Anxiety disorder is a common mental comorbidity of chronic pain, but how chronic pain induces anxiety symptoms remains incompletely understood. Here, using a mouse model of neuropathic pain, we demonstrate the combined contributions of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) trafficking onto synaptic membrane and ambient glutamate-mediated tonic excitation in contralateral ventromedial prefrontal cortex. The results indicate that enhanced AMPAR trafficking is required but not sufficient for chronic pain-induced anxiety-like behaviors. Aberrant tonic excitation potentiates AMPAR-mediated synaptic transmission after AMPAR trafficking and consequently causes anxiety-like behaviors. Furthermore, we find neuronal bestrophin 1 (BEST1)-mediated glutamate release as the source of aberrant tonic excitation. Neuron-specific BEST1 knockout does not relieve chronic pain but alleviates comorbid anxiety-like behaviors and even displays anxiolytic-like effects when chronic pain is relieved by analgesic treatment. Alogether, this study indicates a dual mechanism underlying chronic pain-induced anxiety and proposes BEST1 as an efficacious target for the therapy of comorbid anxiety during chronic pain.
Xiong et al. (2026) studied this question.