Central sensitization, where the input of noxious stimuli enhances the perceptual response of the central nervous system to pain, is caused by tissue inflammation or peripheral nerve damage and plays an important role in persistent pain (Van Griensven et al., 2020). Previous research has shown that a local cutaneous injury can produce primary hyperalgesia within the injured area and secondary hyperalgesia in the normal surrounding skin, for example, an intradermal injection of capsaicin in humans causes intense pain and hyperalgesia to heat and mechanical stimuli in the surrounding skin. Psychophysical studies in humans supported the conclusions that hyperalgesia was predominantly the secondary type and depended on one set of neurons sensitizing another (“neurogenic hyperalgesia”) and that the latter set of neurons is located in the central and not the peripheral nervous system (Baumann et al., 1991). Central sensitization is accountable for spreading pain and hyperalgesia to uninjured tissue, the process is involved in pain-transmission neurons in the central nervous system (CNS), often in the dorsal horn of the spinal cord (Kim et al., 2009). Second-level sensory neurons, or the relay stations of the conduction of the sensory system, are represented by the neurons of the spinal dorsal horn. The ascending fiber tracts are created by the spinal dorsal horn neurons’ axons as they enter the ipsilateral or contralateral white matter. These ascending fiber tracts then transmit the dorsal root afferents’ nerve impulses to the third-level neurons in the ventroposterolateral thalamic nucleus of the brain, which then transmits them to the cerebral cortex. Some results suggested that acupuncture may simultaneously modulate the resting state functional connectivity (rsFC) of key regions in the descending pain modulation (periaqueductal gray, PAG) and reward systems (ventral tegmental area, VTA), and the amygdala may be a key node linking the two systems to produce antinociceptive effects (Yu et al., 2020). This makes sense because it is widely known that ipsilateral acupuncture has an impact on numerous descending inhibitory networks from the amygdala, periaqueductal gray (PAG), and rostroventral medulla (RVM) which primarily modulate nociceptive signals entering the ipsilateral spinal cord and are influenced by ipsilateral acupuncture (Levine et al., 1991; Van Bockstaele et al., 1991; Manning, 1998; Urban et al., 1999). Acupuncture is demonstrated to activate the ascending sensory pathways, such as the spinal dorsal horn and thalamus, or the descending pain inhibitory mechanisms, such as opioid, adrenergic, and serotonergic pathways, however, the precise areas where EA affects pain are not fully established (Skrabanek, 1984; Tian et al., 2006; Li et al., 2007; Koo et al., 2008).

According to previous findings, PNI not only results in localized damage but also trigger the apoptosis of certain spinal cord neurons in corresponding spinal cord segments (Inquimbert et al., 2018). The survival of central neurons plays a key role in determining the effectiveness of peripheral nerve regeneration (Kim and Choi, 2016). After PNI, the corresponding neuron cell bodies will undergo apoptosis because of neurotrophin transmission disorders. And we discovered that glial cell-derived neurotrophic factors and brain-derived neurotrophic factors could alleviate PNI in animal models, and decrease apoptosis and autophagy in vitro cell and cell injury model studies (Chou et al., 2014; Kingham et al., 2014). PNI causes apoptosis in spinal motor neurons and sensory spinal ganglion neurons, but it is not extensive and does not affect the entire spinal cord, it is associated with neurons that are connected to the injured peripheral nerves (Ahmad et al., 2015). According to a previous study, acupuncture can ensure and enhance the continuity between peripheral and central nerves, speeding up the process of repairing injured nerves, laying the groundwork for regeneration, and effectively restoring motor conduction (He et al., 2015), and electroacupuncture could dramatically boost facial nerve regeneration by increasing the expression of GDNF and N-cadherin in neurons, preventing neuronal apoptosis (Fei et al., 2019). Some results indicate that EA suppresses spinal nerve ligation (SNL)-induced neuropathic pain by improving neuronal plasticity via upregulating the adenosine A2A receptor (A2AR) and the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signaling pathway (Wu et al., 2021a), but more research is still needed to understand the underlying mechanism. Table 2 summarizes the evidence of the mechanism of acupuncture on the repair of spinal cord regulation in peripheral nerve injury.

Numerous brain regions and nuclei, including the caudate nucleus, septal area, arcuate nucleus, periaqueductal gray, and nucleus raphe magnus, all of which contain opioid peptides, and μ, δ, and κ receptors, are involved in the transmission of acupuncture signals (Zhao, 2008). The hypothalamic arcuate nucleus is a significant structure in the endogenous opioid peptide system and a crucial region that mediates low-frequency electroanalgesia (Takeshige et al., 1991). Researchers found that acupuncture at HT7 points attenuates behavioral manifestation of alcohol dependence by activating endorphinergic input to the nucleus accumbens (NAc) from the arcuate nucleus(ARC) (Chang et al., 2019). The arcuate nucleus may control electroanalgesia based on the fact that its axons branch out to the adjacent nucleus accumbens, septum, periaqueductal gray, and locus coeruleus. In praxiology and electrophysiology, activating the arcuate nucleus will boost analgesic effects, increased the activity of neurons in the dorsal raphe nucleus and decreased the activity of neurons in the locus coeruleus (Kwon et al., 2004; Yoon et al., 2013). According to studies, more genes were differentially regulated by low-frequency EA than high-frequency EA (154 vs. 66 regulated genes/ESTs) in Arc, especially those related to neurogenesis (Wang et al., 2012). These findings suggest that the opioid-system network that includes the dorsal horn, periaqueductal gray, nucleus raphe magnus, and the arcuate nucleus is crucial for electroanalgesia (Mayer et al., 1977; Han et al., 1991).

