## 3 Percutaneous Electrical Nerve Stimulation (PENS)  
PENS is a mini-invasive neuromodulation technique that alters nerve impulses at the subcutaneous level and might be effective in chronic and refractory pain management [28]. Moreover, the mechanisms underpinning its positive effects in neuropathic pain management involve the physiological gate control theory, recently implemented and revisited [29]. To date, the gate control regulation theory indicates that inhibitory interneurons at the spinal level are the keys that might open or close \"the gate\" to the painful sensation [30]. However, a large heterogeneity of interneurons has been identified, both excitatory (pain facilitation) and inhibitory (pain inhibition). It has been hypothesized that specific anterograde signals might play a crucial role in gate control regulation; however, despite the progress in the last decades in pain modulation circuits understanding, the precise mechanisms underpinning inhibitory interneurons spinal circuits are far from being fully understood [29]. In this scenario, a growing interest has been rising in the research field about neuron-microglia communication with intriguing implications in neuropathic pain modulation. [PERSON] et al. [31] recently suggested that the purinergic receptor P2 \(\times\) 4R might be involved in the processing of somatosensory cardinal symptoms and principal components of neuropathic pain, and in the process of cortex plasticity [31]. The authors concluded that, despite the role of microglia in microgliosis, migration, phagocytosis and synaptic pruning process, its direct effects on the pathogenesis and modulation of neuropathic pain are still unclear. Furthermore, one of the most widely investigated pathways in the spinal inhibitory control of neuropathic pain involves the endogenous neuropeptide Y. However, its role as a pain regulator is far from being completely understood due to the complex expression of its receptors in both post-synaptic neurons and in the central terminals of primary afferents [32]. Moreover, abnormal sensory messages stimulating the cortex areas might induce stimulation in limbic regions that might be implicated in anxiety, depression and sleep problems related to high neuropathic pain ratings [30]. Similarly, the cingulate cortex and amygdala modulate descending controls projections from the periaqueductal grey to the brainstem. At this level, maintenance of the pain state seems to be strictly related to the brainstem excitatory pathways [30]. In this complex framework, a non-painful stimulus of a peripheral nerve could lead to an increase in the neuronal electrical threshold together with a reduction in the conduction velocity, resulting in a lower excitability and inhibition of interneurons interrupting the pain signaling [29]. Therefore, targeting specific levels involved in the neuropathic pain circuits might have a role, not only in the pain relief, but also in the complex pathway mentioned above with potential implication in the pain chronicization mechanisms [30]. Indeed, it has been demonstrated that pain relief induced by PENS treatment is mediated by both A\(\beta\) fibers modulation and the local release of biochemical mediators such as neurotransmitters and endorphins, hindering the pain response [28]. More in detail, an orthodromic stimulus applied on non-nociceptive A\(\beta\) nerve fibers activates respective dorsal horn interneurons and transmits the nociceptive information to peripheral A\(\beta\) and C fibers [28]. According to this neurophysiological dynamic, a non-painful stimulus applied in a peripheral nerve territory can generate a decrease in pain signals [28]. Moreover, non-nociceptive A\(\beta\) nerve fibers, after an anterograde activation, might stimulate superficial layer interneurons in the Rexed laminae 2 and 3 of the dorsal horn, which usually process nociceptive signals and transmit the stimulus from C fibers [33]. How could PENS modulate neuropathic pain?