Animal models - Mimicking the pain of trigeminal neuralgia.

Trigeminal neuralgia (TN) is an episodic facial pain which feels like an electric shock of unilateral origin. This neuropathic disorder is an intensely stressful to bear for patient and impacts the quality of life. Most of the cases of TN arise when the root of fifth cranial nerve, i.e., trigeminal nerve is compressed after a few millimeters of its entry into the pons. This article describes various animal models and the role of biomarkers to study the underlying mechanisms of neuropathic pain in animal models as well as different modes of management of TN.

Introduction

As per the definition by the International Headache Society Trigeminal neuralgia (TN) is an episodic neuropathic pain resembling an unilateral electric shock (lasting from a second to 2 min) and also named by “suicide disease” since this neuropathic disorder has been found to coerce victims to think of ending their life.[123] TN affects the area supplied by any of the three branches of the trigeminal nerve, it occurs in 2nd or 3rd division of the nerve. The pain is of sudden onset as well as termination and is generally evoked by inconsequential stimuli such as smoking, talking, washing, shaving, and/or brushing the teeth.[3] The occurrence of pain affects patient's personal and professional activities.[4]

International Classification of Diseases (ICD)-10-CM Code G50.0-a billable ICD code is used as a diagnostic tool of TN. The ICD code “G500” codes atypical TN or type II TN. The character of pain is not common and the clinical features simulate other disorders making neuralgia uneasy to diagnose.[567]

Etiology

TN may be caused by a primary demyelinating disorder, by sudden compression of nerve root after its entry into the pons. Rare causes include minute infarcts, Gasserian ganglion, angiomas in the pons or medulla, nerve root infiltration by tumor or amyloid.[8]

Role of Animal Models

The role of animal models in the development of novel drugs, vaccines, and newer surgical procedures are very crucial. Animal models have brought several advances in biological fields.[9] A lot of animal models were trialed for elucidating the pathophysiological mechanisms of TN. A robust animal model of neuropathic pain should present behavioral changes as well as drug responses parallel to the clinical features of that condition.[10] Rats and mice have been the most widely used neuropathic pain models of choice, especially rats are more commonly used.[11] Animal studies are time-consuming in nature and it is difficult to quantify and ascertain their characteristics such as pain, stress, paresthesia, or any kind of avoidance behavior and even a number of studies conducted for pain of orofacial region lack quantification in the form of spontaneous behavior.[11]

Animal Models of Neuralgia

The neuropathic pain models of surgical manipulations are mainly performed in a maxillary branch of the trigeminal nerve, i.e., infraorbital nerve (IoN) as the nerve gives off its branches in a fan-like pattern in distal relation to the infraorbital foramen. This feature of the nerve necessitates placement of a wide ligature along the nerve entirely to assemble every branch.[11] Various animal models of TN are briefly explained below:

Animal Model Induced by Cobra Venom Injection

In this technique, animal model was induced by injecting cobra venom into the infraorbital branch of trigeminal nerve in rats. After the injection of cobra venom into the IoN trunk quantitative changes were observed in free behavioral activity. Behavioral changes occurred in two main phases. An early postoperative period lasting for 1–3 days postoperative, changes in free behavior were found to be maximal in early period and late postoperative period lasting for 7–14 days’ postoperative. Demyelination of the infraorbital branch and medulla oblongata was seen which decreased mechanical threshold on the contralateral side of experimental animals similar to changes seen in humans.[11]

Transaction or Crushing of the Infraorbital Nerve

Animal models in the facial area were produced by the means of transaction or severing the infraorbital branch or any subbranch of the nerve. The choice of different nerves varies proportionately to the easiness of surgery as well as on the expected evoked behavior.

Damage to the Nerve

Damage to the nerve can also be induced by using an argon-ion laser and photo-irradiation. Compression of the trigeminal ganglion or its root followed by local demyelination is responsible for neuropathy with features symbolizing TN. Such trigeminal nerve compression or demyelination has also been induced with the use of lysophosphatidic acid (the demyelinating agent).

