Background: Postherpetic neuralgia (PHN) causes chronic pain and emotional dysfunction, but its underlying mechanisms are unknown.

Methods: We first compared the structural and functional magnetic resonance imaging (MRI) of PHN-anxiety patients with healthy controls (HCs). Then, we created a PHN comorbid anxiety-like model by injecting resiniferatoxin (RTX) intraperitoneally and used Fos-CreER::Ai9 mice to validate brain regions with volume differences in MRI. Furthermore, we combined behavioral experiments with electrophysiology, viral tracing, in vivo fiber-photometry, optogenetics, and chemogenetics, to analyze the role of the basolateral amygdala (BLA)-anterior cingulate cortex (ACC) circuit in PHN comorbid anxiety-like mice multi-dimensionally.

Results: According to neuroimages, patients with PHN-anxiety comorbidity have decreased amygdala volume and decreased functional connection (FC) of the BLA and ACC. Furthermore, we created a PHN comorbid anxiety-like model by injection of RTX intraperitoneally, and these mice showed dysesthesia and anxiety-like behaviors 3 weeks after RTX injection. Then, we discovered that BLA and ACC were related to PHN comorbid anxiety-like behaviors using Fos-CreER::Ai9 mice. Immunohistochemistry and electrophysiology revealed enhanced activation of BLA glutamatergic (BLAGlu) neurons in PHN comorbid anxiety-like mice. Opto/chemogenetic activating BLAGlu neurons aggravated pain threshold in PHN comorbid anxiety-like mice. Inhibiting BLAGlu alleviates mechanical nociception, thermal hyperalgesia, and anxiety-like behavior. Moreover, the elevated excitability of BLAGlu neurons resulted in increased excitatory inputs to the ACC. Selective activation or inhibition of the BLAGlu-ACC pathway exacerbated or alleviated the pain and anxiety behavior, respectively.

Conclusion: Findings in this study will provide new insight for understanding the central pathomechanism underlying PHN-anxiety comorbidity, as well as serve as solid theoretical underpinnings for the management of PHN.