behaviors. The pPVTglu- CeAGABA circuit is involved in mechanical hyperalgesia behaviors in chronic migraine, and could be a promising candidate for chronic migraine treatment.