Vascular Compression

Various techniques of vascular compression are-

By injecting agar into cerebellopontine angle so that Trap-Neuter-Return (TNR) is compressed under the guidance of a nerve stimulator

By reaching TNR through the inferior orbital fissure and then inserting a wire to achieve TNR compression

In an attempt to increase accuracy, first a guiding cannula rooted into the left TNR and then 4% agar solution injected by a metal syringe into the dorsal part of the left TNR

A cerebral stereotaxic positioning apparatus was used in addition to a nerve plexus stimulator firstly to locate the TNR at the junction of the pons base and middle cerebellar peduncle (determination of the TNR location-Stimulation of nerve fibers by applied current resulted in depolarization of the nerve cell membrane which in turn generated action potentials and a small amount of current which determined the TNR location). This model presented with strong feasibility and utilized small invasions with no resultant experimental errors.[12]

Chronic Constriction Model

Animal models induced by chronic constriction injury of infraorbital branch possess same clinical features as in humans. Both mice and rat have been used for the constriction model of IoN.[4] Chronic Constriction model (CCI) model of trigeminal nerve includes constriction of a branch of the IoN through several techniques such as invasive, surgical approach (performed by a fine surgical technique), ligature approach (using an application of loose ligation to the ophthalmic branch of the trigeminal nerve), an invasive model, significant hyperalgesia ligature model.[13]

Partial Infraorbital Nerve Ligation

The partial IoN ligation (pIONL) model is an objective and reliable animal model of TN. pIONL is blend of partial nerve ligation model (where medial IoN fibers and dental maxillary nerve fibers are intact) and spared nerve injury model (where ophthalmic division and mandibular division are not injured).[14]

Quantification of Pain (Neuropathic or Inflammatory)

The quantification of pain in rodent models is done by measuring an evoked response. In evoked response, the animal avoids any painful stimuli and the threshold stimulus amplitude to evoke the avoidance is measured quantitatively. Quantification of pain by evoked response predominantly measures allodynia which is pain induced by a stimulus normally not causing pain and hyperalgesia which is an increased pain response initiated by a stimulus that normally causes pain.[15] Since neuralgic pain is of continuous and unavoidable nature such quantification provides only an indirect measure of the subjective pain experience. There is a strict requirement of skilled investigators, meaningful training, and habituation of the animal model since pain is continuous most of the times conditions which do not need any sensory stimulus.[4]

Indicators of Pain

Eye-closure response” - a protein called as Cx43 found in satellite glial cells generates eye closure response which can be prevented for the moment using an analgesic like morphine.

Rat and Mouse grimace scales-these scales are useful in nonhead areas having a duration of short-to-moderate time period and these scales measure “grimaces” among rodents after a painful stimulus. The limitation of this scale is uncertainty about whether the absence or presence of facial inflammation has any effect on the features of the “grimace” or not.[11] Behavior Changes observed in animal models are listed in Table 1.

Table 1

Behavior changes observed in animal models

Animal model	Behavior changes
Rat cobra venom	A profound increase in head-shake behavior Face-grooming behavior[9] Dramatic decrease in exploratory behavior and spent more observation time in resting behavior, they groomed their faces, especially the territory of the injured nerve very frequently and for long periods [9]
CCI model	Prominent hyperalgesia, grooming and weight loss and significant hyperalgesia to heat and pressure stimulation induced by ligature model[13]
pIONL	A transient change of grooming time and prolonged mechanical allodynia[14]
Other models	Aggression, spontaneous grooming, body weight changes Animals showing constriction behavior exhibited freezing, frequent defecation and low weight gain in contrast to controls

pIONL=Partial infraorbital nerve ligation, CCI=Chronic constriction model,

Role of Biomarkers in generation as well as modulation of pain in trigeminal neuralgia

Several biomarkers are involved in the generation as well as modulation of neuropathic pain. These biomarkers generate precise signals which help in the evaluation of possible targets by certain modifications among themselves.

Activating Transcription Factor 3 (ATF3)

It is a marker of damaged neurons, Activating Transcription Factor 3 (ATF3)-LI was found in the nucleus and cytoplasm of axotomized neurons. Its upregulation indicates neuronal and axonal damage. After pIONL and transaction ATF3-LI levels increased in the ipsilateral TG neurons.

Neuropeptide Y and Iba1

Following peripheral nerve injury Neuropeptide Y (NPY) and Iba1 may generate orofacial neuropathic pain.[16] Following pIONL injury microglia and astrocytes were activated[14] with increased expression of microglial markers, i.e., Iba1.[17] After trigeminal nerve injury astrocytes and activated microglial cells may initiate and maintain neuropathic orofacial pain already proved by microglial activation complementary to phenotypic changes in the ipsilateral trigeminal ganglion with marking of anti-Iba1 antisera.[418] Iba1 was also found to be activated in the ipsilateral TGs 14 days after partial IoN injury.[19]

Neuropeptide Y

It is a 36 amino acid peptide extensively present in the peripheral and central nervous system (CNS) and possess excitatory as well as inhibitory effects.[16] After ION injury and inferior alveolar nerve injury and mental nerve injury NPY was upregulated with an increased expression in ipsilateral TGs in rats.