According to some studies, corticospinal tract(CST) and spinothalamic tract (STT) fibers are similarly altered when peripheral nerve injury occurs (Zhang et al., 2019). Previous research demonstrated that neural pathway injuries, such as brain and spinal cord injuries, caused STT fibers to adapt or be maladapt (Wang and Thompson, 2008; Wasner et al., 2008). According to findings from a rat study, chronic pain stimuli of the sciatic nerve could lead to the hyperexcitability of ventral posterior thalamus neurons, which were the major termination of STT fibers and responsible for the signal relay (Miki et al., 2000). Neuronal hyperexcitability could be an inappropriate reaction to a reduction or absence of sensory input. Although there was little evidence that acupuncture improved sensory function, some researchers thought that the plasticity alteration in STT may also be predicted to restore sensory function. Previous studies found that acupuncture treatment has a complex effect on the corticospinal system for a variety of disorders (Chen et al., 2015; Yang et al., 2017). It is demonstrated that based on routine rehabilitation treatment, scalp acupuncture plus low-frequency rTMS can promote white matter tracts repair better than scalp acupuncture alone for stroke hemiplegic patients (Zhao N. et al., 2018). Prior research changed the focus of plasticity from gray matter, which includes the motor cortex, to white matter, which includes the CST. Cortical alterations were anticipated to lead to modifications in efferent neural pathways (Matsumoto-Miyazaki et al., 2016). Acupuncture also aided in the recovery process and ameliorated the efferent neural pathway’s longitudinal prognosis (Zou et al., 2019). Table 4 summarizes the evidence of the mechanism of acupuncture on the regulation of brain regions in peripheral nerve injury.

Nerve growth factor (NGF) is the earliest discovered neurotrophic factor and can nourish neurons and promote neurite sprouting (Yu et al., 2014).In response to nerve damage, NGF expression was upregulated, creating the ideal conditions for axon regeneration, the restoration of the connection between axons and Schwann cells, and the reinnervation of target locations to enhance nerve growth (Tang et al., 2013). After peripheral nerve damage, EA may strengthen new axonal connections, which would ultimately accelerate the transfer of NGF. Additionally, EA was able to promote the growth of Schwann cells, which greatly increased the amount of NGF released (Hu et al., 2018).

In the peripheral nervous system, Schwann cells (SCs) are the predominant glial cells. Following PNI, SC migration and proliferation result in the release of a variety of neurotrophic factors (NTFs), which are beneficial for preserving the survival of injured neurons, encouraging nerve fiber regeneration, and fostering the formation of new synapses (Dai et al., 2013). It has been demonstrated that EA may promote the recovery of neuroplasticity in rats subjected to spinal cord transection. This could be attributed to the systematic regulation of NTFs and their receptors after EA.EA stimulation at ST36 in rats increases the expression of axonal growth-associated protein 43 in neurons of the dorsal root ganglia, promoting axonal development (Wang et al., 2017). EA may alleviate tibialis anterior muscle atrophy induced by sciatic nerve injection injury by upregulating agrin and AChR-ε and downregulating AChR-γ (Yu et al., 2017). Some studies found that EA increased NT-3 levels and promoted differentiation of oligodendrocyte-like cells from grafted NR-MSCs in the demyelinated spinal cord and induced MSC transplantation combined with EA treatment not only increased MSC differentiation into oligodendrocyte-like cells forming myelin sheaths but also promoted remyelination and functional improvement of nerve conduction in the demyelinated spinal cord (Liu et al., 2015). Some researchers indicate that electroacupuncture and moxibustion promoted nerve regeneration and functional recovery, which mechanism might be associated with the enhancement of Schwann cell proliferation and upregulation of nerve growth factor (Hu et al., 2018).

As one of the most significant NTFs, persistent exogenous BDNF release in the damaged peripheral nerve may be a helpful tool to boost axonal density (Lopes et al., 2017). In the recovery process after peripheral nerve injury in rats, electrical muscle stimulation increases intramuscular BDNF levels (Willand et al., 2016). Studies have shown that BDNF actively contributes to the regeneration of motor neurons and the restoration of motor function. The amount of the protein BDNF, which has been identified as a crucial regulator of axon regeneration, was significantly enhanced in the spinal cord and DRG following PNI (Santos et al., 2016; Sanna et al., 2017; McGregor and English, 2018).

