Neuropathic Pain: Pathophysiology, Current Treatment, and Future Directions

1.1. Definition of pain

Pain is a source of suffering and disability to many patients and a main cause for seeking medical care.^[1] It can be classified by origin into two major categories: nociceptive and NP [Table 1]. Although different types of pain have common characteristics in terms of mechanism and treatment, several factors can be beneficial in differentiating NP from other types of pain, such as the absence of transduction, poor prognosis, and the tendency to be more refractory to conventional analgesics.^[2] The differences between the nociceptive and neuropathic pain can differentiate between the cause of pain and highlight the appropriate treatment. These differences lie in the cause of the pain itself. While actual or potential damage to tissue during exposure to sudden injury (noxious stimulus) causes nociceptive pain through sending signals from the specialised sensory neurons (nociceptors) to the brain, NP is caused by dysfunction in the nervous system and lesions in the nerves.

1.2. Definition of neuropathic pain

Neuropathic pain (NP) is a chronic secondary pain condition that develops due to direct damage (lesion) or disease occurring in the peripheral or central nervous (somato-sensory) system as a consequence of nerve injury.^[3] The damage ranges from the injured neurons up to the regulatory pathways in the Central Nervous System (CNS).^[2] The injured nerve fibres make an environment change around themselves, giving false firing that reaches the pain centres in the brain.^[4] NP can be stimulus-evoked, which is characterised by allodynia and hyperalgesia, or stimulus-independent/spontaneous pain such as burning or stabbing.^[5,6] On the other hand, NP might affect the lesion area negatively by loss of neurological sensation along with cognitive or motor deficits.^[7] NP is classified into peripheral and central according to its origin.^[1]

1.3. Origin of neuropathic pain

NP originates either peripherally, centrally, or mixed between both in the nervous system, such as in spinal stenosis and cancer pain, according to the location of the lesion or injury. This is defined by the International Association for the Study of Pain (IASP). The subtypes of each category are illustrated in Figure 1.^[3,8] The chronic peripheral NP “Trigeminal Neuralgia” is an orofacial ache resembling an electric shock due to mechanical stimulus or involuntary contractions that lasts up to two minutes.^[3] Chronic peripheral NP, after peripheral nerve injury, is due to trauma, burn injury of tissues, or chronic post-surgical pain, which develops after a surgical procedure.^[3,9] Painful polyneuropathy is a heterogeneous group of NP that is subdivided into diabetic and nondiabetic groups, which originates due to other factors such as drug-induction, toxicity, genetic factors, metabolic disorders, autoimmune diseases, and certain infections such as HIV. Postherpetic neuralgia (PHN) is a chronic pain that develops secondary to Varicella zoster viral infection. It is characterised by affected cranial nerves or spinal dorsal root ganglia and has a duration of 4 months. Painful radiculopathy is a pain that originates from a lesion or disease of the cervical, thoracic, lumbar, or sacral nerve roots.^[3,10] The chronic central NP is defined as a disease/lesion of the central somatosensory nervous system and is related to brain/spinal cord injury, stroke, or multiple sclerosis. Post-stroke NP mechanism is highlighted in patients who have thalamic or parietal lobe vascular lesions predominantly in the right hemisphere.^[3,11] The origin of NP pain in multiple sclerosis depends on the localisation of the lesion in the somatosensory system.^[3]

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Figure 1:

The International Association for the Study of Pain (IASP) classification of chronic neuropathic pain.

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1.4. Mechanism of neuropathic pain as a target for pharmacotherapy

