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.