A Rodent Model of Trigeminal Neuralgia

Article (PDF Available)inMethods in molecular biology (Clifton, N.J.) 851:121-31 · January 2012with30 Reads
DOI: 10.1007/978-1-61779-561-9_8 · Source: PubMed
Trigeminal Neuralgia (Tic Douloureux) is a neuropathic pain syndrome caused by compression of the trigeminal nerve root and is characterized by severe paroxysms of pain in the face commonly triggered by light mechanical stimulation to the peri-oral area. Trigeminal neuralgia is very difficult to treat in part due to the lack of an suitable animal model for testing novel therapeutic approaches. This chapter describes a model of trigeminal neuralgia in which crystals of a superabsorbent polymer are placed next to the trigeminal nerve root of rats, producing ongoing mechanical compression of the nerve root. The chapter then describes means of behaviorally assessing the robust mechanical hypersensitivity consequent to the compression that can be used to determine the efficacy of potential therapies for this devastating condition.
Z. David Luo (ed.), Pain Research: Methods and Protocols, Methods in Molecular Biology, vol. 851,
DOI 10.1007/978-1-61779-561-9_8, © Springer Science+Business Media, LLC 2012
Chapter 8
A Rodent Model of Trigeminal Neuralgia
David C. Yeomans and Mikhail Klukinov
Trigeminal Neuralgia (Tic Douloureux) is a neuropathic pain syndrome caused by compression of the
trigeminal nerve root and is characterized by severe paroxysms of pain in the face commonly triggered by
light mechanical stimulation to the peri-oral area. Trigeminal neuralgia is very diffi cult to treat in part due to
the lack of an suitable animal model for testing novel therapeutic approaches. This chapter describes a model
of trigeminal neuralgia in which crystals of a superabsorbent polymer are placed next to the trigeminal nerve
root of rats, producing ongoing mechanical compression of the nerve root. The chapter then describes
means of behaviorally assessing the robust mechanical hypersensitivity consequent to the compression that
can be used to determine the effi cacy of potential therapies for this devastating condition.
Key words: Neuropathic pain , Orofacial , Trigeminal neuralgia , Tic Douloureux , Craniofacial ,
Rat behavior , Allodynia , Compression
Considered one of the most painful of all medical conditions ( 1, 2 ) ,
trigeminal neuralgia is a chronic neuropathic pain syndrome in
which patients experience intense paroxysms of lancinating pain in
the face along one or more branches of the trigeminal nerve (
3– 5 ) .
There is overwhelming evidence that trigeminal nerve root demy-
elination or dysmyelination is the underlying cause of trigeminal
neuralgia, most frequently as a result of nerve root compression.
Focal nerve root compression by an artery or vein as the cause of
trigeminal neuralgia was fi rst thoroughly described by Jannetta in
1967 (
6 ) , and it is now thought that 80–90% of all cases of trigemi-
nal neuralgia result from vascular nerve root compression (
7– 14 ) .
Evidence for vascular compression is given by (a) recent imaging
studies and intra-operative observations, consistently showing a
blood vessel contacting the nerve root (
10, 15, 16 ) ; (b) the fact
that surgical microvascular decompression (MVD) provides at least
1. Introduction
122 D.C. Yeomans and M. Klukinov
temporary pain relief in most patients ( 15, 17 ) ; (c) the fi nding that
intra-operative recordings often show an immediate improvement
of nerve conduction velocity slowing after MVD (
15, 18 ) ; and
(d) the observation that sensory defi cits also recover after MVD,
albeit more slowly (
15, 19 ) . Various other non-vascular compres-
sive lesions have also been associated with trigeminal neuralgia, includ-
ing posterior fossa tumors, cysts, and bony compression (
14 ) .
It has been shown convincingly that demyelination occurs at
the site of nerve root compression in trigeminal neuralgia patients
14, 15, 20– 22 ) . In addition to demyelination associated with
compression, there is a well-established association of multiple
sclerosis (MS) and trigeminal neuralgia (
15, 23– 27 ) . That the
common pathological fi nding in trigeminal neuralgia patients with
nerve root compression and those with MS is a demyelinated
region of the nerve roots near the brainstem (
28 ) provides strong
evidence of demyelination, most commonly secondary to compres-
sion, as the underlying cause of trigeminal neuralgia. Furthermore,
anatomical and physiological studies have demonstrated that
peripheral nerve constriction results in substantial loss of large
myelinated nerve fi bers (
25 ) , with signifi cant functional consequence
29– 39 ) . Demyelination leads to changes in sodium channel distri-
bution along the axon, leading to enhanced excitability despite
slowed conduction (
40 ) .