In clinical practice, determining the underlying mechanism of NP is challenging, and most of the methodologies used are thought to be imperfect and generate predictive values.^[2,12] Several drugs that show promising results in the preclinical trial fail in clinical ones, as most of the pain treatments are mechanism-based, targeting a specific underlying mechanism.^[2,13] Nerve injury/lesion leads to altered neurophysiological characteristics of afferent neurons, leading to ectopic activity, increased sensitivity to stimuli, and spontaneous pain.^[14] The underlying complex alterations in molecular mechanisms are linked to central and peripheral nervous system sensitization. The peripheral sensitization is due to several factors, such as trauma or infection leading to nerve injury that increases the release of pro-nociceptive neurotransmitters. The latter leads to increased stimuli at the dorsal horn of the spinal cord, increased excitability, and reduced threshold of nociceptive neurons.^[15] On the other hand, central sensitization is due to the augmented response of the nociceptive neurons in the central nervous system due to a stimulus that is sub-threshold. This results in intensified spontaneous pain, mechanical allodynia, and hyperalgesia.^[8,14,16] These mechanisms could cause alterations in the neuroplasticity of the somatosensory nervous system, which in turn leads to activation of inflammatory cells and mediators such as cytokines interacting with nociceptors. This could change the expression of voltage-gated ion channels, the expression of receptors, and the synthesis of neurotransmitters, which finally control the higher and ectopic excitability and conductivity.^[8,16] This ectopic activity is modulated by voltage-gated neuronal sodium channels and transient receptor potential (TRP) channels.^[14] NP consists of positive symptoms, including paresthesias and increased pain, which are responsive to anticonvulsants, while other symptoms are categorised as negative symptoms, such as sensory loss and numbness, which respond to antidepressants.^[17]

1.5. Estimated cost of neuropathic pain health care and its socio-economic burden

Neuropathic pain is one of the most costly types of chronic pain.^[8] A recent study in the U.S reported that the annual cost of chronic pain healthcare is $300 billion, and it was suggested that NP represents a quarter of the annual cost. Chronic pain also has a dramatic effect on productivity, leading to a decrease that was estimated as $335 billion.^[18,19] Another study proved that the annual healthcare charges $17,355 for patients with NP compared to the control group $5,715, which is three-fold higher.^[20] In 2006, a study showed that management of NP in Canada has a significant economic burden to the healthcare system with Three-month direct costs of $1,137, of which 77% was due to NP prescriptions, medications, and medic, while the indirect costs were estimated at $1,430.^[21] A study was performed to estimate the direct and indirect costs of NP across several European countries, including France, Germany, Italy, Spain, and the UK. Total cost per patient, including direct and indirect (sick leave) cost of NP was €10,313 in France, €14,446 in Germany, €9,305 in Italy, €10,597 in Spain, and €9,685 in the UK. This cost is high for the patients and their families. Also, as the sick leave costs appeared to be the majority in all countries, most of the society’s loss was due to decreased work and productivity.^[22]

1.6. Epidemiology and prevalence of NP

Pain management has been a major concern for the public health community due to the elevation in the number of people with incidents of acute or chronic pain accompanied by degenerative diseases worldwide.^[23] NP is a devastating condition associated with several diseases. The percentage of the general population affected by NP is estimated to be between 7% and 10%, of which 20 to 25% of individuals suffer from chronic pain. This is believed to be underrated due to limitations in epidemiological studies. Also, the analysis accompanied by the diagnosis and treatment of NP is not completely illustrated in different populations.^[7,24,25] A recent study, performed to measure the prevalence of chronic post-surgical pain (CPSP) in children, found that, out of the 10.9% prevalence of CPSP, 64.3% was of NP origin.^[26] NP occurs in 25-40% of adolescents and adults with sickle cell disease (SCD).^[27] In a study consisting of 892 cancer patients, 40% of the patients showed NP symptoms, while only 8% of them were treated with co-analgesics, which indicates the need for higher analgesic requirement.^[28,29] Some well-conducted prospective studies, systematic reviews, and meta-analyses provided valid estimations regarding the prevalence of NP as shown in Table 2.^[7,30]

Several studies manifested that neuropathic pain is more prevalent in older people above 60 years than in younger patients, and they highlighted a gender difference perspective where the prevalence in women was more than men.^[7] A systematic review of the epidemiology of chronic pain reported that 60.5% of patients with NP were women who are manual workers, as well as living in rural areas.^[6] Regarding the severity of NP, it was stated that it is more severe than non-neuropathic pain, with the back and legs being the most affected body parts.^[7] The NP is not only associated with several diseases, but also has obvious detrimental effects on sleep and quality of life, and could induce several symptoms of anxiety and depression.^[7,31]

