Based on gate-control theory, the stimulation of large myelinated Aβ-fibers with low-intensity electrical signals was introduced to modulate the pain signals conducted by the unmyelinated C-fibers [2]. SCS is a well-established technique among other neuromodulatory methods. It acts upon nerves and alters nerve activity by providing electrical stimuli to the target site [57]. SCS is a clinical application arising directly from the revolutionary “gate-control” theory of pain suggested by Melzack and Wall [58]. This theory hypothesized the concept of an intrinsic pain control mechanism [59]. For SCS therapy, a series of electrodes (4–16) is placed in the epidural spaces partly covering the dorsal columns of the vertebra; the dorsal column should innervate the painful area as well [60]. The low-voltage electrical current in the nerve fibers of the spinal cord is supplied by a pulse generator which is directly connected to a power source. The electrical stimulation thus generated can have both an inhibitory effect and stimulatory effect on pain signals and nerve impulses, respectively [61].

The attenuation of neuropathic pain by stimulating the spinal cord involves the inhibition of nociceptive input carried by thinly myelinated or unmyelinated fibers (Aδ as well as C-fibers), and interruption in the transmission of nociceptive signals to the brain [62]. The neurochemical mechanism comprises the release of various neurotransmitters involved in pain attenuation, such as GABA, serotonin, acetylcholine, and norepinephrine [63]. In the process of SCS, neurotransmitters may stimulate spinal GABAergic circuitry receptors located on GABAergic interneurons present in the spinal dorsal horn cells, and thereby contribute to the SCS-induced analgesia [64]. Shechter et al. discovered that mechanical hypersensitivity was intensity- and frequency-dependent when compared with high-frequency and conventional methods of spinal cord stimulation in neuropathic pain [65]. The relative safety, cost-effectiveness, and reversibility of SCS have indicated SCS to be an attractive strategy for managing refractory chronic neuropathic pain [66,67,68,69]. Interestingly, a number of systematic reviews, case series, and randomized controlled trials provide evidence regarding the sustained (~24 months) long-term efficacy of combined therapy of SCS and medical treatment [70,71,72,73,74,75,76]. Two clinical trials have reported greater pain relief and enhanced quality of life in painful diabetic neuropathy patients compared with controls [77,78]. Additionally, a weak recommendation was provided by the current European guidelines for the use of SCS (in combination with medical treatment) in neuropathic pain, especially in diabetic neuropathic pain [12,56,79].

The amplitude and time course of attenuating mechanical hypersensitivity were different in both cases, one of which was applied with 50 Hz and the other with 1 kHz. Therefore, it was suggested that the differences in both might be due to the involvement of different peripheral and spinal segmental mechanisms [80,81]. Randomized controlled clinical trials conducted for treating complex regional pain syndrome and chronic lower back syndrome using SCS have proven to be efficacious [82].

In the treatment of neuropathic pain, SCS is used as an effective substitute for local non-surgical therapies. However, SCS is not easy to implement, because it requires the placement of electrodes in direct contact with the spinal cord and necessitates the implantation of electrical hardware. This makes this procedure surgical, which includes significant risks such as infection (4.5% cases) and pain at the generator site (12.0% cases). Other risks include potential nerve damage, bleeding, and epidural punctures [83,84,85]. Proper aseptic procedures, systematic check-ups, and follow-ups can minimize these types of complications [86,87]. Apart from the risk associated with patients, malfunctioning hardware (such as lead and instrumental failure) may be the other factors associated with SCS [88]. Additionally, these types of stimulation devices are usually the last resort and are usually used in patients that have failed conventional medical management.