The extent to which new treatments can be developed based
on mechanistic knowledge and empirical evidence has been limited
by the lack of an adequate animal model that accurately refl ects
human pathology. This chapter describes a new rodent model for
trigeminal neuralgia that simulates the natural cause and symptoms
of the disease by introducing an artifi cial compression of the
trigeminal nerve root. The model lends itself to behavioral, elec-
trophysiological, molecular biological, anatomical, and pharmaco-
logical experiment assessments of the mechanisms and potential
therapies for this devastating neuropathic disease.
1. Animal anesthesia machine (ours was custom built using a
vaporizer from Ohio Medical Products, Airco, Madison, WI).
2. Isofl urane IsoThesia (Butler Animal Health Supply, Dublin,
3. Single arm stereotaxic frame with 45° Ear Bars (WPI,
4. Rat anesthesia mask adaptor (WPI, Mod.502054) can be used,
but we prefer a custom built, prototype described in ref.
41 .
2. Materials
2.1. Polymer Injection
1238 A Rodent Model of Trigeminal Neuralgia
5. Betadine Solution (Povidone–iodine 10%) (The Purdue Frederick
Company, Stamford, CT).
6. Cotton-tipped applicators, 3 in. (Puritan Medical Products,
Guilford, ME).
7. Electric shaver (Oster, Minnville, TN).
8. Fiber optic illuminator (WPI).
9. Germinator 500 Dry sterilizer (Roboz, Gaitherburg, MD).
10. Scalpel handle No. 3 (BRI Stainless, Germany).
11. Bard-Parker Rib-back scalpel blade (Becton Dickinson
AcuteCare, Franklin Lakes, NJ).
12. 2 in. Bulldog clamps, curved (2) (BRI Stainless, Germany).
13. Hemostat Mixter 5 ½ in., curved (2) (Roboz, Gaitherburg, MD).
14. Cotton pellets No. 3 (Richmond, Charlotte, NC).
15. Forceps micro dissecting 4 in., straight serrated (Roboz,
Gaitherburg, MD).
16. Wizard rotary tool (Black and Decker, New Britain, CT).
17. Micro Drill Steel Burr 1.4 mm (Meisinger, Germany).
18. Superabsorbent biocompatible polymer LiquiBlock 14G-50
(Emerging Technologies, Greensboro, NC).
19. Superabsorbent biocompatible polymer Norsocryl S-35
(Emerging Technologies, Greensboro, NC).
20. Polymer injection needle, custom built by tapering 3.5 in.,
Quincke point, 20 G, Spinal needle (Becton Dickinson
AcuteCare, Franklin Lakes, NJ).
21. Bone Wax (Ethicon, Somerville, NJ).
22. Michel Clip Applying-Removing Forceps, 5 in. (Roboz,
Gaitherburg, MD).
Michel wound clips, 7.5 mm (Perfect, France).
24. Antibiotic ointment (CVS Pharmacy, Woonsocket, RI).
1. Plexiglas observation cage (30 cm × 30 cm × 40 cm).
2. Rat chow biscuit (approx. 5 g each; LabDiet 5P00 Prolab
RHM 3000; PMI, Gray Summit, MO).
3. Timer with alarm (Triple-Display Timer, VWR, Batavia, IL).
4. 10 × 10 Weigh paper (VWR, Batavia, IL).
5. Balance is (ZSA 80, Scientech Boulder, CO).
1. Rat cage.
2. Touch-test sensory evaluator (von Frey monofi laments) 1, 6,
10, 26, and 60 g (North Coast Medical, San Jose, CA).
2.2. Feeding/Peri-oral
2.3. Touch Allodynia
124 D.C. Yeomans and M. Klukinov
1. Rat cage.
2. Air-puff device is based on a Tetra Whisper 60 aquarium Air
Pump with both outlets y-connected to a 4-mm elastic tubing.
A Benzomatic fl exible stem gas lighter was used to make a handle.
After removing all lighter-related parts, 3.5-mm polyethylene
tubing is run through the housing and connected it to a plastic
nozzle glued to the tip of the stem. System produces force of
0.35 g—measured by fi xing tip 7 mm from balance. For safety
reasons, the pump is switched on and off with a relay controlled
by a button installed in the handle (Fig.
1 ).