1.7. Shortcomings and aim of the review

A recent study was performed to detect the treatment model and direct cost of health care associated with NP, with a follow-up of two years after diagnosis in Colombia.^[25] A systematic review was done on oral and topical pharmacotherapy for NP by The Neuropathic Pain Special Interest Group (NeuPSIG) in order to evaluate the relation between treatments available in the market and recent clinical trials, and the outcome of patients. They concluded that there are poor diagnostic criteria followed by decreased efficacy. Because large responses were observed due to the placebo being the main reason for the poor outcome of the trials, this should be considered for future purpose.^[32] NP patients are characterised by low quality of life that leads to severe effects on the personal level of the patient, followed by society and economic significant cost.^[32]

The management of NP is challenging because of the multiple causes and the discrepancies in clinical conditions.^[8] In addition, the low diagnostic effectiveness, adverse effects of opioid medications, and the limited efficacy of available medical interventions due to the difficulty of targeting the specific underlying mechanism add to the difficulties. Moreover, the ambiguity and complexity of the pathophysiology play a huge role in the urgency and strong demand for novel exploration of new drug targets and drug candidates.^[16] There is a great need for research to ensure the efficacy of neuropathic pain treatments, develop clinical practice guidelines, and discover novel therapeutic approaches, as most of the medical agents that are used currently for NP treatment have moderate efficacy along with side effects that restrict their use.^[6] The aim of this review is to provide a comprehensive look at the pathophysiology pf NP as well as the state-of-the-art of the agents used for the treatment or those in the pipeline.

3.1. Proposed mechanisms in PNS

The PNS consists of nerves extending from the sensory receptor to the dorsal horn. When a nerve is cut/injured, it will either regenerate in the presence of myelin sheath and trophic factor or the injury leads to neuromas and PNS sensitization if it is connected to the nerve sheath itself. This directs the afferent nerve towards hyper-excitability through altered channel expression (increase in sodium ion channels expression) on Aβ and Aδ neurons, presence of ectopic discharges, decrease in the threshold of action potential, and increased sensitivity to certain biological modulators.^[5,35] The nociceptive terminals produce inflammatory mediators such as substance P that lead to edema and escape of injury byproducts, which in turn lead to sensitization and hyper-excitability.^[2] This injury could extend from the highly excitable afferent nerves towards non-injured nociceptive peripheral nerves. This occurs through the nonephaptic crosstalk between dissimilar nerves by the increase in neurotransmitters and cellular potassium. On the cellular level, neurogenic inflammation takes place by the production of inflammatory mediators via the adjacent neuronal and non-neuronal cells, which migrate to the dorsal horn and lead to activation and sensitization of C-fibres.^[4,5] Also, phenotypic switch can take place where certain neuro-modulators that are known to be produced in certain types of cells or fibres can be produced in other fibres which doesn’t normally produce it, such as substance P in C-fibres.^[2]

3.2. Proposed mechanisms in the CNS

The CNS consists of the nerves extending from the dorsal horn to the brain. The NP mechanism in the CNS can be described by loss of inhibitory function due to an increase in glutamate, loss of inhibitory interneurons, and a decrease in GABA/Glycine.^[5] The expression of µ opioid receptors is shown to be decreased after nerve injury but increased by inflammation. Researchers believe that this is the reason for the higher doses of opioids required for NP compared to acute and chronic nociceptive pain.^[2] There are several underlying mechanisms for this medical condition in the CNS. Central sensitization by a hyper-excited nerve in the PNS leads to hindering the inhibitory function at the dorsal horn. A shift to excitation over inhibition occurs due to the change in normal balance between modulatory systems (Excitation/Inhibition), leading to the NP. Another mechanism for CNS NP is deafferentation, which occurs by the destruction of axon and its myelin sheath of an injured peripheral nerve and sprouting of Aβ fibres.^[5] The changes occurring in the CNS due to the damage of nerves in the PNS can remain for a long time even after healing of the PNS, leading to the chronic NP.^[5]

3.3. Wind-up theory

The wind-up theory is built upon the interaction between the injured nerves in the PNS with uninjured nerves in the PNS, which then reaches the dorsal horn and the brain. This leads to the above-mentioned mechanisms in both PNS and CNS with a later effect on inflammatory modulators, neuro-modulators, neuropeptides, and gene expression of a wide variety of receptors and ion channels.^[5] This occurs due to the hyperactivity of NMDA receptors along with their signalling cascade, such as protein kinase C, that results in repetitive stimulation of C-fibres leading to firing of dorsal horn neurons and central sensitization.^[2]