SCS has the potential to become a revolutionary treatment for chronic neuropathic pain. SCS treatment can minimize chronic pain and helps in improving lifestyles in patients with sciatica, arachnoiditis, and spinal cord injuries [89]. A recently developed wireless SCS system (Stimwave Technologies Inc., Pompano Beach, FL, USA) uses an external battery implanted on the buttock for transmitting the energy. This is very useful for pediatric patients due to its simplified procedure, less implanted hardware, and flexibility in programming [84]. SCS has also been reported to affect the cortical regions of the brain, especially those which regulate motivation and emotions [90]. Therefore, SCS not only helps in the attenuation of neuropathic pain, but may also help in treating co-morbidities such as depression and stress associated with it [91]. However, there is more bias in using SCS for treating neuropathic pain because various waveforms are used, and prospective clinical trials of SCS are required to clinically practice SCS for treating neuropathic pain [92]. Major complications associated with SCS mainly include hardware dysfunctions such as disconnection, migration, and electrode breakage, which potentially require additional surgery [74,93]. Additionally, pain at the implant site may be reported. The risk of damage to the spinal cord, either by direct lesions or indirect compression (epidural hematoma), is extremely low. Nevertheless, the success of SCS in the management of neuropathic pain depends on the proper selection of individuals based on sensory phenotypes, psychological traits, reduced conditioned pain modulation, and augmented central sensitization. Moreover, over the last few decades, SCS has emerged as a potentially valuable treatment; however, the exact mechanisms, including the biochemical and neurophysiological mechanisms, are only partially understood. Preclinical studies for neuropathic pain have only explored the therapeutic mechanisms at spinal and supraspinal level, and extensive clinical studies are also needed to improve their effectiveness because the current SCS computer model still presents significant failure at a rate of 30%. Other components of the pain pathway, including the dorsal horn, are also crucial to be further elucidated with respect to SCS for them to actually be utilized at clinical level for the effective treatment option for neuropathic pain.

A perineural steroid injection effectively provides transient relief from neuropathic pain, particularly compression-related and trauma-related peripheral neuropathy [94]. In a clinical study, methylprednisolone-mediated peripheral nerve blocking was also found to provide pain relief by effectively reducing abnormal neuronal discharge. Moreover, it was also found to be significantly more effective than lidocaine. Meta-analysis and systemic reviews of epidural steroid administration have demonstrated immediate moderate relief from pain [12,95,96]. However, no significant effects were seen in reducing the risk of undergoing surgery. A weak recommendation has been provided for the use of epidural steroids and local anesthetic nerve blockades to manage acute zoster-associated neuropathic pain and lumbar radiculopathy [2]. Additionally, uncertainties in the actual position of neuronal injury and accuracy of the nerve blockage remain major limitations of steroid injection and neuronal blockage. Additionally, the sympathetic ganglionic blockade has also been used to manage the complex regional pain syndromes, although the long-term benefit is yet to be determined [2].

Transcranial magnetic stimulation, or TMS, is a method wherein neural tissues such as the cerebral cortex, spinal nerve root, and peripheral, as well as cranial nerves, are stimulated using a magnetic field [97]. The basic principle involved in TMS is electromagnetic induction, which was discovered by the renowned physicist Michael Faraday in 1838. While performing a TMS session, a non-conductor coil is placed over the scalp near the head region that delivers brief magnetic pulses and stimulates the nerve cells [98]. TMS can provide either a single pulse of stimulation or repetitive stimuli at various frequencies split up by differing intervals to the affected region [99]. The literature indicates that the application of repetitive electromagnetic induction of 10 Hz on the motor region of the brain exerts an analgesic effect in chronic neuropathic pain patients [100]. This analgesic effect may be attributed to the fact that repetitive electromagnetic induction stimulation may cause the release of striatal dopamine in the human motor cortex and thereby help in pain modulation pathways. However, the exact mechanism of repetitive electromagnetic-induction-mediated pain relief is not known [101].