1. Adult, male Sprague–Dawley rats (250–300 g) are deeply anes-
thetized with isofl urane (2.5%) in a chamber, and then moved
to a stereotaxic frame with ear bars coated with soft plastic to
prevent tympanic membrane damage. The frame is equipped
with a mask to deliver fresh isofl urane (2.5%) and remove
expired isofl urane in a balance of oxygen-supplemented room
air (30/70%).
2. The dorsal head and neck are shaved, and iodine solution
applied to the area for asepsis.
3. Using a #10 scalpel blade, a midline skin incision is made from
bregma to 10 mm caudal from the inter-aural line, spanning
~1.5 cm.
2.4. Air-Puff Testing
3. Methods
3.1. Trigeminal Root
Compression Model
Using Stereotaxic
Polymer Injection
( See Note 1 )
Fig. 1. Photographic illustration of air-puff stimulator. Individual components are indicated
by arrows and labels.
1258 A Rodent Model of Trigeminal Neuralgia
4. Connective tissue and periosteum are scraped clear on the
entire left dorsal surface of interparietal bone.
5. Using a rotary tool with a round 1.4-mm burr bit a round
trephination window (diameter 2.5–3 mm) is made in the left
laterocaudal-most part of interparietal bone dorsal surface.
6. Bone hemostasis is then achieved with cotton pellets and bone
wax (see Note 2 ).
7. The caudal edge of the left transverse sinus is, at this point,
clearly visible through the intact meninges (Fig.
2 ). A tapered
spinal injection needle with fi tted steel stylet (20 gauge)
preloaded with ~0.5 mm
of superabsorbent biocompatible
polymer (SAP) granules is then installed in a micromanipulator
at 35° caudally from perpendicular to the skull with the bevel
side oriented laterocaudally, and zeroed to lambda ( see Notes
3 and 4 ).
8. The manipulator is then used to position the needle 3.5 mm
lateral and 3 mm caudal to lambda (Fig.
3 ).
9. Using a standard 23-G injection needle, meninges are carefully
cut just caudally to the left transverse sinus, with attention paid
to avoid damage to the sinus.
10. The injection needle is then advanced 8.5 mm into the trigeminal
canal, its tip eventually sliding toward the pars petrosa of
temporal bone and reaching the space between the trigeminal
sensory root and the temporal bone.
11. The polymer crystals are then administered by manually pushing
a metal stylet through the barrel of the injection needle such
that it becomes fl ush with the tip.
Fig. 2. Appearance and location of transverse sinus.
126 D.C. Yeomans and M. Klukinov
12. The needle is then withdrawn, the hole in the dura and skull
sealed with bone wax, and the incision closed using wound
13. The rat is then placed in its home cage under a heat lamp until
it has recovered from anesthesia.
Trigeminal neuralgia patients experience ectopic, spontaneous uni-
lateral pain paroxysms as well as paroxysms evoked by light touch.
Thus, natural behaviors, such as eating, as well as responses evoked
by mechanical stimuli, such as von Frey monofi laments (
39 ) ;
and air puff (
42– 44 ) are used as an indication of the presence and
extent of sensory disturbance in rats after trigeminal nerve root
compression. These behavioral indices can be used to examine the
potential effi cacy of pharmacologic agents and other therapeutics
in the treatment of trigeminal neuralgia.
1. Before and at various time points after polymer injection, eating
behaviors will be quantifi ed as an indication of peri-oral hyper-
sensitivity ( see Note 5 ).
2. Rats are fi rst habituated to the Plexiglas observation cage
(30 cm × 30 cm × 40 cm) during three daily sessions and for at
least 15 min on the fi rst day of testing.
3. On the day before polymer application, rats are food deprived
overnight for 12–14 h.
4. On the day of polymer application, rats are given a pre-weighed
rat chow biscuit on a large piece of weigh paper and allowed
20 min to eat.
5. After 20 min, rats are removed from cage and remaining biscuit
3.2. Behavioral Testing
3.2.1. Feeding/Peri-oral
Sensitivity Operant
Fig. 3. Correct placement of injection needle.
1278 A Rodent Model of Trigeminal Neuralgia
6. At 7, 14, and 28 days after polymer injection, procedure is
repeated to determine effects of trigeminal root compression
on peri-oral sensitivity ( see Notes 6 and 7 ).
7. At desired endpoints, some rats can be euthanized and trigeminal
tissue removed for molecular biological or immunochemical
analysis (see Note 8 ).
1. Rats are tested in their own home cages after habituation to
the investigator and the von Frey fi bers until they appear
indifferent to their presence.