4.1. Screening tools

The screening tools are developed as questionnaires retrieved from the verbal pain descriptors, then validated and used worldwide for assessing NP by clinicians. These are used for epidemiological studies in the global population, clinical research studies, and education. Five questionnaires have been validated, and the most used questionnaires globally are LANSS (Leeds Assessment of Neuropathic Symptoms and Signs), DN4 (Douleur Neuropathique en 4 questions), and Pain Detects. These questionnaires for differentiating between NP and other forms of pain showed high sensitivity up to 85% and specificity up to 90%.^[7]

4.2. Clinical assessment

The diagnosis and assessment of the complex NP is challenging due to the diversity of causes and underlying mechanisms, absence of biomarkers, and total dependence on clinical criteria.^[8] The global world is in need of standard and effective approaches, which are not only important for the healthcare of the patient, but also for better elucidation of targeted mechanisms for drug design research that will help in mitigating the illness of the patients.^[7] Several tools and questionnaires are validated and applied to patients to differentiate between NP and other forms of pain.^[8] The diagnosis of NP mainly depends on history and physical examination. Other screening tools have certain inadequacies in assessing the patients, which lead to low diagnostic quality.^[30] Pain assessment passes through several stages to give a definite diagnosis of NP. If the patient feels pain, the clinician must examine his history for the presence of any neurological lesion or disease that is localised to a neuroanatomic region causing an area of sensory deficit. If yes, then this pain is termed “Possible NP”. The next stage is clinical examination by bedside testing or quantitative sensory testing for the sensory signs in order to give stronger proof of the specific type of pain. If the evidence proves that the type is NP, it is now termed “Probable NP”. The last step is the objective diagnostic test that includes neurophysiological tests and a skin biopsy to confirm the lesion/disease of the somatosensory nervous system. If the test confirmed the lesion/disease, it can now be called a “Definite NP”. The start of treatment takes place from “Probable NP” stage.^[30,36] We will discuss these different diagnostic methods in detail.

In the clinical examination, bedside testing is done in order to differentiate between the symptoms and detect if there is hyperalgesia, “less painful stimulus causing higher pain”, or allodynia, “non-painful stimulus eliciting pain”. It is done by exposing the patient to a stimulus that can be repeated under the same conditions. Then, the patient can express his sensation to detect whether it is a gain or loss of function in the somatosensory nervous system.^[30,37] On the other hand, the quantitative sensory testing detects the gain or loss of function for the whole afferent fibre classes (Aβ, Aδ, and C fibres) using a standard mechanical or thermal stimuli test to assess pain thresholds, for example, for cold and heat stimulations.^[30,38]

For the objective diagnostic tests, neurophysiological tests such as the laser-evoked potentials (LEPS) are used. In this test, a laser beam stimulates Aδ and C nociceptors in the superficial layers of the skin. The response from these activated nociceptors is recorded through the scalp with waveforms, each with a different latency.^[30,39] The contact heat evoked potentials and concentric electrodes for pain-related evoked potentials are used in assessing the NP.^[30,40,41] Another form of diagnostic test is the skin biopsy involves unmyelinated C fibre terminals and few small Aδ fibres that reach the epidermis as unmyelinated free nerve endings by losing their myelin sheath.^[30,42] It is considered the most sensitive diagnostic tool for small fibre neuropathies.^[43] The corneal confocal microscopy technique depends on assessing the corneal nerve fibre damage to detect peripheral neuropathy. It has certain disadvantages in diagnosis as it is an invasive and in vivo method. On the other hand, on the economic level, its low availability in clinics, in addition to the high cost to patients, limit its use.^[30] Regarding the scientific point of view, no studies have assured whether any eye disease or syndrome can affect its results for neuropathic pain diagnosis.^[44]

The neuropathic pain questionnaire is built upon pain descriptors like screening tools. Several types are available, such as the Neuropathic Pain Scale, the Neuropathic Pain Symptom Inventory (NPSI), the Pain Quality Assessment Scale, and the McGill Short-Form Questionnaire 2. These questionnaires are a good step towards personalized medicine as they give more information about the patient’s symptoms and the intensity of pain. In addition, they evaluate the efficacy of treatment by indicating which symptoms are responding and being mitigated by the therapy.^[30]

