Introduction
Neuropathic pain (NP) is frequently defined as a persistent scorching or shooting pain brought on by nerve breakdown or damage in the somatosensory nervous system, which affects peripheral nerve fibers such as Aβ, Aδ and C fibers and central neurons (Colloca et al., 2017). According to (Tripathi & Verma, 2016), NP is defined by the International Association for the Study of Pain (IASP) as "pain caused by damage or disease affecting the somatosensory nervous system." This occurs due to certain conditions such as metabolic disorders, infection, cancer, trauma, medicines, and toxins.
NP is marked by spontaneous greater pain reaction to stimuli that are painful or innocuous. The somatosensory nervous system is involved with the conscious awareness of sensations that come from the muscles, joints, skin, and fascia, such as touch, pressure, pain, warmth, position, movement, and vibration. Amputation, alcoholism, chemotherapy, diabetes, facial nerve problems, HIV infection, multiple myeloma, multiple sclerosis, arthritis in the spine, spine surgery, syphilis, thyroid issues, vitamin B12 deficiency, Charcot-Marie-tooth, post-herpetic neuralgia, post-sternotomy, post-mastectomy, post-thoracotomy, and post-herniorrhaphy are some common causes of NP. Lesions in the somatosensory nervous system brings undesirable change in the transmission of sensory signal to an electric signal in the nervous system. NP shows gloves and stockings pattern of distribution, it mainly affects feet, calves, hands and forearms. NP brings changes or modulation, or alteration in pain signaling, pain transmission neurons, inhibitory interneurons and descending modulatory control systems, Ion channel, second-order nociceptive neurons and pain mechanisms (Kumar, Kaur, & Singh, 2018).
The NP broadly divides in two types central neuropathy and peripheral neuropathy.
Central neuropathy
According to the IASP, central pain is pain that originates from or is brought on by a primary CNS injury or dysfunction (Finnerup, 2008). A group of persistent NP disorders known as central pain syndrome are brought on by CNS injury. Central pain may arise after a traumatic brain injury and spinal cord injury (Colloca et al., 2017), like syringomyelia, multiple sclerosis, stroke (infarction or hemorrhage), Parkinson’s disease, tumors, and epilepsy (Boivie, 2006). The characteristics of central pain are it is chronic, disabling, and resistant to treatment due to which it has a major influence on mood and lifestyle quality of the patients suffering from it. The clear diagnostic criteria for central pain are not established, which makes the diagnosis difficult (Finnerup, 2008). In recent times the NP scale (NPS) is the only validated tool for assessment of central neuropathic pain. The available treatments are only effective in reducing pain to some extent (Finnerup, Otto, Mcquay, Jensen, & Sindrup, 2005). Approximately 8% of stroke patients and 25% of multiple sclerosis individuals experience central pain (Finnerup, 2008) and 50% of spinal cord injury patients. Example of Central NP includes harm to the spine or brain, a stroke, or multiple sclerosis.
Peripheral neuropathy
Peripheral neuropathy is a condition developed due to damage to the peripheral nerves. Peripheral nerves are located outside the brain and carry signals to and from the brain and spinal cord. It is the common, chronic, disabling sometimes mortal condition that causes sufferings to the patient. Peripheral neuropathy has heterogenicity in etiopathogenesis, manifold pathology, and diversified severity. Glove and stocking sensory loss, absence of tendon reflexes, distal wasting and weakness, and progressive polyneuropathy are the hallmarks of this condition (Hughes, 2002; Martyn & H, 1997). Chronic NP can develop as a result of peripheral nerve injury in several ways (Kuner & H, 2016). It is evident that hyperglycemia is crucial for the onset and development of diabetic neuropathy and other microvascular consequences of diabetes. which are mainly driven by (Khan, Kaur, Sharma, & Author, 2015). Trigeminal or postherpetic neuralgia, peripheral nerve damage, uncomfortable polyneuropathies, or radiculopathies are examples of peripheral neuropathy.