2. Prior to polymer application, rats are subjected to fi ve trials on
each side of the face of stimulation, with each of the four dif-
ferent von Frey fi bers used (0.4, 1.4, 6, and 15 g). The response
to each stimulation trial is scored as: 0 = no response; 1 = non-
aversive response (detection, weak withdrawal); 2 = mildly
aversive response (moderate withdrawal and swipe towards the
ber with the forepaw); 3 = moderately aversive response
(strong withdrawal and pushing the fi ber away from the face
with the forepaw); and 4 = strongly aversive response (attack or
vocalization). This scoring method is similar to that described
by Vos et al. (
39 ) .
3. The scores of the three trials are averaged for each side of the
face in each rat and for each of the four fi bers.
4. At 7, 14, and 28 days after polymer injection, rats are retested
to determine effects of trigeminal root compression on tactile
5. At desired endpoints, some rats can be euthanized and trigeminal
tissue removed for molecular biological or immunochemical
1. A custom-designed, pressure-regulated air-puff stimulator is
used to provide air stimulation to rats before and after trigeminal
nerve root compression.
2. Rats are habituated to the investigator and the hand-held air-
puff stimulator until they appear indifferent to their presence
(at least 15 min).
3. Ten consecutive trials of constant-pressure air puffs, 4 s duration,
10 s interstimulus interval (
42 ) is performed on each side of
the face.
4. At 7, 14, and 28 days after polymer injection, rats are retested
to determine effects of trigeminal root compression on tactile
5. At desired endpoints, some rats can be euthanized and trigeminal
tissue removed for molecular biological or immunochemical
3.2.2. von Frey Allodynia
3.2.3. Air-Puff Allodynia
128 D.C. Yeomans and M. Klukinov
In addition to behavioral changes, anatomic changes (dismyelination,
nodal displacement, and ion channel rearrangement) and electro-
physiologic changes (ectopic discharge, decreased thresholds,
prolonged responses in trigeminal ganglia, and nucleus caudalis
neurons) are useful in examining the mechanisms underlying the
pain of trigeminal neuralgia.
1. The duration of the procedure is about ~35 min, including
induction time.
2. Bleeding is usually easily controlled, and rats recover quickly.
3. Sham surgery is identical except that no polymer is loaded into
the needle prior to insertion.
4. SAP is a biocompatible, non-toxic substance (sodium poly-
acrylate) that slowly expands over time by absorbing water or
in this case, extracellular fl uid. Within the closed volume of the
skull, this increase takes place over several days, gradually
producing an increasing degree of compression of the trigem-
inal nerve root (Fig.
4 ). This method allows for visual guidance
of the needle, minimizing the risk of transverse sinus damage;
it does not penetrate brain or skull structures; is at low risk
of damaging the ventrally located motor trigeminal root.
However, due to the precision necessary for this procedure, as
well as individual anatomical variations, risks still exist of major
bleeding or stroke from perforated sinus or other blood ves-
sels, and from damage to the cerebellum or auditory nerve.
3.3. Other Measures
4. Notes
Fig. 4. Stereophotomicrograph of underside of brain 2 weeks after application of polymer to
trigeminal root entry zone ( arrow ) demonstrating compression of the trigeminal nerve root.
1298 A Rodent Model of Trigeminal Neuralgia
5. Model provides a natural, operant assessment of peri-oral
sensitivity—which is symptomatic of trigeminal neuralgia.
6. Additional time points can be added as needed.
7. Rats with trigeminal root compression typically “freeze” at
certain points during biscuit eating. Freeze latencies and dura-
tions can also be measured by video analysis to provide assessment
of paroxysmal sensations.
8. At any of the time points, experimental treatments can be used
prior to testing in order to examine potential analgesic therapies.
The authors would like to acknowledge the assistance of Dr. Yanli
Qiao and Neil Manering. They would also like to acknowledge the
support provided by PHS grant R01DE018531, “Chronic
Compression of the Trigeminal Ganglia”.