4.3. Prevention

There is an increased consideration for the prevention of neuropathic pain as the available treatments have moderate effects. This comes with a healthy lifestyle, behavioural education, and clinical prevention. The clinical prevention comes on three levels. First, healthy patients could prevent neuropathic pain using vaccines that protect them from serious conditions and diseases that can be accompanied by neuropathic pain, like the herpes zoster vaccines that can prevent postherpetic neuralgia. Second, prevention of chronic postsurgical pain by giving preventive interventions to those who are at high risk due to an injury or illness. Third, those who have a disease or a condition that makes them more prone to chronic NP should have suitable management of this disease before symptoms of NP appear.^[30,45-47]

5.1. Current pharmacological management of NP

The IASP NP Special Interest Group has developed protocols and guidelines to be followed in pain treatment by clinicians.^[4] There are several current medications for the NP that are sub-grouped into three categories according to the analgesic efficacy and dose-related side effects.^[8] Examples of the first line, second line, and third line of treatment are shown in Table 3. The current medications available for treatment either alleviate the symptoms or, in a few cases, treat the etiological cause. The first line of treatment consists of gabapentinoids, tricyclic antidepressants (TCAs), and selective serotonin–norepinephrine reuptake inhibitors (SNRI). The second line of treatment consists of Lidocaine, Capsaicin, and Tramadol. The third line of treatment includes strong opioids and botulinum toxin-A (BTX-A).^[6]

5.2. Non-pharmacological treatment

Several methods of interventional therapies are used with more severe cases of NP. It includes peripheral nerve blockade, which is done by injecting anesthetics alone or in combination with opioids, clonidine, or steroids locally. Epidural steroid injection is done using some corticosteroids such as methylprednisolone. Blockade, neurolysis, or ablation of the sympathetic nerve or ganglion also represents a type of interventional therapy. Another type is intrathecal drug delivery. This type of therapy succeeded in two drugs, morphine and ziconotide. The usage of the above-mentioned therapies is still indecisive and debatable in all etiological medical causes. Last is the neuro-stimulation that is applied to mitigate the NP. It is either peripheral neuro-stimulation, such as peripheral nerve/field stimulation, dorsal root ganglion (DRG) stimulation, or central neuro-stimulation. Physical therapies are applied in conditions that need to augment the results when the improvement by pharmacological management is not enough. It includes heat and cold applications, massage, ultrasound, high-voltage galvanic stimulation, and laser. Moreover, psychological treatment aims at improving the quality of life beyond the treatment. This type of treatment could include psychotherapy and cognitive behavioural treatment.^[3] We carried out a literature review using the Reaxys database, covering the period from 2000 to 2025, to retrieve clinical candidates investigated for the management of NP.

6.1. Voltage-gated Ion channels

As Ion channels play a major role in the imbalance of the regulatory mechanisms of pain, which leads to the disturbance, hyper-excitability, and false firing, they are one of the main targets to look through.^[48] Voltage-gated sodium channel Nav1.7, encoded by the SCN9A gene, is expressed in nociceptors in the dorsal root ganglion (DRG). It is responsible for action potential initiation, neuropeptide release, and synaptic transmission in the dorsal horn of the spinal cord. Nav1.7 was experimentally targeted by microRNA MiR-30b, which targets the SCN9A gene selectively.^[49] Sodium channel blockers had good results in pain relief by reducing neuronal firing, but, unfortunately, they showed a negative outcome in Phase 2a clinical trial. Cav3.2 is a subunit of the low-voltage-activated T-type channels, which are largely found in sensory neurons in the DRG. It has a role in NP pathology, and it enhances the calcium current. Blockers of this type of channel showed success in vitro and in vivo but failed in clinical trials compared to the placebo.^[50] Kv7 channel is a voltage-gated, non-inactivating potassium ion channel. This ion channel was found to be down-regulated in hyper-excitability medical conditions such as NP, which indicated that it has a role in the pain process. Although till now, it has not fully proven its efficacy in NP, activating Kv7 is a promising methodology by selectively targeting Kv7.5, the specific subunit in C-fibres.^[15]

