Neuropathic pain is a chronic pain syndrome induced by abnormalities or damage to the somatosensory nervous system, which has a long and recurrent cycle and seriously affects patients’ quality of life (Finnerup et al., 2021, Baron et al., 2010). In the context of complex and undefined pathogenesis, treatment of neuropathic pain has mainly recourse to pharmacological intervention, with commonly used drugs of anticonvulsants and antidepressants, but these drugs have limited efficacy and serious side effects (Baron et al., 2010, Cavalli et al., 2019). Actively seeking new therapeutic strategies and exploring the mechanism of neuropathic pain may provide reference for clinical treatment.
With the development of traditional Chinese medicine resources, importance has increasingly been attached to relevant research and development (Wang et al., 2023). An increasing number of neuropathic pain patients are trying to seek relief from their symptoms by means of Chinese medicine (Li et al., 2020). Herbal monomers have good analgesic effects, including flavonoids, glycosides, alkaloids, etc (Li et al., 2020, Xu et al., 2012, Tian et al., 2021). Paeoniflorin is the main active ingredient of the Chinese medicines Paeonia lactiflora and Peony, which has a wide range of demonstrated pharmacological effects, such as antidepressant, anti-inflammatory, analgesic, and antitumor properties (Zhou et al., 2020, Qi et al., 2020). A review unveiled that paeoniflorin can regulate various signaling pathways, including cytokine-related janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathway and Transforming growth factor β (TGFβ)/Smads (Zhang and Wei, 2020). Previous studies have repeatedly demonstrated that paeoniflorin can relieve neuropathic pain (Liu et al., 2020, Chen et al., 2022a). Accordingly, we set out to further expound the mechanism of action of paeoniflorin.
Moreover, High Mobility Group Box 1 (HMGB1) has been widely confirmed as a potential therapeutic target for neuropathic pain (Maeda et al., 2013). Heat Shock Protein 90 Alpha Family Class A Member 1 (HSP90AA1) has been found to regulate the translocation and secretion of HMGB1 from the nucleus to the cytoplasm through direct action (Kim and Kwak, 2021). Besides, a previous study showed that HSP90AA1 promotes inflammation by regulating autophagy (Zhang et al., 2022). HSP90AA1 is also considered to be a microglial activation marker in Parkinson’s disease (Smajić et al., 2022a). HSP90AA1 colocates with astrocytes, and downregulation of HSP90AA1 may decrease microglial activation and amyloid-β clearance (Astillero-Lopez et al., 2024). Interestingly, SwissTargetPrediction analysis revealed that paeoniflorin is able to target HSP90AA1. Therefore, whether the HSP90AA1-HMGB1 axis constitutes the mechanism of paeoniflorin in neuropathic pain is the focus of our interest.
Neuroinflammatory reaction is an important pathological link in neuropathic pain, and microglia-astrocyte crosstalk plays an important role in the development of neuropathic pain (Wang et al., 2022, Asano and Hayashi, 2020). Studies have shown that many traditional Chinese medicines and compounds have the effect of inhibiting microglia activation (Chen et al., 2022b, Tang et al., 2022). Microglia are the primary source of microvesicles containing HMGB1, a protein associated with inflammation (Coleman et al., 2017). Elevated levels of HSP90AA1 characterize microglial activation during inflammatory processes (Smajić et al., 2022b). Therefore, we hypothesized that paeoniflorin reduces inflammation-induced neuropathic pain by preventing the translocation of HMGB1 from the nucleus to the cytoplasm in astrocytes via targeting HSP90AA1. Chronic constrictive injury (CCI)-induced neuropathic pain is one of the most important types, often used in in vivo experimental investigations (Hu et al., 2022). We utilized a CCI rat model and a lipopolysaccharide (LPS)-induced inflammation model to reveal the association between paeoniflorin, the HSP90AA1-HMGB1 axis, and microglia-astrocyte inflammatory crosstalk.