Pathways Involved in neuropathic pain
Diabetic Neuropathy and the Polyol Pathway
Extremely high intracellular glucose levels result from hyperglycemia in nerve cells, which also results in the glycolytic pathway being saturated. The enzymes aldose reductase and sorbitol dehydrogenase convert extra glucose into sorbitol and fructose (Vinik, Nevoret, Casellini, & Parson, 2013).Myoinositol is decreased as sorbitol and fructose buildup, which in turn affects the activity of the membrane Na+/K+ ATPase, impairs axonal transport, and damages the structural integrity of neurons. According to (Brownlee, 2005) the aldose reductase (AR)-mediated conversion of glucose to sorbitol depletes the antioxidant nicotinamide-adenine dinucleotide phosphate (NADPH), which is necessary for the renewal of reduced glutathione (GSH). Nitric oxide synthase requires NADPH as a cofactor; when NADPH levels are low, nitric oxide synthase produces less nitric oxide, which results in less vasodilation, which lowers blood flow to the nerve. Galactosaemic animals peripheral nerve ATPase causes myoinositol levels to drop (Edwards, Vincent, Cheng, & Feldman, 2008). It triggers a chain of events that includes decreased membrane Na+/K+ ATPase activity, intra-axonal sodium accumulation, and structural breakdown of the neuron as a result.
Protein Kinase-C (PKC Activity in Diabetic Neuropathy
PKC pathway is another way by which hyperglycemia damages the tissue. Diacylglycerol (DAG) concentration is stimulated by high glucose levels, and this triggers the PKC pathway. Increased PKC-ß-isoform production has been linked to the vascular endothelial growth factor (VEGF), PAI-1, NF-B, and TGF-ß are angiogenic proteins that are overexpressed along with diabetic complications.
Hexosamine Pathway in Diabetic Neuropathy
Considered an important mediator in the pathophysiology of diabetes induced oxidative stress and its consequences. Fructose -6 phosphate is a metabolic intermediate step in glycolsis. Some fructose -6-phosphate is diverted from the glycolytic pathway to the hexosamine pathway during the breakdown of glucose. The hexosamine pathway experiences increased flux under hyperglycemic circumstances, which leads to an excess of GlcNAc and abnormal gene expression changes (Brownlee, 2005).
Advanced Glycation End Products (AGE in Diabetic Neuropathy)
AGE, which is produced as a consequence of nonenzymatic glycation of proteins, nucleotides, and lipids in hyperglycemia, may interfere with integrity and mechanisms for neuronal repair (Edwards et al., 2008).
Table 1
Non-Pharmacological remedies for the Prevention of Peripheral Neuropathy (Pattan, Maid, & Harhe, 2010)
Importance of Natural products and Bioactive compounds
Natural products and bioactive compounds there have been extensively utilized in ages to cure a variety of illnesses. Usage of plants, bioactive substances and natural products in advancing and advanced countries has been escalated nowadays because of their healing properties, biological activities, nutritional values and fewer side effects (Ekor, 2014). In contradiction a number of ailments such as cardiac, diabetes, reproductive, melanoma, and neurodegenerative diseases have shown that natural ingredients have a protective impact and their bioactive compound and have been reported within the ancient eras (Sairazi, Sirajudeen, & S, 2020). For the treatment of neurological conditions Natural compounds are now being used as neuroprotectants (Lim & Kim, 2016). Table 1 shows non-pharmacological remedies with their examples for the prevention of peripheral neuropathy.
Animal Models for Assessment of Neuropathic Pain
Animal models play a crucial role in studying neuropathic pain, as they provide valuable insights into the underlying mechanisms and aid in evaluating potential therapies. NP is a complex state that arises from dysfunction of the neurological system, resulting in persistent pain signals and abnormal sensory processing. By utilizing animal models, researchers can investigate various aspects of neuropathic pain, including its etiology, pathophysiology, and treatment options. One of the primary advantages of animal models is their ability to replicate certain features of human neuropathic pain. These models are designed to mimic specific neuropathic conditions by inducing nerve injury or disease-like symptoms, allowing researchers to study the associated pain behaviours and physiological changes. By observing animals responses to pain stimuli and analyzing their neurobiological alterations, scientists can gain insights into the mechanisms involved in neuropathic pain. Animal models also enable researchers to explore the effects of potential therapies for neuropathic pain. They provide a controlled experimental setting where interventions can be tested and their efficacy assessed. This includes pharmacological interventions, such as administering analgesic drugs or investigating novel compounds, as well as non-pharmacological approaches like physical therapy or neuromodulation techniques. Animal models allow for the evaluation of treatment outcomes, dose-response relationships, and potential adverse effects, providing valuable information to guide clinical studies in humans. There are various animal studies available for the screening of NP and research has shown the effectiveness of each model and the excellent effects of natural products on neuropathic pain. The various screening models are listed in Figure 1. Here are some typical animal models for NP research include:
Diabetic Neuropathy Models
Animals with experimentally induced diabetes, such as streptozotocin (STZ)-treated rodents, can develop peripheral neuropathy resembling diabetic neuropathy observed in humans. These models are utilised to study the underlying diabetic NP.
