Basolateral amygdala astrocytes modulate of diabetic neuropathic pain and may be a potential therapeutic target for koumine

Background and Purpose: New remedies are required for the treatment of diabetic neuropathic pain (DNP) due to insufficient efficacy of available therapies. Here, we used chemogenetic approaches combined with in vivo pharmacology to elucidate the role of BLA astrocytes in DNP pathogenesis and provide new insights into DNP therapeutic strategies. Experimental Approach: A streptozotocin-induced DNP model was established. Designer receptors exclusively activated by designer drugs (DREADDs) were used to regulate the activity of astrocytes. Mechanical hyperalgesia was assessed using the electronic von Frey test. Anxiety-like behaviors were detected by open field and elevated plus maze tests. Astrocytic activity was detected by immunofluorescence, and cytokine content was determined by ELISA. Key Results: BLA astrocytes were regulated by DREADDs, and inhibition of BLA astrocytes attenuated mechanical allodynia and anxiety-like behavior in DNP rats. Contrastively, temporary activation of BLA astrocytes induced allodynia without anxious behavior in naive rats. In addition, we found that koumine alleviates mechanical allodynia and anxiety-like behavior in DNP rats, inhibits the activation of BLA astrocytes and suppresses the inflammatory response. Furthermore, persistent activation of BLA astrocytes by chemogenetic mimics chronic pain, and koumine can alleviate its pain hypersensitivity and anxiety-like behavior. Conclusion and Implications: DREADDs bidirectionally regulate the activity of BLA astrocytes, which proves for the first time the role of BLA astrocytes activation in the pathogenesis of DNP and represents a novel therapeutic strategy for DNP. Koumine ameliorated DNP, perhaps by inhibiting the activation of BLA astrocytes and reveal KM as a potential candidate for treating DNP.