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    • "A current pain treatment modality using herpes simplex type I virus to target neuronal expression of enkephalin is currently in clinical trials [7]. Examples of this method's effectiveness have been demonstrated in an infraorbital nerve ligature model and a facial inflammatory model [8,9]. Current research is testing viral expression vectors to enhance enkephalin concentrations and treat pain [10,11]. "
    [Show abstract] [Hide abstract] ABSTRACT: Clinical studies have tested the use of an engineered herpes virus to treat pain. We hypothesized that subcutaneous injections of an engineered herpes virus that expresses enkephalin would attenuate orofacial nociception and hypersensitivity in male and female rats by a central mechanism. Herpes virus was injected subcutaneously around the mouth of male and female rats seventy-two hours before ligatures were placed on the masseter tendon, control treatment groups received either no virus or no ligature. Enkephalin expression was measured and von Frey filament testing and meal duration were utilized to measure mechanical hypersensitivity and the nociceptive response, respectively. Naloxone or naloxone methiodide was administered to rats injected with the enkephalin expressing virus to test if enkephalin was acting peripherally or centrally. Ligature significantly lengthened meal duration and reduced the threshold to von Frey filaments for 18 days. Infection with the enkephalin transgene significantly decreased this response for at least 11 days but only in male rats. Virus injection significantly increased expression of enkephalin in the mental nerve that innervates the mouth region, the trigeminal ganglia and the trigeminal nucleus caudalis but no increase was observed in the masseter nerve after virus injection. Naloxone but not naloxone methiodide reversed the response to the enkephaline expressing virus. The data suggests that sex should be a considered when using this virus and that viral transfection of the mental nerve with an enkephalin transgene can reduce nociception and hypersensitivity through a central mechanism.
    Full-text · Article · Dec 2015
  • [Show abstract] [Hide abstract] ABSTRACT: The detection and processing of painful stimuli in afferent sensory neurons is critically dependent on a wide range of different types of voltage- and ligand-gated ion channels, including sodium, calcium, and TRP channels, to name a few. The functions of these channels include the detection of mechanical and chemical insults, the generation of action potentials and regulation of neuronal firing patterns, the initiation of neurotransmitter release at dorsal horn synapses, and the ensuing activation of spinal cord neurons that project to pain centers in the brain. Long-term changes in ion channel expression and function are thought to contribute to chronic pain states. Many of the channels involved in the afferent pain pathway are permeable to calcium ions, suggesting a role in cell signaling beyond the mere generation of electrical activity. In this article, we provide a broad overview of different calcium-permeable ion channels in the afferent pain pathway and their role in pain pathophysiology.
    Full-text · Article · Jan 2014
  • [Show abstract] [Hide abstract] ABSTRACT: Patients with chronic pain usually suffer from cognitive impairment, with memory deterioration being the most common deficit that affects daily functioning and quality of life. The causes for this impairment are not clear despite intensive clinical studies. Few studies have evaluated impaired learning using animal models of persistent pain. In this study, a new trigeminal neuralgia model induced by cobra venom was adopted to explore effects of chronic pain on spatial learning and memory in rats. Controlled animal study. Department of Anesthesiology, Pain Medicine & Critical Care Medicine, Aviation General Hospital of China Medical University. Thirty adult male Sprague-Dawley rats were randomly divided into 2 groups (n = 15): NS control group and cobra venom group, 0.9% sterile saline or cobra venom solution was injected into the sheath of the infraorbital nerve (ION), respectively. The development of trigeminal neuralgia was accessed by changes in free behavioral activity 3 days before the surgery and 3, 7, 12, 20, and 30 days after the surgery to identify whether the model was successful or not. Morris water maze test determined the abilities of spatial learning and memory at the time points before the surgery, and 2 weeks and 5 weeks after the surgery. We also observed the ultrastructure of the ION and medulla oblongata of rats following 8 weeks of chronic trigeminal neuropathic pain. Rats with the cobra venom injection displayed significantly more face grooming and fewer exploratory activities compared to the NS control group or baseline (P < 0.01). Both groups improved their latency to reach the platform with the largest difference on the first day (P < 0.01), but without memory deficits in a probe trial for the second water maze protocol. For the third water maze testing, the rats in the cobra venom group experienced decreased abilities of spatial learning and memory, a longer latency with spatial memory deficits during the probe trial (P < 0.05). At the ultrastructural level, we found changes in the medulla oblongata after cobra venom injection resulting in severe demyelination and loss of axons that might be implicated in the causes of cognitive deficits. Limitations include partial vision loss in the eye on the lesion side of the rats that might be missed and the absence of evaluating the ultrastructural changes in other parts of the brain. The results of this study suggest that trigeminal neuralgia induced by cobra venom in adult rats can impair spatial learning and memory function over time and results in demonstrable changes in the ultrastructure of the medulla oblongata. This new animal model may be useful for future studies on the effect of chronic pain on learning and cognition. Cognitive deficits, memory deterioration, cobra venom, trigeminal neuralgia, electron microscopy.
    Article · Mar 2015
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