Two approaches for conditioning repetitive TMS (rTMS) have recently emphasized. One of which is short-duration rTMS with low-intensity and high-frequency stimulation and is called ‘theta-burst’ stimulation, whereas the other is the direct application of weakly negative or constant positive currents on the scalp to enact changes in brain impulses [102]. In a recent study, it was also found that four continuous rTMS sessions can recover refractory central neuropathic pain over three weeks by applying electromagnetic induction of 20 Hz on the primary motor cortex [103]. Therefore, TMS could represent an incredible alternative for treating neuropathic pain. These techniques are convenient because they can be used as portable devices as well. Certain TMS findings will be helpful in the early diagnoses and prognostic predictions of multiple sclerosis, psychogenic paresis, plexus neuropathy, stroke, and cervical spondylosis [104,105,106]. However, rTMS is contraindicated in patients with deep brain electrodes, aneurysm clips, cochlear implants, cardiac pacemakers, and an epilepsy history [2].

Similarly, transcranial direct current stimulation (tDCS) and epidural motor cortex stimulation (EMCS) have also been proposed for the management of refractory cases [107]. tDCS has been found to be beneficial in several peripheral neuropathies [108], whereas a meta-analysis has shown the effectiveness (>40% pain relief) of EMCS in about 60–65% of patients [107]. In general, EMCS requires the precise placement of the stimulating electrode in the motor cortex region. European guidelines provide a weak recommendation for the use of tDCS in peripheral neuropathic pain, and rTMS and EMCS in refractory chronic neuropathic pain [2,74].

Long-term intracranial stimulation in the management of neuropathic pain remains debatable. Multiple-site DBS, targeting potential brain regions, including the motor cortex, nucleus accumbens, sensory thalamus, internal capsule, periaqueductal/periventricular grey, septum, anterior cingulate cortex, and posterior hypothalamus, has been assessed to control pain sensations [109,110]. Although the U.K. National Institute for Health and Care Excellence (NICE) guidelines recommend using DBS in refractory patients, recent evidence suggests significant risks of DBS, including wound infections, lead fractures, and intra-operative seizures [111]. In contrast, European guidelines provide inconclusive recommendations for the use of DBS [2,79].

Percutaneous neuromodulation therapy (PENS) is an innovative and minimally invasive technique used as an interventional therapy to reduce pain hypersensitivity. PENS is an electroanalgesic therapy that amalgamates transcutaneous and electrical nerve stimulation as well as electroacupuncture by placing disposable acupuncture needle-like probes percutaneously to stimulate peripheral sensory nerves innervating the region of neuropathic pain [112]. It is a better alternative for patients who failed to achieve pain relief from transcranial electrical nerve stimulation or electroacupuncture due to the conduction constraints [113]. The term ‘percutaneous neuromodulation therapy’ precisely illustrates the neurophysiologic foundation for PENS-induced analgesia. It includes placing a disposable needle probe (10, 32 gauge) into the soft tissue and/or muscle just below the skin surface close to the specific nerve to electrically stimulate peripheral sensory nerves, innervating the region of neuropathic pain [114]. The treatment plan consists of thirty-minute sessions, either once or twice a week, requiring approximately eight to ten sessions.

Although the detailed mechanism of PENS-induced analgesia is not yet known, it is conjecture that electrical stimulation blocks the transmission of pain signals and releases endorphins and serotonin within the central nervous system [115]. It has also been reported that PENS is highly effective in short-term pain management, because there was a difference in the quality of life of patients who showed improved mood, functionality, and quality of sleep [116]. This can be used in several pain conditions, but not as a replacement for conventional pain medications and only as a supplementary therapy that could decrease the dosage in the extensive regimen.

In addition to the SCS, stimulation of the subcutaneous peripheral nerve field present external to the spinal cord (e.g., DRG and peripheral neurons) has been found to be effective in several forms of chronic neuropathic pain, including PHN and occipital neuralgia [117,118]. A prospective cohort trial found that DRG stimulation reduced pain by 56% in patients with chronic neuropathic pain, with a 60% responder rate (i.e., pain reduction of more than 50%) [119]. Nevertheless, these preliminary findings are undergoing further assessment in controlled clinical trials. Neuroablative procedures such as pulsed radiofrequency (PRF) usually work by the application of an electrical field (or heat bursts) to the targeted site (such as the DRG) without causing any permanent damage to the nerves [119].