Spinal Cord Injury (SCI) Models
SCI models involve contusion, compression, or transection of the spinal cord. These models not only mimic the sensory and motor deficits observed in human spinal cord injury but also lead to the evolution of NP symptoms.
Spinal Nerve Ligation (SNL) Model
In this model, a specific spinal nerve is surgically ligated, leading to the evolution of NP symptoms in the corresponding dermatomes. It mimics certain aspects of nerve damage-related NP observed in humans.
Chronic Constriction Injury Model (CCI)
This model involves the placement of a ligature around a peripheral nerve, resulting in sustained compression and chronic constriction. It induces neuropathic pain-like behaviors and is particularly useful for studying peripheral nerve injury-induced pain.
Spared Nerve Injury (SNI) Model
In this model, some of the major branches of a peripheral nerve are carefully spared, while others are injured. It produces robust and long-lasting behavioral changes, allowing researchers to study mechanisms of both allodynia (pain from non-painful stimuli) and hyperalgesia (increased sensitivity to painful stimuli).
Chemotherapy-Induced Neuropathy Models
Various chemotherapeutic agents, such as paclitaxel or vincristine, can be used to induce peripheral neuropathy in animals. These models are relevant for studying NP associated with chemotherapy treatment.
Streptozotocin-Induced Diabetic Neuropathy in Rats and Mice
The classic model was developed by Jakobsen and Lundbeck and the classic model was developed by Filho and Fazan for phrenic nerve neuropathy in rats. The toxicity produced by Streptozotocin is due to presence of nitrosoamide moiety, it damages the DNA of insulin secreting beta cells present in pancreas and produces toxicity (Islam, 2013). The level of damage to beta-cells is dose dependent. Due to the similarity with glucose STZ get easily transported through glucose transporter GLUT2.The diabetes is developed in animals by giving a single injection of STZ through an intraperitoneal or intravenous route. Different factors such as age, strain, and species are responsible for the sensitivity of animals to STZ. The development of Diabetic neuropathy using STZ reduces diameters of the myelin sheath, axon, and nerve fiber, shows impairment in motor performance and significantly decreases the myelination of the phrenic nerves and the right and left fascicular regions (Islam, 2013). As STZ increases AR activity, oxidative-nitrosative stress, toll-like receptor 4, protein kinase C, PARP and ACE activations, C-peptide deficiency, impaired neurotropism and proinflammatory response streptozotocin induced diabetic animal models are extensively used to understand diabetic NP (Gao & Zheng, 2014). Table 2 and Table 3 shows the list of natural products used in the screening of diabetic neuropathy along with the parameters assessed by the researcher.
Alloxan Induced Diabetic Neuropathy
Alloxan is very unstable weak barbituric acid derivative which is first isolated by Brugnatelli in 1818 (Ighodaro, Adeosun, & Akinloye, 2017; Szkudelski, 2001). Alloxan is selectively up taken by the beta cells of pancreas due to the similarity with glucose in molecular shape and hydrophilicity, it gets accumulated in the cells and produces diabetogenicity (Szkudelski, 2001). Alloxan produces diabetes through a partial degeneracy of the beta (β) cells present in islets of pancreas and brings a considerable change in insulin production by β-cells both qualitatively and quantitatively (Szkudelski, 2001). It is First time used as McLetchie. It produces type 1-DM by a) b)hrs of administration of single dose by intraperitoneal route (Szkudelski, 2001). Table 4 shows the list of natural products used in the NP with the parameters assessed by the researcher.
Spinal Cord Injury (SCI)
NPmodel by SCI is developed by using one the following technique-Contusion or weight dropping
i. Spinal cord compression
ii. Excitatory neurotoxins
iii. Photochemical-induced ischemia
iv. Spinal cord transaction
v. Crushing of the spinal cord
vi. Clip Compression Injury
vii. Spinal Cord Displacement
viii. Canal Stenosis
ix. Spinothalamic Tract LesionTable 5 shows the list of natural products used in the management of SCI neuropathy with the parameters assessed by the researcher.