P2 × 3

Purinergic receptors (P1, P2X, and P2Y) are extensively present in mammalian tissues. P2X receptors play a role in nociceptive processing. After trigeminal nerve injury, P2 × 3 has been expressed transiently in rat TGs.

Neuronal nitric oxide synthase

In the CNS Neuronal nitric oxide synthase (nNOS) modulates pain and produces nitric oxide (NO) which acts as a neuronal neurotransmitter as well as neuromodulator and may also act in initial stages of neuropathic pain following injury. After peripheral nerve injury, nNOS is regulated in TGs. Hypersensitivity and allodynia induced by nerve injury can be treated by pharmacological agents.

Phosphatidylinositol 3-Kinase)

In the trigeminal system Phosphatidylinositol 3-kinase (PI3-K)/AKT signaling promotes survival of neuronal cell and outgrowth of axons.

Neuropeptides (Substance P, Intestinal Vasoactive Polypeptide and Peptide Related to Calcitonin Gene and Neuropeptide Y)

Nerve injury changes the expression of neuropeptides such as substance P (SP), intestinal vasoactive polypeptide (VIP), peptide related to calcitonin gene (CGRP), and NPY in nerve and ganglion. At injury site nerve terminals discharge vasoactiveneuropeptides which result in neuropathic pain.[19] CGRP mediates interleukin-1 (IL-1 β) pro-inflammatory effects[419] and neuropathic pain behavior in the CCI rats.[18]

Cytokines

Following injury to peripheral nerve astrocytes and microglia are activated which release pro-inflammatory cytokines such as cyclo-oxygenase-2, IL-1 β, and tumor necrosis factor-α (TNF-α) which mediate chronic neuroinflammation and generate neuropathic pain. IL-1 β causes sensitization of nociceptors, i.e., transient receptor potential cation channel subfamily V member 1 (TRPV1).[18]

Transient receptor potential vanilloid type-1

TRPV1 is activated from noxious heat, capsaicin, and resiniferatoxin, endogenous compounds such as endocannabinoids and products of lipoxygenases.[20] In constriction model of the IoN at the site of nerve injury, monocytes and macrophages released byproducts resulting in increased oxidative stress. TRPV1 mediates this pain-like behavior.[21]

Neurotrophic factors

After trigeminal nerve injury an increased nervous growth factor expression in rat model induces mechanical allodynia in nerve as well as in nuclei whereas decreased production of neurotrophic factors, glia-derived neurotrophic factor causes peripheral neuropathies. When nerve injury occurs, this factor is solely responsible for neuronal survival and plasticity.[22]

Adenosine Monophosphate-Activated Protein Kinase

Adenosine monophosphate (AMP)-activated protein kinase (AMPK) is an emerging target which is responsible for chronic pain through sensitization of peripheral nociceptors. Resveratrol activates AMPK which downregulates activation of astrocytes and microglia-induced inflammation and thus alleviate TN.[18]

Management of Trigeminal Neuralgia

Trans cutaneous Electric Nerve Stimulation

Transcutaneous electric nerve stimulation (TENS) is a noninvasive method with no side effects, used in the treatment of peripheral nerve lesions. TENS in combination with drugs gives better results for neuropathic pain. TENS was observed to be safe used in addition to anticonvulsant drug for TN. TENS is found to be safe in geriatric patients also. The analgesia happens due to physiological blockage, gate control theory, and endogenous pain inhibition. TENS produces electro-analgesia in the spinal cord (dorsal horn). The mechanism of analgesia may be endogenous pain control, presynaptic block, blockage of an unusually excited nerve, etc.[23]

Alcohol block

Alcohol block in the form of peripheral and ganglionic blocks are recommended but with a disgrace because of unpredictable outcomes. Adverse effects and complications such as facial nerve palsy and loss of vision have also been reported with these blocks. Alcohol injections are painful and cause edema at the site. This makes it unfavorable to choose and is indicated only in those refusing extensive surgery or those who are feeble or unhealthy.