Cyroneuroablation is emerging as a novel alternative for the management of pain. Recent advances have also rapidly focused on the painless CRYO-S approach because interventional pain management provides long-term relief from pain (up to 1 year). Cryoneuroablation does not cause permanent damage to neuronal structures, thus allowing them to recover without any risk of neuritis due to procedural inefficacy. Moreover, evidence has associated cryoablation with better outcomes as compared with radiofrequency ablation by an increased rate of atrial contractility and showing better functioning of the left ventricle [120].

Interestingly, novel approaches have aimed to reduce associated adverse effects such as dysesthesia, rebound neuralgia, and sensory loss, while improving the symptoms and durability of pain relief. Recently, a low-temperature PRF ablation or coblation technology was examined for its effectiveness in treating neuropathic pain [121]. This treatment modality utilizes radiofrequency to excite the electrolytes of a conductive medium (e.g., saline) to form energized plasma, which creates radicals that cause tissue dissolution at 40–70 °C. However, coblation may suppress DRG stimulation to downgrade the erroneous ectopic input to the central nervous system, which is the probable mechanism in neuropathic pain relief [122].

In addition, cryoneurolysis, an existing although considerably under-utilized modality that works by freezing the nerves and preventing sensory nerve conduction, has recently been upgraded as an “ultrasound-guided cryoneurolysis modality” for refractory neuropathic pain. A recent study (n = 22) evaluated the efficacy of percutaneous cryoablation in refractory peripheral neuropathic patients [123]. It exhibited a statistically significant reduction among the pre- and post-procedural pain scores and showed no major procedural complications.

Chemogenetics and optogenetics are approaches that have drastically transformed research in the field of neuroscience in the past decade, because they allow us to maneuver anatomically and genetically restricted neurons for assessing physiological or behavioral consequences and could potentially be a highly valuable therapeutic approach in the future [124,125].

Chemogenetics is a technique in which small molecules are used as a ligand to activate the G-protein-coupled receptors (GPCRs) or generate ionic conductance, eventually affecting neuronal excitability [125]. The vital tool in this technique is designer receptors exclusively activated by designer drugs (DREADDs), wherein ligands such as clozapine-N-oxide (CNO) or perlapine are used to activate the GPCRs instead of the previous muscarinic acetylcholine receptors that were activated by the endogenous agonist acetylcholine. A recent development is that a new DREADD has been developed in which the receptor is the κ-opioid, whose endogenous ligand is dynorphin A [124,126,127]. Chemogenetics are currently used to decipher the role of glia, especially astrocytes, because they play a crucial role in neuropathic pain. It has also been found that modification of Gi-DREADD signaling in the microglial cells may cause a reduction in neuropathic pain by regulating the pro-inflammatory cytokine levels [128]. Interestingly, it was found that chemogenetic inhibition of the amygdala could terminate comorbid symptoms such as anxiety associated with neuropathic pain [129]. Therefore, chemogenetics might be a good therapeutic approach for treating neuropathic pain in the future. However, further studies are required to obtain insight into implementing chemogenetics as a treatment method for neuropathic pain.

Optogenetics is a field that uses light to activate photosensitive targets for modulating neuronal activity [124]. Light of a specific wavelength is used as a stimulus for modifying genes responsible for transmembrane channels, thereby allowing spatial and temporal influence on particular neurons. The system includes an opsin (light-modulated gene or product), a vector for delivering, and a light-delivering instrument. Channels such as light-sensitive halorhodopsin or channelrhodopsin are being explored. A new opsin, named step-function inhibitory channelrhodopsin, has been developed, which increases chloride conductance and is expressed in the unmyelinated primary afferent nociceptors that produce inhibitory responses in mechanical-, thermal-, and formalin-induced nociception. Recently a light-reactive μ opioid receptor (MOR) has been designed to study the spatiotemporal dynamics of MOR signaling, which was upgraded to a higher level when a GPCR chimera receptor was combined with rat rhodopsin RO4 and MOR intracellularly and named opto-MOR. It has been found that optogenetics could reverse mechanical allodynia and hyperalgesia in neuropathic pain mouse models [130,131]. The advantage of using optogenetics is that we can specifically target the neurons and control their activity. However, specific issues arise while applying optogenetics to pain treatment, such as optimizing the opsins to establish a stable neuronal activity that can last longer. Further development of optogenetics into translational research will mark it as a powerful therapeutic approach for treating neuropathic pain [132].