The Chronic Construction Injury model (CCI) model
This model was developed in rats by Bennett and Xie in 1988 and in mice by Sommer in 1997, model was designed in such a way that it mimics the peripheral nerve damage in patients of NP. This model is produced under anesthesia by the constriction of the nerve most commonly sciatic nerve and in some cases infraorbital nerve and the median nerve (Sommer, 2007), in which the nerve is tied using several ligatures resulting in incomplete nerve injury involves epineural inflammation, intraneural edoema, and Wallerian degeneration (Kumar et al., 2018). After 1 from the injury, the allodynia and hyperalgesia develops as described in Table 4. Pain hypersensitivity testing is done by measuring the mechanical and thermal withdrawal threshold & latency (Kumar et al., 2018). In Table 6, a list of natural products used in the management of CCI Neuropathy with the parameters assessed by the researcher.
Partial Sciatic Nerve Injury Model (PNI)
In this model the peripheral neuropathy is developed by tight ligation of peroneal nerve or tibial nerve. Unlike STZ-induced diabetic animals, PNI induced neuropathic animals were not chronically ill, growth rate is not reduced, polyuria is not observed, diarrhea, and enlarged and distended bladders is not found. Signs and symptoms of neuropathy develop after 1 week of surgery. This model initiates long-lasting mechanical hyperalgesia but thermal hyperalgesia is not produced by this model. PNI is evaluated by, Morphine and L-Baclofen. The major limitation of PNI is that the major pathogenesis was not characterized (Islam, 2013). Table 7 shows the list of natural products used in the management of PNI Neuropathy with the parameters assessed by the researcher.
Anticancer agents induced neuropathy
Chemotherapy have many side effects, from which peripheral neuropathy is the usual side effect. Chemotherapy damages somatosensory nervous system which may be the reason for development of peripheral neuropathy. The antineoplastic agents used in chemotherapy damages the healthy cells including nerves that affect feeling and movement in the hands and feet (Islam, 2013).
Table 2
Natural products used in the screening of diabetic neuropathy induced by STZ
Table 3
Bioactive compounds used in the screening of diabetic neuropathy induced by STZ induced by STZ
Table 4
Natural products in the treatment of Alloxan induced Neuropathy
Table 5
Natural products in the management of Spinal Cord Injury (SCI) Neuropathy Models
Table 6
Natural products in the management The Chronic Construction Injury model (CCI) Neuropathy Models
Table 7
Natural products in the management of Partial Sciatic Nerve Injury Models (PNI)
Sr.No. | Chemical constituent | Animal | Parameters | References |
1. | Euphol | Male Swiss mice | • Mechanical Hyperalgesia, Mechanical • Allodynia, Locomotor activity, Catalepsy, Cytokine levels, RT-PCR, MPO | |
2. | Hesperetin | Wistar rats | • Radiant heat hyperalgesia test, Cold allodynia test, Randall Selitto, Von-Frey hair, pinprick test, Rota-rod, Spontaneous locomotor (exploratory) test, MNCV, Total protein content • LPO, NO, Interleukin-1β and Interleukin-6 by ELISA, RT-PCR | |
3. | Cassine | Male Swiss mice | • Mechanical hyperalgesia, heat hyperalgesia, MPO, IL-1b, IL-6 and KC levels, Immunohistochemical analysis, Hypothermia, Catalepsy, • Locomotor activity | |
4. | Myricitrin/flavonoid (genus Eugenia) | Adult female Swiss mice | • Von Frey test, Algesimeter, Behavioral tests, Mechanical hyperalgesia, Thermal hyperalgesia | Hagenacker, Hillebrand, Wissmann, Büsselberg, and Schäfers (2010) |
5. | Tormentic acid/triterpene (Vochysia. divergens) | Male and female Swiss mice | • von frey tests, Open-field test, • Behavioral tests | |
6. | Linalool/monoterpene | Adult female Swiss mice | • Mechanical and Cold hypersensitivity, Proinflammatory Cytokines |
Table 8
Natural products in the management of Vincristine-Induced NP Models
Table 9
Paclitaxel-Induced NP Models
Animal | Dose of paclitaxel | Route of administration | Dosing Time | Sign and symptoms developed (Kumar et al., 2018) |
Rat | 1 or 2 mg/kg | i.p. | Four alternate days | Endoneural edema and Allodynia |
Rat | 16 mg/kg | i.p. | Once a week for 5 weeks | Motor impairment or systemic toxicity Electrophysiological, Morphological, and degenerative changes |
Mice | 10 mg/kg | i.p. | Single dose | Peripheral neuropathy |
Table 10
Paclitaxel-Induced NP Models
Table 11
Oxaliplatin -Induced NP Models
Table 12
SpinalNerve Ligation (SNL) Model of Neuropathic Pain
Hoke, 2012). Various Antineoplastic agents are used by researchers to develop the CIPN model such as paclitaxel, cisplatin, carboplatin, and oxaliplatin and others such as vincristine, thalidomide, suramin, and bortezomib (Hoke, 2012).