Peripheral neurectomy

The neurectomy procedure is performed both extraoral and intraoral. Extraoral incision is given at the eyebrow (supra-orbital nerve) and intraoral incision is given at the site of infraorbital, alveolar, and lingual nerves. After dividing and avulsing all branches, the relevant foramen is clogged with the help of bone wax, silicone plugs, or wooden sticks. The remaining part of the nerve may also be cauterized. Neurectomy is advised and preferred only in cases when other procedures are not effective.[24]

Homeopathy

Homeopathy is not always found to be effective but when it acts its effects are unforgettable.[2] Homeopathy works on the principle that like cure like. Homeopathy is strongly indicated for new cases not ready for conventional medicines and patients resistant to the traditional medicines. In homeopathy, different medicines are prescribed on the basis of the triggering factor and region involved [Table 2]. Homeopathic treatment has also been reported as favorable treatment in patients of Idiopathic TN.[25]

Table 2

Homeopathic medicines for different regions and triggering factors for trigeminal neuralgia

Region involved and triggering factor for TN	Homeopathic medicines	Reference
Right side of the face	Magnesium phosphoricum	[27]
	Kalium phoshphoricum
Left sided of face	Spigelia and Lachesis
Facial pain accompanied by numbness. one side of face is red and hot other side being pale and cold	Chamomilla i
Left side	Verbascum thapsus
Right side of face being worse from eating	Mezereum
By twitchings
Face is very red hot and swollen	Belladona
When there is sensation of icy cold needles piercing through the face	Agaricus muscarius
After an injury	Allium cepa - left side
	Hypericum perforatum - right side
Triggered by emotions	Coffea cruda i
Triggered by exposure to cold air	Aconitum napellus dry cold wind exposure and Dulcamara wet cold wind exposure
Arising after tooth extraction	Hekla lava
Caries of teeth, middle ear infection	Plantago major

TN=Trigeminal neuralgia

Carbamazepine and other drugs

Carbamazepine has been found to be effective against TN but the mechanism of pain relief is not known. This drug alone was found to be effective in the chronic cases whereas combination with phenytoin was found to be helpful in acute cases of trigeminal hyperalgesia.[13] Other drugs found effective are oxcarbazepine, gabapentin, pregabalin, topiramate, phenytoin, and topiramate, clonazepam, valproate, and mexiletine. There is a need to titrate Lamotrigine a large number of days and it possesses limited value in severe pain. Small studies in TN reported baclofen as an alternative drug of choice.[27]

NMDA receptor antagonists are recently found analgesic agent but it possess risk of developing adverse drug reactions of ketamine. In contrast certain NMDA antagonists with low affinity, for example, “CHF3381” have shown hopeful findings in preclinical trials. It showed tolerance in a better way and less adverse drug reactions. Memantine alone and the combination of capsaicin and memantine has also been found to be effective analgesic in acute model of TN.[27]

Capsaicin

Capsaicin (a TRPV1 receptor agonist) is a pungent compound found in hot chili peppers. TRPV1 receptors in nociceptive neurons in peripheral nervous system modulate pain and integrate various painful stimuli in central and peripheral nervous system and possess selective action on A and C fibers of primary sensory neurons.[28] The treatment with capsaicin is effective in neuropathic pain. In inflammatory state, capsaicin-induced analgesia is long lasting as compared to basal state. Capsaicin activates TRPV1, which is responsible for analgesia during inflammation. Piezo proteins are cation-selective ion channels in all mammals which react to mechanical stretch. TRPV1 inhibits these piezo proteins by calcium-dependent activation of phospholipase Cδ (PLCδ).[2829]

Curcumin

Curcumin (Cur) is a yellow colored pigment obtained from plant namely Curcuma longa, possessing antinociceptive, anti-inflammatory, neuroprotective activities, and analgesic activity against various neuropathic pains. In cobra venom-induced animal models (rats) of TN curcumin improved pain behaviors and cognitive impairments. Curcumin provided a protection against neuron degeneration induced by neuropathic pain and synapse damage in hippocampus. Curcumin affects synaptic-proteins and inhibits Aβ activity on synapses in hippocampus. Curcumin is observed effective in cognitive impairment due to chronic neuropathic pain.[30]

Emodin

It is an active anthraquinone extract from rhubarb possessing several properties such as antimutagenic, anti-inflammatory, anti-diuretic, anti-cancer, vasorelaxant and it increases the threshold of mechanical hypersensitivity. Emodin was found to relieve TN pain by mechanism of reducing the P2 × 3 receptor expression CGRP expression and increasing the threshold of mechanical hypersensitivity in TN rats.[31]

Resveratrol

Resveratrol is an antibiotic of natural origin derived from fruits and plants mostly grapes and red wine. It possesses anti-inflammatory and neuroprotective properties. Resveratrol has a sustaining analgesic effect. It is found that resveratrol downregulated the expression of Iba marker through upregulating AMPK to lessen mechanical allodynia in CCI rat model and reverse the generation of TNF-α and IL-1 β. The activation of AMPK stops neuroinflammatory process.

