ABSTRACT
Background and Purpose: Emerging evidence links astrocytes to
mechanical nociceptive processing, and the basolateral amygdala (BLA) is
a cerebral cortex region that is known to play a key role in pain
regulation. However, the association between BLA astrocytes and diabetic
neuropathic pain (DNP) pathogenesis remains largely unexplored. 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
pain-related negative emotions 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.