Recent pre-clinical and clinical studies have demonstrated the potential application of chemogenetics and optogenetics by interfering with and manipulating the activity of the neurons [133]. However, one of their limitations is in actually pinpointing the injured nerve fiber and thoroughly understanding the difference between the genetics of damaged neurons to normal functioning neurons, because a small mislocation can result in major hampering of the normal functioning neuronal circuits [134]. Additionally, the major concerns of the gene and AVV delivery system in humans restrict it to emerge as a potential therapeutic approach for neuropathic pain. Thus, future research should focus on non-invasive technologies such as the systemic administration of lipid-based microbubbles and transcranial FUS, resulting in non-invasive neuronal stimulation [135,136]. Although chemogenetics and optogenetics pose serious limitations at the current point, they have the potential to be developed into powerful therapeutic approaches due to their high specificity, thereby probably providing a permanent solution to neuropathic pain.

Gene therapy is a technique which was introduced about three decades ago that helps to correct flawed genes either by replacing them with healthy ones or by adding genes to counteract the disease-causing effect of the defective ones. This helps to increase the expression of specific proteins involved in the formation of receptors, ion channels, neurotransmitters, and biochemical mediators that play a significant role in maintaining physiological conditions in the body. It has several advantages over traditional pharmacological treatments because it can be used to find targets at the genetic level and not merely treat the symptoms of the disease, thus making it comparatively more effective [137]. It also reduces unwanted adverse effects because it is target-specific and not likely to develop tolerance [138]. It can also be combined with other conventional treatment methods.

Gene therapy has enabled us to work with mechanisms that were not previously approachable by pharmacotherapy. Considerable research is being undertaken in this field, and several interesting approaches have been demonstrated so far. Essential molecular targets used in gene therapy for pain relief include spinal opioid gene therapy and anti-inflammatory cytokine gene therapy [139].

Due to the increased usage of opioid-based drugs in the intervention of neuropathic pain, opioid systems have become an interesting target for gene therapy. The intrathecal delivery of opioids has been sufficient to produce an analgesic effect [140,141]. Therefore, transferring a particular opioid gene using a vector such as the recombinant adeno-associated virus (AAV) into DRG is widely practiced to reduce chronic pain in pre-clinical studies [142,143]. The vector contains complementary DNA of the opioid receptor, which has to be inoculated into the rats’ primary afferent neurons, leading to an upregulation of opioid receptors in the DRG, which may last for up to 6 months [144,145]. Moreover, all these techniques are under preclinical trial, and have not yet been used in humans [146,147].

Two key strategies that developed from spinal opioid gene therapy have proven to be efficacious to induce analgesia in neuropathy in preclinical models. Glorioso and Fink described a novel approach for attenuating pain without the induction of tolerance or systemic side effects by the intradermal inoculation of an HSV vector delivering pain-modulating transgenes to sensory neurons in vivo along with standard pain treatments [148]. The other approach based on opioid delivery included the administration of opioid receptor encoding genes [149]. These approaches were proven to be successful in reducing hyperalgesia and mechanical allodynia in various neuropathic and inflammatory pain models of rodents [150]. This development may eradicate the noxious effect of opioids being administered exogenously, such as the extra-spinal effect seen in peripheral tissues as well as in the central nervous system [151].

In various animal models of pain, anti-inflammatory cytokines, namely, interleukin (IL)-4, IL-10, and IL-13, were found to exert analgesic effects. IL-10 is an anti-inflammatory cytokine which is involved in the inhibition of pro-inflammatory cytokines; therefore, the delivery of IL-10 encoding genes may help to reduce chronic neuropathic pain. The delivery of IL-10 is performed using various vectors such as HSV and AAV [152]. The expression of IL-10 was able to attenuate allodynia as well as hyperalgesia, a finding which demonstrated that insertion of the AAV vector might lead to overexpression of the IL-10 receptor [153].

