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In This Article
 »  Abstract
 » Introduction
 » Etiology
 »  Role of Animal M...
 »  Animal Models of...
 »  Animal Model Ind...
 »  Transaction or C...
 » Damage to the Nerve
 » Vascular Compression
 »  Chronic Constric...
 »  Partial Infraorb...
 »  Quantification o...
 » Indicators of Pain
 »  Role of Biomarke...
 »  Activating Trans...
 »  Neuropeptide Y a...
 » Neuropeptide Y
 »  Phosphatidylinos...
 »  Neuropeptides (S...
 » Cytokines
 »  Adenosine Monoph...
 »  Management of Tr...
 » Conclusion
 »  References
 »  Article Tables

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 Table of Contents    
REVIEW ARTICLE
Year : 2022  |  Volume : 54  |  Issue : 2  |  Page : 138-145
 

Animal models - Mimicking the pain of trigeminal neuralgia


1 Department of Clinical Research, Dasmesh Institute of Research and Dental Sciences, Faridkot Punjab, India
2 Department of Hospital Administration, Guru Gobind Singh Medical Hospital, Faridkot Punjab, India
3 Department of Oral & Maxillofacial Surgery, Dasmesh Institute of Research and Dental Sciences, Faridkot Punjab, India

Date of Submission10-Aug-2019
Date of Decision11-Jun-2021
Date of Acceptance23-Mar-2022
Date of Web Publication10-May-2022

Correspondence Address:
Dr. Ravinder Nath Bansal
Hospital Administration, Guru Gobind Singh Medical Hospital, Faridkot, Punjab
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijp.ijp_296_19

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 » Abstract 


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.


Keywords: Animal model, biomarker, neuropathic pain, pain, trigeminal neuralgia


How to cite this article:
Gupta S, Bansal RN, Singh Sodhi SP, Brar GK. Animal models - Mimicking the pain of trigeminal neuralgia. Indian J Pharmacol 2022;54:138-45

How to cite this URL:
Gupta S, Bansal RN, Singh Sodhi SP, Brar GK. Animal models - Mimicking the pain of trigeminal neuralgia. Indian J Pharmacol [serial online] 2022 [cited 2022 Jun 25];54:138-45. Available from: https://www.ijp-online.com/text.asp?2022/54/2/138/344959





 » Introduction Top


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.[1],[2],[3] 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.[5],[6],[7]


 » Etiology Top


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 More Details, angiomas in the pons or medulla, nerve root infiltration by tumor or amyloid.[8]


 » Role of Animal Models Top


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 Top


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 Top


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 Top


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 Top


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 Top


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 Top


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 Top


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) Top


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 Top


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

Click here to view



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


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) Top


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 Top


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.[4],[18] Iba1 was also found to be activated in the ipsilateral TGs 14 days after partial IoN injury.[19]


 » Neuropeptide Y Top


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) Top


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) Top


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 vasoactive neuropeptides which result in neuropathic pain.[19] CGRP mediates interleukin-1 (IL-1 β) pro-inflammatory effects[4],[19] and neuropathic pain behavior in the CCI rats.[18]


 » Cytokines Top


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 Top


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 Top


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

Click here to view


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).[28],[29]

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[35],[36],[37],[38] are listed in [Table 3].
Table 3: Recent advances in treatment of trigeminal neuralgia

Click here to view


Ayurvedic treatment of TN

Acharya Craak-“even poison in small amount acts like nectar”. Ayurvedic management provides analgesia without surgical intervention.[39],[40] 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.[26],[44] 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

Click here to view



 » Conclusion Top


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.



 
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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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