INVITED REVIEW

J Neurosurg 139:1471–1479, 2023

The pathophysiology of trigeminal neuralgia:

a molecular review
*Bryan Dong,1 Risheng Xu, MD, PhD,1 and Michael Lim, MD2

Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, Maryland; and 2Department of
1

Neurosurgery, Stanford University School of Medicine, Palo Alto, California

OBJECTIVE The goal of this study was to provide a comprehensive overview of the current understanding of molecular
and genetic mechanisms underlying the pathophysiology of trigeminal neuralgia (TN).
METHODS The authors searched PubMed systematically for primary research literature investigating specific molecular
mechanisms from samples derived from patients with TN. The genes/molecules of interest from the selected literature
were then cross-referenced with corresponding studies in animal models of TN.
RESULTS From approximately 345 articles, a total of 12 articles were selected and included in the review, focusing on
ionotropic channel expressivity and mutations, reactive oxygen species expressivity, inflammatory marker expressivity,
and microRNA expressivity. Of the 12 included articles, only 4 had studies completed in other animal models regarding
the corresponding TN mechanism found in humans.
CONCLUSIONS The current literature does not suggest a conclusive disease mechanism for TN in humans. In addition
to neurovascular conflict/compression of the trigeminal nerve, recent studies have indicated that TN may be linked to
inflammatory and reactive oxygen species signaling as well. Recent genetic studies in patients with TN have yet to be
investigated further in animal models.
https://thejns.org/doi/abs/10.3171/2023.2.JNS23274
KEYWORDS trigeminal neuralgia; pain; trigeminal ganglion; reactive oxygen species; TRPA1; NRF2;
neuroinflammation

T
rigeminal neuralgia (TN) is an orofacial pain syn-
drome characterized by chronic neuropathic pain
in the trigeminal nerve distribution. TN remains
a significant medical challenge, given that the associated
pain may profoundly interfere with activities of daily liv-
ing.1–3 To date, the pathophysiological mechanisms under-
lying TN are yet to be fully understood. TN traditionally
has been attributed to physical compression of the trigemi-
nal nerve from vascular compression or other underlying
pathologies.1–3 However, recent evidence points to a role of
intrinsic cellular pathways in potentially mediating TN.4,5
In this review, we will summarize the current literature on
the molecular mechanisms of TN.
The trigeminal nerve provides motor input to the man-
dible and somatosensory innervation of the face. The
branches of the trigeminal nerve include the V1 (ophthal-
mic), V2 (maxillary), and V3 (mandibular) distributions, of
which their afferents supply the dermatomes of the upper,
middle, and lower face and jaw, respectively.1 The afferent
fibers of V1, V2, and V3 converge onto the somas of the
trigeminal ganglion (TG) neurons, which send their cen-
tral projections to the trigeminal sensory nuclear complex
in the pons.1 TN is the most prevalent neuropathic pain
disorder affecting the orofacial distribution, and mani-
fests as a severe, piercing pain in the dermatome of the
trigeminal nerve, most commonly affecting the V2 and
V3 distributions.1 TN is classified symptomatically, with
type I TN defined by intermittent/paroxysmal bursts of
pain, and type II TN defined by constant pain.2 Addition-
ally, TN is classified based on disease origin, with clas-

ABBREVIATIONS CGRP = calcitonin gene–related peptide; 4-HNE = 4-hydroxynonenal; GABA = γ-aminobutyric acid; GABAAR = GABA type A receptor; IL = interleukin;
ION = infraorbital nerve; miRNA = microRNA; MS = multiple sclerosis; NRF2 = nuclear factor erythroid 2–related factor 2; NVC = neurovascular contact; ROS = reactive
oxygen species; SP = substance P; TG = trigeminal ganglion; TN = trigeminal neuralgia; TNFα = tumor necrosis factor–α; TRP = transient receptor potential; TRPA1 = TRP
ankyrin 1; VIP = vasoactive intestinal peptide.
SUBMITTED February 6, 2023. ACCEPTED February 10, 2023.
INCLUDE WHEN CITING Published online March 31, 2023; DOI: 10.3171/2023.2.JNS23274.
* B.D. and R.X. contributed equally to this work.

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 Dong et al.

FIG. 1. Flowchart of search strategy according to the PRISMA 2020 statement. Data added to the PRISMA template (from Page
MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline
for reporting systematic reviews. BMJ 2021;372:n71) under the terms of the Creative Commons Attribution (CC BY 4.0) License
(https://creativecommons.org/licenses/by/4.0/). Figure is available in color online only.