Tumor necrosis factor-alpha (TNF-α) is one of the key cytokines involved in the progression of chronic neuropathic pain-like states. However, the activity of TNF-α can be suppressed using treatment with IL-10. Guedon et al. demonstrated that the downregulation of TNF-α was observed in a chronic constrictive injury (CCI)-induced neuropathic pain model by administering IL-10 intrathecally through the AAV vector [139]. IL-10-based gene therapy was found to be effective in varicella-zoster virus-induced pain because it reduced the allodynia [139,154]. IL-4 is another important anti-inflammatory cytokine whose role is being investigated in different models of pain. Treatment with IL-4 has shown significant results in pain associated with diabetic neuropathy and the spinal nerve ligation model of neuropathic pain [155,156].

It is a well-established fact that the process of pain transmission and signaling depends upon ion channels, which can thus be considered a primary target in treating conditions such as chronic neuropathic pain. Voltage-gated channels or leak channels could regulate the resting membrane potential [157,158]. Damage, nerve lesion, or inflammation could result in hyper-responsiveness of the ion channels, thus leading to unregulated neuronal firing [159]. Modulation of these ion channels should be studied for possible analgesic effects. This review focuses on recent developments of various ion channels that determine hyperexcitability of the sensory fiber and are emerging as promising targets for the treatment of pain. Currently, certain venom peptides are also being studied for their ability to modify ion channels and are believed to be a powerful therapeutic approach for treating complex neurological disorders in the future [160].

Generation of the action potential in any excitable cell, even in neurons, could be triggered by sodium channels [161]. Neuronal excitability and synaptic plasticity are the central mechanisms involved in pain; therefore, targeting these channels could be a useful approach [162]. Nine types of sodium channels have been identified that have a similar overall structure with a few minor differences in the sequence of amino acids (Na_v1.1 to Na_v1.9) [158]. Among these, subtypes Na_v1.3, Na_v1.6, Na_v1.7, Na_v1.8, and Na_v1.9 were found to have a role in nociception, because they were upregulated in several pain models [157].

In many patients, pain disorders are inherited due to mutations in genes that encode voltage-gated sodium channels. In pre-clinical studies, Na_v1.6, which is present at nodes of Ranvier has been found to be essential for nociception. Knockout of Na_v1.6 in mice has been found to completely ameliorate the painful condition. Additionally, because Na_v1.6 excites repetitive neuronal firing, which causes pain transmission, its inhibition via siRNA significantly reduces pain along with local inflammation. Moreover, high expressions of Na_v1.6 have been actively reported in bursting cells of inflamed DRG. These mutations either lead to a gain or loss of function. Modification in the Na_v1.7 subtype was found in a condition called erythromelalgia, which is manifested by extreme heat hyperalgesia [161,163], whereas Na_v1.8 and Na_v1.9 were associated with small-fiber neuropathy [164]. Adverse effects such as double vision, delirium, and somnolence are major limitations of the available non-specific sodium channel blockers; therefore, it is essential to develop new molecules [165]. A few molecules under clinical trials are being investigated for their anti-hyperalgesic properties, including PF-04531083 (Na_v1.8 blocker, Pfizer, New York, NY, USA) for diabetic neuropathy; CNV1014802, also known as raxatrigine (Na_v1.7 blocker, Convergence,) for trigeminal neuralgia and lumbosacral radiculopathy; and XEN402 (funapide) (Na_v1.7 blocker, Xenon, and Teva Pharmaceuticals) for inherited erythromelalgia and postherpetic neuralgia [164]. Among various voltage-gated sodium channels, Na_v1.7 is considered a particularly promising target because congenital pain insensitivity is due to the mutation occurring in Na_v1.7. However, translation of these studies is difficult because animal models do not show complex pain states, and pain cannot be terminated by a single target because it is not unifactorial. Continuing research in this field might help further the development of novel potent analgesics [166].