6.1.1. Sodium channels

Voltage-gated sodium channels (Na_Vs) have been the subject of multiple studies proving their significant involvement in nociceptive pathways and NP. As of now, nine Na_V receptor subtypes have been identified (Na_V1.1-1.9), named in descending order of their response to tetrodotoxin (TTX), a powerful naturally derived sodium-channel blocker. Na_V1.7, 1.8, and 1.9 are prevalently expressed in peripheral neurons, and interestingly discovered in mutated forms in some cases of neuropathy,^[2] making them very promising targets for novel analgesics targeting NP.

Na_V 1.7 Inhibitors:

Gain-of-function mutations in Na_V 1.7 have been noticed in multiple inherited pain disorders, namely erythromelalgia (EM), small fibre neuropathy (SFN), and paroxysmal extreme pain disorder (PEPD). Furthermore, loss-of-function mutations were found in patients suffering from congenital insensitivity to pain (CIP), offering further confirmation.^[51] The aryl sulfonamide PF-05089771 is an orally active selective Na_V 1.7 inhibitor (IC₅₀ = 11 nM), developed by Pfizer, with 10x higher affinity to Na_V 1.7 than the most structurally similar isoform, Na_V 1.2.^[52] Pfizer sponsored multiple clinical trials examining its efficacy in treating different forms of NP. The most recent phase 2 trial was performed to compare PF-05089771 [Figure 2] to Pregabalin to treat pain associated with diabetic peripheral neuropathy (DPN) (NCT02215252).^[53] The study revealed a mean improvement in daily pain by 30% of 28.57 and 31.58, respectively, indicating the effectiveness of the new drug; however, less than standard treatment.^[6] Although Pfizer announced that no further trials will be done on this agent, a study published in 2020 by researchers at Harvard suggests that co-administration of PF-05089771 with Lidocaine improves its activity synergistically. This opens the door for further investigation and optimisation of PF-05089771 to, hopefully, become a valid treatment option for NP. The orally active proline derivative Vixotrigine (BIIB074) Figure 2 is a centrally and peripherally acting sodium channel blocker previously used in the treatment of bipolar disorder before being repurposed as an analgesic for NP disorders by Biogen.^[54] This was initially considered a selective Na_V 1.7 blocker (IC₅₀ = 1.76-5.12 μM), however, studies suggest it shows inhibitory activity on other isoforms as well. Recently, Biogen has focused its attention on trigeminal neuralgia, as after the success of phase 2 trials, two double-blind, randomised phase 3 trials are currently in progress (NCT03070132 and NCT03637387) to assess the safety and efficacy of the drug.^[55] Vixorigine would be considered a great alternative to the current treatment of NP. A study done at Yale university that this agent was 25 times more potent than the carmazeoine and better tolerated.^[56]

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Figure 2:

Voltage-gated Ion channel blockers entered clinical trials for neuropathic pain (NP) treatment.

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6.2. TRPA1 inhibitors

Transient Receptor Potential Ankyrin 1 (TRPA1) is found in primary sensory neurons that supply the airway and functions as a chemical sensor for irritants like acrolein, ozone, isocyanate, tear gas, and chlorine 17,18. Activation of TRPA1 helps detect harmful substances in the respiratory tract, leading to reflex responses such as coughing and sneezing. This protein plays a critical role in pain perception and inflammation. It is a promising drug target for treating pain, inflammation, and other conditions like asthma and even Alzheimer’s disease. The inhibitors gained a lot of interest from both academia and industry, and multiple high-affinity TRPA1 antagonists are currently in phase I/II clinical trials. LY3526318 [Figure 3] is an investigational, orally administered, small-molecule antagonist of the TRPA1 ion channel, being developed by Eli Lilly for chronic pain indications. After successful Phase 1 studies in healthy volunteers, the compound advanced into Phase 2 proof-of-concept trials across multiple chronic pain indications, knee osteoarthritis (OA), chronic low back pain (CLBP), and diabetic peripheral neuropathic pain (DPNP), under Lilly’s Chronic Pain Master Protocol (CPMP). as of late December 2024, LY3526318’s Phase 2 trials have completed with mixed outcomes: modest signal in one pain indication (CLBP), but no overall efficacy and a liver safety concern, leading to a halt in active development, with its current status considered inactive.^[63]

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Figure 3:

The transient receptor potential ankyrin 1 (TRPA1) inhibitor LY3526318 and the P2X receptor inhibitors Eliapixant, Gefapixant, BLU-5937, Sivopixant, and Filapixant.