Previous research demonstrated that glial cell-derived neurotrophic factor (GDNF) was the most effective survival factor described for motoneurons in vitro (Höke et al., 2002). Recent investigations have proven GDNF’s function in neuronal protection and axonal regeneration in vivo (Allen et al., 2013; Kopra et al., 2015). Researchers discovered that GDNF mRNA is expressed in the cytoplasm membrane, notably in the neuromuscular junctions, and less in the axons and Schwann cells (Suzuki et al., 1998). To protect neurons, GDNF binds to N-cadherin and initiates the intracellular PI3K/Akt signaling pathway (Wang et al., 2014). Researchers found that EA with high-frequency and long-term stimuli at acupoint ST-36 can induce regeneration of lost enteric neurons in diabetic rats, and GDNF and PI3K/Akt signal pathway may play an important role in EA-induced regeneration of impaired enteric neurons (Du and Liu, 2015).

Cadherins tend to form dimers or multimers, and the extracellular peptide chain partially folds to form five or six repeat domains (Stevens et al., 2023). Calcium ions are bound between the repeat domains, thus imparting rigidity and strength to the cadherin molecule (Oroz et al., 2011). The more calcium ions are bound, the more rigid the cadherin is, so when calcium ions are removed, the rigidity of the extracellular part of the cadherin is lost. Researchers revealed that electroacupuncture may encourage nerve regeneration through an increase in calcium concentration, which activates neuron outgrowth and repair (McCaig et al., 2002). Similarly to NCAM and integrin 1, N-cadherin is a calcium-dependent neuronal cell surface protein that facilitates adhesion and signal transduction (Neugebauer et al., 1988). Ret has a cadherin-like domain in its extracellular region that interacts with the GDNF/GDNF family receptor α1 (Oppenheim et al., 1995; Kjaer and Ibáñez, 2003). Some studies have confirmed that electroacupuncture promotes regeneration of peripheral facial nerve injury in rabbits, inhibits neuronal apoptosis, and reduces peripheral inflammatory response, resulting in the recovery of facial muscle function, which is achieved by up-regulating the expression of GDNF and N-cadherin in central facial neurons (Fei et al., 2019). GDNF binds to N-cadherin, a transmembrane cell adhesion molecule, to exercise its neuroprotective impact on dopaminergic neurons (Cao et al., 2010; Patil et al., 2011; Zuo et al., 2013).

MicroRNAs (miRNAs), which comprise between 2 and 3 percent of all human genes and primarily function to silence genes by binding to people’s targets’ 3′ untranslated regions (3′ UTR), are a vital and significant component of the regulation over a variety of signaling pathways and biological functions in the restoration of PNI (Wanke et al., 2018; Treiber et al., 2019), so MiRNAs have gained growing interest in the field of peripheral nerve regeneration (Yu et al., 2015). Numerous studies have shown that miRNAs play a key role in the recovery process after PNI. For instance, miRNA expression in rat dorsal root ganglia (DRG) tissues was drastically altered following sciatic nerve damage (Li et al., 2012). To increase rat DRG neurons’ survival and prevent apoptosis following sciatic nerve damage, miR142-3p can target CDKN1B and TIMP3. MiR-7 influences repair following PNI by targeting cdc42 and preventing neural stem cell migration and proliferation. By targeting GF1-A-binding protein 1, miR-221-3p may prevent SCs from maturing into myelin sheaths when they are cocultured with DRG neurons (Nab1) (Zhao L. et al., 2018; Zhou et al., 2018). Researchers have demonstrated miR-1-targeting BDNF in the regulation of SC proliferation and migration following nerve injury; in addition, miR-1 modulated chronic neuropathic pain in rats by targeting cx43 and BDNF, and miR-206 can target BDNF to the regulation of the MERK-ERK signaling pathway to influence neuro stress pain (Neumann et al., 2015; Yi et al., 2016; Sun et al., 2017). Liu et al. (2018) have discovered that miR-1b overexpression inhibited RSC96’s migration and proliferation while boosting cell apoptosis. Similar targets and expression profiles are used to identify miRNAs that belong to the same family. Numerous miRNAs, including miR-129 and miR-195, had altered expression following PNI, according to studies (Shi et al., 2013; Zhu et al., 2018). Using miR-132 to target SOX2-mediated axonal regeneration, it has been found that EA improved neurobehavioral functional recovery after ischemic stroke (Zhao X. et al., 2018). According to another study, let-7b-5p, miR-148a-3p, miR-124-3p, miR-107-3p, and miR-370-3p were confirmed to participate in EA tolerance probably through the functional categories related to nerve impulse transmission, receptor signal pathways, and gene expression regulation, as well as pathways related to MAPK, neurotrophin, fatty acid metabolism, lysosome, and the degradation of valine, leucine, and isoleucine (Cui et al., 2017). MiR-1b expression was initially found to be highly downregulated in the local nerve following EA in a prior investigation, and EA may promote the proliferation, migration of SC, and nerve repair after PNI by regulating miR-1b, which targets BDNF (Liu et al., 2020). Table 5 summarizes the evidence of the mechanism of acupuncture on the regulation of factors associated with neuronal response in peripheral nerve injury.