Voltage-gated calcium channels play a major role in the conduction of pain signals in nociceptive neurons at the spinal level [167]. Three main types of channels are recognized, which are categorized as Ca_v1, Ca_v2, and Ca_v3. Overexpression of Ca_v2.2 in the outermost surface of the dorsal horn, which is considered to be the nociceptive region of the spinal cord, leads to neuropathic pain [168]. N-type calcium channels in the DRG neurons are involved in pain signaling, which could be studied to establish new targets [169]. N-type channels play an important role in developing pain, whose activation can be inhibited by suppressing the release of substance P or using MOR agonists, such as morphine, which block these channels [170]. The most popular drug in clinical practice, gabapentin [171], acts upon the α2-δ subunit of N-type calcium channel and reduces the release of calcium in DRG neurons and synaptosomes, thereby producing an effective analgesic action in neuropathic pain patients, particularly with conditions such as trigeminal neuralgia, diabetic neuropathy, PHN, and migraine [172]. The U.S. FDA has approved a potent N-type Ca_v antagonist, Prialt (Elan Pharmaceuticals, San Diego, CA, USA), with a generic name of Ziconotide, also identified as omega conotoxin MVIIA. It is a 25-amino-acid disulfide-bridged polypeptide derived from the venom of Conus magus [173]. In a recent study, it has also been found that the natural compound physalin F was able to block the voltage-gated calcium channels, and also reduced pain hypersensitivity in peripheral neuropathy induced by paclitaxel [174]. Hence, targeting voltage-gated calcium channels might be a good approach for discovering novel analgesics to treat neuropathic pain.

Potassium channels have a crucial role in maintaining neuronal excitability because they cause hyperpolarization, which inhibits continuous depolarization that causes the hyperexcitability of neurons. Downregulation of potassium channels is observed in nociceptive signaling. There are several potassium channels, among which the K_v1.2 subtype has been studied thoroughly [40]. Fan et al. suggested that K_v1.2 expression was downregulated in a time-dependent manner in DRG neurons following L5 spinal nerve ligation and sciatic nerve axotomy models of neuropathic pain [175]. They further reported that downregulation was rescued by the overexpression of DRG K_v1.2 RNA upon the injection of AAV5-K_v1.2 viral particles [176]. There is a predominant expression of different potassium channel subunits in different neurons, such as K_v1.1 and K_v1.2 in myelinated sensory axons and K_v1.4 in C-fibers [177]. In another study, it was found that K_v1.2 expression was downregulated in the CCI model of neuropathic pain, and the use of an miR137 antagonist reversed this condition and resulted in attenuation of the nociceptive response [177]. K_v7 channels are also being targeted because they can suppress the hyperexcitability of neurons. Researchers have shown special interest in the K_v7 channels, because their activators can help to reduce neuronal hyperexcitability and attenuate pain. Retigabine, a K_v7 activator, was able to ameliorate cold hyperalgesia and hypersensitivity of a damaged paw in the CCI model of neuropathic pain. However, the use of retigabine in treating seizures has been stopped due to its undesired effects. Further studies on the K_v7 channel are required before suggesting the clinical use of K_v7 activators to treat neuropathic pain [178]. Regulating K_v function through the modulation of silent subunits may be an interesting approach to treatment [165]. To date, no analgesic drugs modulate pain signaling through potassium channels.

In addition to potassium ion channels, the dysregulation of chloride ion channels has been found to be associated with increased levels of pain hypersensitivity. Restoring the GABA-mediated inhibition in nerve injury models of mice by KCC2 blockade has also been shown to give rise to allodynia and the increased spiking of neuronal firing, causing pain behaviors in animals. Furthermore, the differential homeostasis of chloride ions in rodent spinal dorsal horns has been found to generate sensitization via spontaneous neuronal firing, initiating pain.