CGRP is a mediator of trigeminal nociceptive processing and resveratrol blocks release of CGRP in CCI model.[18]

Botulinum toxin

There are several botulinum neurotoxins (A, B, C1, C2, D, E, F and G) and botulinum toxin Type A (BoNT-A) is one of the serotypes obtained from clostridium botulinum. (BoNT) retards neuropathic pain in several animal models. It inhibits discharge of pain mediators (CGRP, SP and glutamate) from the ganglions and nerve endings. It deactivates Na channel, has anti-inflammatory action around the nerve endings, and shows axonal transfer.[32] BoNT-A has been observed to significantly increase the mechanical stimulation threshold in IoN chronic constrictive injury model which is most widely accepted model of TN.[33]

Low-level laser therapy

Low-level laser therapy (LLLT) makes use of solo wavelength light source. It induces pain relief with no side effects. For the treatment to be successful it is important to demarcate atypical facial pain from neuralgia. Therapeutic effects of LLLT are increased nerve function and improved myelin production capacity as well as growth of axons after nerve injury in animal models. LLLT reduces biochemical markers (IL-1 β, mRNA Cox 2, PGE2, TNF-α), influx of neutrophils, oxidative stress, hemorrhage, and edema in according to dose. Higher energy level can produce analgesia through disrupting rapid transport of axons in small diameter fibers. Central sensitization is reduced by repeated treatments.[34] Recent treatment available for TN[35363738] arelisted in Table 3.

Table 3

Recent advances in treatment of trigeminal neuralgia

Method	Technique/indications	Effects observed	Complications	Reference
Glycerol rhizotomy	Glycerol is injected in the trigeminal cistern	Relieves pain due to demyelination, axonal fragmentation	Corneal numbness, weakness of masseter muscle, herpes labialis, dysesthesias	[35]
Radiofrequency thermocoagulation	Electrocoagulation of the gasserian ganglion rootlets and trigeminal nerve	>90% relief of pain	Weakness of masticatory muscles, dysesthesia, and numbness of cornea, and the permanent damage of minute, nonmyelinated pain fibers	[35]
Gamma knife radiosurgery (least invasive, lowest risk)	Indicated in patients with concurrent medical Illness and refuse more invasive surgery or poor candidates for MVD	Cures through nerve lesioning and avoids vascular compression	Facial numbness, anesthesia dolorosa Irreversible dysesthesias	[3536]
Cryoneuroablation (cryoanalgesia or cryoneurolysis)	Cold application to tissues simulates local anesthetic effect	Cryoanalgesia disrupts structure of nerve and creates wallerian degeneration, vasonervorum damage	Endoneural edema, chronic pain relief	[37]
MVD (most invasive, highest risk	Minimally invasive access to the CPA	For decompressing the trigeminal nerve	Numbness of face, infections, cerebrospinal fluid leakage, facial palsy, and auditory defect	[353638]
PBC	Percutaneous procedure performed with the patient under general anesthesia	Low cost, simplicity	Numbness, dysesthesia, and very rare temporary weakness of masseter muscle
Neuromodulation MCS DBS	MCS-for chronic pain, DBS-used in cases when conventional surgeries and medicines are not effective	MCS-precentral cortex stimulation DBS targets the pHyp	MCS - intracranial bleeding, infection, and permanent neurological deficits DBS-meningitis, intracranial hemorrhage, encephalitis, and scalp infections	[35]

pHyp=Posterior hypothalamus, CPA=Cerebellopontine angle, MCS=Motor cortex stimulation, DBS=Deep brain stimulation, PBC=Percutaneous balloon compression, MVD=Microvascular decompression

