The role of rostral ventromedial medulla astrocytes in the pathogenesis and modulation of diabetic neuropathic pain

Diabetic neuropathic pain (DNP), characterized by persistent spontaneous pain and evoked pain, poses clinical challenges including treatment resistance and frequent comorbidities with affective disorders such as anxiety and depression. Despite its clinical importance, the underlying mechanisms of DNP remain unclear. In our study, we reveal that hyperactivated astrocytes in the rostral ventromedial medulla (RVM) are functionally associated with both mechanical allodynia and anxiety-like behaviors in DNP. Chemogenetic inhibition of RVM astrocyte activity significantly alleviated mechanical allodynia and anxiety-like behaviors in DNP model rats. Conversely, targeted activation of RVM astrocytes in control rats induced neuropathic pain-like symptoms and pain-related aversion. Furthermore, we discovered that RVM astrocyte bidirectionally modulated glutamatergic neuronal activity; that is, astrocyte activation suppressed neuronal activity, whereas its inhibition increased neuronal excitability. These findings establish RVM astrocyte activation as a critical mediator of DNP pathogenesis, revealing a promising cellular target for the development of novel analgesics and providing therapeutic insights for DNP management.