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6.3. Purinergic P2X Receptors

Purinergic P2X receptors (P2X) are ATP-gated ion channels widely expressed in the brain, particularly in the hypothalamus. Hypothalamic neurons express several subtypes of P2X, and the role of P2X in hypothalamic functions is not yet fully understood. P2X receptors are involved in several biological processes, including modulation of cardiac rhythm and contractility, modulation of vascular tone, mediation of nociception, especially chronic pain, platelet aggregation, and apoptosis. seven separate genes coding for P2X subunits have been identified and named as P2X1 through P2X7, based on their pharmacological properties. Animal models suggest that P2X3 is important for peripheral pain responses and might be implicated in the progression of NP. It was reported that P2X3 receptor knockout mice showed a reduced pain response. Also, phosphorylation or upregulation of this receptor leads to neuronal hypersensitivity, contributing to chronic neuropathic and inflammatory pain syndromes. Therefore, peripheral inhibition of P2X3 receptors could be useful for the treatment of several diseases associated with hypersensitive nerve fibres, including NP. Several antagonists of the P2X3 receptor are currently investigated in clinical trials. These antagonists aim to inhibit the ATP-mediated signalling at P2X3 receptors, thereby modulating sensory nerve activation associated with pathological conditions. Gefapixant (MK-7264) [Figure 3], one of the most advanced P2X3 antagonists, has shown significant efficacy in reducing chronic refractory cough in multiple Phase 2 and 3 trials. Other notable agents include Eliapixant (BAY 1817080), BLU-5937, Sivopixant (S-600918), and Filapixant [Figure 3], each demonstrating varying degrees of selectivity and tolerability. A key challenge in developing P2X3 antagonists has been minimizing taste-related side effects, such as dysgeusia, due to off-target effects on P2X2/3 heterotrimers. The ongoing development of more selective compounds aims to preserve therapeutic efficacy while improving the side effect profile.^[64]

6.4. Sigma 1 receptor

Sigma receptors represent a well-defined class of proteins and are highly expressed in the central nervous system as well as in peripheral organs and tissues. These receptors are endoplasmic reticulum-resident transmembrane proteins that eluded their molecular cloning and crystallization for a long time. These receptors were eventually classified into two subtypes, sigma 1 (S1R) and sigma 2 (S2R). These biological targets have recently attracted a lot of interest from leading pharmaceutical companies and funding agencies due to their implication in the pathophysiology and treatment of various disease conditions. Recent studies suggest that S1R modulators possess therapeutic potential for chronic neurologic pain and drug abuse. On the other hand, S2R is found to be over-expressed in tumour cells and, hence, its modulators could act as promising anticancer agents. Following the differentiation of the two sigma receptor subtypes, huge efforts were directed towards the design of selective ligands for each subtype. (+)-Pentazocine [Figure 4], the first selective ligand, exhibited 500-fold selectivity over sigma-2 receptor. Also, a haloperidol derivative, E-5842 [Figure 4], showed an affinity of 4 nM for sigma-1 receptors and 55-fold selectivity. Later on, a dipropylamine class of compounds (e.g., NE100) [Figure 4] was reported to have high affinity for sigma-1 receptors and moderate selectivity of 55-fold over sigma-2 receptors. . On the other hand, compound CB-184 Figure 4 was the first reported highly selective sigma-2 receptor ligand. This was followed by several other S2R selective ligands such as ibogaine, seramesine, benzamides (RHM-1) Figure 4, and rimcazole analogs. As mentioned above, only a few sigma receptor ligands have entered clinical trials for pain management or cancer treatment. Recently, E-52862 Figure 4 has reached Phase II clinical trials in Europe for pain management. However, it showed poor selectivity towards other targets such as 5-HT_2B.^[65]

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Figure 4:

Examples of potent Sigma 1 receptor inhibitors.