Ayurvedic treatment of TN

Acharya Craak-“even poison in small amount acts like nectar”. Ayurvedic management provides analgesia without surgical intervention.[3940] Aconitum ferox (vatsanabha) deadly poison in Ayurveda benefits in several diseases of the body and also called as smanchen, “great medicine.” Its crushed roots assorted with bezoar stones act as universal antidote. The root is indicated for the treatment of malignant tumors and for vataroga (diseases of nervous system).[26] Proper Srotoshodhana and Doshanulomana therapies have been found to relieve the pain of TN[41] thus such a painful condition could be effectively managed by Ayurveda.[39] In human body Vikruta Vata responsible for all types of pains. Different treatments normalize Vata Dosha and nourish Shirah (Head). Thus, Vata, i.e., the whole nervous system gets treated and normalized. Ayurvedic treatment includes use of herbal oils which restore the imbalance of TN known as Ananta vata (according to Ayurveda) and improve the microcirculation within the nerve, and all unusual pain sensations are reduced to the acceptable levels so that the nerve starts functioning at an optimum level. Ayurvedic medicines are also prescribed in addition to oils which target the Trigeminal nerve reducing the pain perception of the patient.[42]

Gene therapy for trigeminal neuralgia in mice

A viral vector encoded for encephalin was injected as single dose directly in behavioral mice pain model for provoking a extensive expression of the transgene resulting in analgesia. Herpes simplex virus type 1 based vector encoded for human preproenkephalin (SHPE) was injected into mice trigeminal ganglia and an orofacial formalin test was performed. Increasing nociceptive behavior at intervals was observed post injection. It might be considered a good technique especially when it is not possible to access dura. Analgesic effect produced by SHPE injection was found to be reversed by injecting μ-opioid receptor antagonist, i.e., naloxone subcutaneously.[43]

Acupuncture

Acupuncture is part of the traditional Chinese medicine. It is an effective and efficient natural cure to relieve TN pain.[2644] Acupuncture plays a role as analgesic by increasing mediators (serotonin encephalin, endorphin) in the brain tissue and plasma.[44] It is a treatment in which fine needles are inserted along specific energy meridians (channels along which the Chi or energy flows in the body). Any obstruction in these meridians affects the free flow of the Chi resulting in a variety of diseases. Acupuncture removes these obstructions thus relieving the patient.[26] Acupuncture can be manual acupuncture or electroacupuncture it stimulates pain points of the body.[45] From safety point of view, it is good but with few complications such as local infection, metal allergy, bruising or hematoma at the site of pric.[44] The role of biomarkers involved in trigeminal pain mechanism is listed in Table 4.

Table 4

Biomarkers involved in trigeminal neuralgia pain and their pharmacological interaction

Biomarker	Pharmacological interaction
Iba1	Resveratrol blocks glial cell activity and alleviate glia induced neuroinflammation through activation of AMPK, and causes desensitization in subthalamic nucleus producing analgesia[18]
P2X3	Emodin relieves TN pain by new mechanism of reducing the expression of P2X3 receptor
Cytokines	Low-level laser therapy decreases biochemical markers such as Cox 2, IL-1β, TNF-α and relieves inflammatory pain
Neuropeptidescalcitonin gene related protein (CGRP), substance P, glutamate	Resveratrol suppresses the increased CGRP level[20] BoNT (Botulinum toxin) results in reduction and alteration of neuralgia in animal models by its mechanism of inhibiting the pain mediators (substance P, calcitonin gene related protein etc) from the neuronal endings[36]
AMPK	Resveratrol, an AMPK activator, increases pressure threshold eliciting a response which is nocifensive in the fifth cranial nerve ligated animal models[18]
TRPV1	Capsaicin activates TRPV1 which is responsible for analgesia during inflammation[29]
Encephalin, endorphin and serotonin	Acupuncture induces analgesia by increasing levels of these mediators in the brain tissue and plasma[44]
Synaptic-related proteins (CaMKII and synapsin1)	Curcumin act as modulator of synaptic proteins like CaMKII and synapsin1, so as to ameliorate neuronal and synapse damages[31]

TRPV1=Transient receptor potential vanilloid type-1, TN=Trigeminal neuralgia, AMPK=Activated protein kinase, CGRP=Calcitonin gene-related peptide, COX-2=Cyclo-oxygenase-2, IL-1β=Interleukin-1 β, TNF-α=Tumour necrosis factor-α

Conclusion

Neurologists and neurosurgeons pose several challenges in treatment of TN. Complex pathogenesis of TN complicates the satisfaction of the medical therapy. Recent neuroradiological techniques have helped in achieving advanced pathogenesis and surgical treatment. Lack of sufficient data for measuring pain behaviors is a barrier in better understanding of orofacial pain. There is still a need to develop novel animal models and refining accessible methods, which may generate new approaches for alleviating trigeminal nerve-related pain. In addition to that and most importantly prior assessment of functional and capacity limitations should be considered.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.