Vincristine-Induced Neuropathic Pain
Vincristine is used as antineoplastic agent. It belongs to the vinca alkaloid family. It is used in treatment of malignant tumors (Higuera & Luo, 2004), lymphoma and leukemia (Kumar et al., 2018). Use of vincristine causes peripheral neuropathy which limits its use. Vincristine develops neuropathy by altering microtubular structures of intracellular tubulin and damages peripheral axons results in dysfunction in primary afferent fibers like Aβ-, Aδ-, and C-caliber, which results in dose-dependent neuropathy. The early signs of neuropathy by vincristine administration is paranesthesia, which progresses to hyperesthesia. This model developed by giving IV injection or by continuous intravenous infusion of vincristine (Higuera & Luo, 2004). The sufficient dose for development of neuropathy by vincristine is as low as 50 μg/kg. It induced consistent and long-lasting signs and symptoms of neuropathy like Allodynia, hyperalgesia(mechanical) and hypoalgesia (thermal) similar to the vincristine treated cancer patients, which makes it a potential study tool for studying the pharmacological mechanisms of vincristine induced NP (Kumar et al., 2018). Table 8 shows a list of natural products used in the therapy of Vincristine induced Neuropathy with the parameters assessed by the researcher.
Paclitaxel-Induced Neuropathic Pain
Paclitaxel, a vinca alkaloid is a potential antineoplastic agent as a treatment for breast cancer, head and neck cancer, melanoma and ovarian cancer. By inhibiting the polymerization of microtubules and binding to tubulin, paclitaxel causes sensory neuropathy and myelosuppression and interferes with mitosis. In models receiving low doses of paclitaxel, loss of pain perception, morphological abnormalities, neurophysiologic problems, and changes to motor function are rare. So it is better to study these changes with the model of higher doses (Kumar et al., 2018; Sousa, Lages, Pereira, & Slullitel, 2016). The Paclitaxel-Induced NP model proved that, they produced slightest effects on the rats health and mimics the conditions developed in patients treated with taxens , which makes it a potential study tool for studying the pharmacological mechanisms (Kumar et al., 2018). Table 10; Table 9 shows the list of natural products used shows the list of sign and symptoms of Paclitaxel-Induced neuropathy with the parameters assessed by the researcher.
Oxaliplatin-Induced Neuropathic Pain
It is a third-generation antineoplastic drug based on platinum that is used to treat colorectal cancer that has progressed. Oxaliplatin develops neuropathy by inhibiting DNA synthesis and the replication of DNA, damages the neuronal cell bodies, decreases SNCV and axons in peripheral nerves are deteriorating (Toyama, Mt, & S, 2014). Development of neuropathy at combined dosages (36 and 48 mg/kg i.p.) (Kumar et al., 2018). Table 11 shows the list of natural products used in the management of Oxaliplatin -Induced Neuropathy with the parameters assessed by the researcher.
Spinal Nerve Ligation (SNL Model of Neuropathic Pain
The SNL framework serves as a technique for researching medication for neuropathic pain that is chronic. The experimental drugs with analgesic qualities that are utilised as remedies for persistent neuropathic pain are found using this model. In order to produce peripheral pain, the L5 and L6 spinal nerves are surgically ligated. Table 12 shows the list of natural products used in the management of SNL neuropathy with the parameters assessed by the researcher.
Conclusion
Natural products including plant extracts as well as bioactive components are having potential due to the presence of various active biomolecules. Due to this they possess various medicinal values. From the present review it is has been concluded that natural products have potential to prevent neuropathy and further studies are required at molecular as well as cellular level to confirmed there potential.