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6.5. Angiotensin 2 receptor

Angiotensin 2 Receptor (AT2R) is a G-Protein Coupled Receptor (GPCR) responsible for the signal transduction of the vasoconstricting effect of the hormone angiotensin II within the renin–angiotensin system. Like other class A GPCRs, AT2R consists of 7 transmembrane α-helical domains, with an extracellular amino terminus and an intracellular carboxy terminus. The helical receptor is coupled with four sub-classes of G-proteins distinguished from each other by sequence homology (G_αs, G_αi/o, G_αq/11, and G_α12/13). Upon activation, the α subunit of the G protein dissociates and modulates the activity of adenylate cyclase or phospholipase C-β (PLCβ) according to its type. It was found that AT2R is also expressed on sensory neurons and immune cells; its blockade reduces neurite sprouting, neuroinflammation, and hyperexcitability. Several AT2R antagonists, whether they are already in use or in preclinical development, showed neuroprotective effects. Examples include Azilsartan, Fimasartan, and Olodanrigan [Figure 5]. The latter demonstrated early human efficacy signals (e.g., postherpetic neuralgia) but development stalled after safety program issues. Recently, the work continues with new AT2R antagonists showing promising preclinical data, such as TDI05 [Figure 5], which produced dose-dependent analgesic effects in rodent NP models. Overall, the mechanism of alleviating NP via AT2R modulation remains promising, but human validation should be re-evaluated with newer agents.^[66]

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Figure 5:

Angiotensin 2 (AT2) Receptor inhibitors in use or in preclinical development.

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6.6. Toll-like receptor 4 (TLR-4)

Toll-like receptors (TLRs) are a family of pattern-recognition receptors responsible for the initiation of innate and adaptive immunity. Their molecular structures are composed of leucine-rich repeats representing the ectodomain, and cytosolic Toll-interleukin-1 (IL-1) receptor (TIR) domains, which activate the downstream signals. The leucine-rich extracellular domain is responsible for the recognition of pathogen-associated molecular pattern (PAMP) structures such as the endotoxin lipopolysaccharide (LPS). TLR4 is widely expressed on endothelial cells, CNS resident macrophages, myocytes, thyroid cells, mesangial cells, and adipocytes. Upon activation, the TLR4 receptor dimerizes with the co-receptor myeloid differentiation protein 2 (MD-2) and binds the ligand, initiating the recruitment of intracellular TIR-adaptor molecules. This eventually leads to the activation of two major intracellular signalling pathways: the myeloid differentiation primary response 88 (MyD88)-dependent pathway and the TIR-domain-containing adapter-inducing interferon (IFN)-β (TRIF) pathway. Overall, the modulation of TLR-4 controls the production of inflammatory cytokines such as tumour necrosis factor α (TNFα), IL-1, IL-2, and IL-6. When nerve injury occurs, spinal microglial TLR4 directly activates a pro-inflammatory cascade, upregulating the expression of IFN-γ, IL-1β, TNFα, and NF-kB. Hence, it was reported that TLR-4 antagonists possess the potential to inhibit pro-inflammatory cytokine production and alleviate NP. TAK-242 (Resatorvid) [Figure 6] is the first direct TLR4 antagonist to be studied in clinical trials. It was found to covalently bind to Cys747 in the intracellular TLR4 domain, irreversibly inactivating the receptor. TAK-242 advanced to phase II and III randomised controlled studies but did not significantly suppress key cytokines (e.g., IL-6) or improve mortality outcomes. One of the most prominent examples is Eritoran (E5564) [Figure 6], which is a lipid A mimic that binds to the MD-2 component of the TLR-4 complex. Eritoran was generally well tolerated. However, a phase II trial found it did not substantially attenuate systemic inflammation. Another interesting example is the NI-0101, which is a TLR-4–targeting antibody developed for rheumatoid arthritis, which reached Phase II clinical trials. Other promising candidates in Preclinical or Early Development stages include P5779, M62812, CRX-526 [Figure 6], and OPN-401, which are all small molecules characterised in vitro as direct antagonists of TLR-4 antagonists.^[67]

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Figure 6:

Toll-like receptor 4 (TLR4) inhibitors in clinical trials or in early development stages.

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