1. INTRODUCTION
Diabetic neuropathic pain (DNP), a common chronic complication in diabetes, is recognized as one of the most difficult types of pain to treat (Peltier et al., 2014; Alam et al., 2020). It has long been thought that neuronal hyperexcitability and increased synaptic transmission contribute to sensitization of the central nervous system, which promotes the initiation and maintenance of neuropathic pain (Campbell and Meyer, 2006). Neuron-targeting drugs are the main treatment for neuropathic pain, but they are limited by the lack of obvious efficacy and serious side effects (Rosenberger et al., 2020; Finnerup et al., 2021). In fact, it was recently discovered that the opioid analgesic morphine significantly prolonged the duration of hypersensitivity to pain in rats with neuropathic pain (Grace et al., 2016). This problematic feature of the current DNP therapeutic strategies highlights the urgent need to advance our understanding of the mechanism underlying DNP and to identify novel therapeutic targets.
In recent years, the role of astrocytes in neuropathic pain has gradually attracted attention and the focus has gradually shifted from the spinal cord level to the pain-related brain matrix above the spinal cord. (Ji et al., 2019; Tang et al., 2021). Basolateral amygdala (BLA) is an important component of the limbic system, which plays a key regulatory role in pain modulation and emotional disorders (such as fear, anxiety and depression) (Adhikari et al., 2015; Sah, 2017; Hartley et al., 2019, 2019). Even though it has been reported that BLA astrocytes are involved in the development of pain, there is no direct evidence of the role of BLA astrocytes in the pathogenesis of DNP due to the lack of tools for direct and precise regulation of astrocytes. With the advent of chemogenetic tools, designer receptors exclusively activated by designer drugs (DREADDs) has provided the possibility to specifically regulate astrocyte activity in vivo(Shen et al., 2021). In previous studies, we used DREADDs to specifically regulate the activity of motor cortex (MCx) astrocytes, and found that the activation of MCx astrocytes was involved in the exacerbation of neuropathic pain in rats(Lu et al., 2021). Therefore, this study aimed to specifically regulate the activity of astrocytes by DREADDs and provide direct evidence for the involvement of BLA astrocytes in the pathogenesis of DNP.
Koumine (KM) is one of the main alkaloids of Gelsemium elegansBenth . Due to its suitable biological activities and few side effects, it has attracted increasing attention from researchers. Previous studies have shown that KM can significantly increase pain thresholds in animals with neuropathic pain by inhibiting glial cell activation in the spinal dorsal horn, and KM administration does not result in tolerance or dependence and is safe (Jin et al., 2018, 2021; Shoaib et al., 2019). In addition, neuropathic pain is often accompanied by comorbidities like anxiety, and we found that KM has a significant anti-anxiety effect (Chen et al., 2017). However, whether KM can alleviate anxiety-like behaviors caused by chronic pain and its effect on astrocytes in the BLA remain to be clarified.
In the present study, we employed astrocyte-specific expression of DREADDs to clarify the role of BLA astrocytes in the development of DNP and observed the relationship between the anti-DNP effect of KM and the activation of BLA astrocytes. We provide evidence for the first time that targeting BLA astrocytes may be a potential strategy for the treatment of DNP. KM may significantly reduce mechanical pain and anxiety-like behavior in DNP rats by inhibiting BLA astrocyte activation, and may be a potential new drug candidate for DNP treatment.