sic TN occurring from neurovascular contact (NVC) at
the trigeminal nerve root entry zone and secondary TN
arising from other underlying neurological disorders.3,6,7
However, 7%–29% of patients with TN—those classified
with idiopathic TN—do not present with any identifiable
physical abnormalities of the trigeminal nerve.3,8–10 Mo-
lecular factors that contribute to orofacial pain in these
patients remain poorly characterized. Moreover, NVC at
the trigeminal entry zone may also be observed in patients
who are asymptomatic for TN.11 These findings strongly
suggest that physical compression of the trigeminal nerve
alone cannot entirely account for TN. Here we review our
current understanding of potential molecular mechanisms
underlying TN.
Methods
The search strategy was conducted according to the
PRISMA 2020 statement (Fig. 1). We searched PubMed
systematically for primary research literature published
before January 2023 on patients with TN who were part
of a discovery cohort of at least 10 participants in whom
gene/RNA/protein mutations, polymorphisms, expres-
sivity, or other molecular mechanisms were investigated.
Articles were searched using the human species filter on
PubMed and the following combination of keywords:
trigeminal neuralgia, genetic, molecular, gene, mutation,
channel, and inflammation. The titles and abstracts of ar-
ticles of interest were individually checked to determine
whether the article was an original clinical study inves-
tigating a specific pathophysiological mechanism in pa-
tients with TN. Articles were also manually checked to
ensure a discovery cohort of at least 10 patients. Articles
that met these two standards were individually reviewed
on a whole-text basis. Articles regarding trigeminal neu-
ropathic pain were not included.
From the selected articles on patients with TN, the
genes/molecules of interest were identified manually for
each article. We then searched PubMed systematically for
primary research literature on animal models of TN in
which those genes/molecules of interest were investigated.
Articles were searched on PubMed using the following
combination of keywords: trigeminal neuralgia, the gene/
molecule of interest, animal, mouse, and rat. The titles
and abstracts of potentially related articles were manually
checked to verify that the correct genes/molecules were

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studied in the same mechanistic context as in the selected
article on human TN.
From the included human clinical articles, the fol-
lowing data were extracted: lead author, published year,
discovery cohort size, TN modality in discovery cohort,
genes/molecules of significance in the study, study find-
ing, and related animal study on the genes/molecules of
significance.
Results
From approximately 345 articles yielded in the initial
search, 17 were identified for manual review. A total of 12
articles were selected and included in the review, focusing
on ionotropic channel expressivity and mutations, reactive
oxygen species (ROS) expressivity, inflammatory marker
expressivity, and microRNA (miRNA) expressivity. Of the
12 included articles, only 4 had studies completed in other
animal models regarding the corresponding TN mecha-
nism found in humans.
Discussion
TN as an Ionotropic Channelopathy
Molecular investigations have identified potential ab-
normalities in the expressivity or function of cation chan-
nels as being associated with TN and other pain syn-
dromes.12 Historically, a nonsense mutation of SCN9A, the
gene encoding Nav 1.7, attracted initial interest because it
was attributed to a rare congenital loss of nociception in
3 consanguineous families, strongly implicating the pain-
sensing role of Nav 1.7.13 However, Nav 1.7 and similar
channel Nav 1.6 variants ultimately have not been estab-
lished as a significant feature in TN pathology, given that
SCN9A and SCN8A polymorphisms were not correlated
with patients who have TN.14,15 Moreover, vixotrigine, a
Nav 1.7 antagonist used to treat TN, failed to reach its
phase II trial primary endpoint.16 The lack of evidence at-
tributing Nav 1.7 dysfunction to TN specifically and the
failure of vixotrigine imply that orofacial pain in TN is
likely to be mechanistically distinct from that of other pe-
ripheral neuropathic pain disorders.
Within the last 5 years there has been increased genetic
evidence suggesting that rare but damaging mutations
may predispose a subset of patients with TN to orofacial
pain (Table 1). A genetic study in patients with familial
TN revealed mutations in ionotropic channels, including
genes for transient receptor potential (TRP) channels,
voltage-gated potassium channels, and voltage-gated cal-
cium channels (Fig. 2).17 For instance, exome sequencing
in patients with TN revealed prominent structural muta-
tions in the γ-aminobutyric acid (GABA)–gated chloride
channel GABA type A receptor (GABAAR) and the T-
type low voltage–gated calcium channel Cav3.2.18 Mutant
mice expressing the GABAAR variant displayed mechani-
cal allodynia and pain behavior in the trigeminal distribu-
tion, highlighting the possibility of pathological GABA-
mediated signaling in trigeminal neuralgia. A recent study
also independently confirmed the role of mutant Cav3.2 in
a mouse model of TN; Cav3.2 expression was elevated in
a mouse model of infraorbital nerve (ION) ligation, and
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Dong et al.
application of Cav3.2 channel blockers lessened thermal
nociceptive behaviors.19
A wide variety of TRPM family cation channels were
also shown to have pathological variants related to TN.
For instance, a TRPM8-associated mutation discovered in
2 siblings with TN lowered the activation threshold, in-
creased channel current, and heightened TRPM8 receptor
sensitivity to methanol,20 possibly leading to deleterious
neuronal hyperexcitability and pain. Separately, a TRPM7
mutation was discovered in a family with multigeneration-
al TN that increased inward sodium leak current, reduced
mutant TG neuron activation threshold, and also reduced
depolarizing resting membrane potential, ultimately lead-
ing to aberrant neuronal activity.21 TRPM expressivity
may also regulate TN, given that a rat ION constriction
model showed increased TRPM3 and TRPV4 levels in tri-
geminal spinal subnucleus caudalis.22
Currently, a limited number of discovered channel
mutations in human TN genetic studies have been vali-
dated to have abnormal nociceptive processing in animal
models of TN. Notably, GABAAR and Cav3.2 have been
identified as potential pathological channels for TN im-
plicated in humans as well as validated in mouse mod-
els.18,19 However, other human polymorphisms detected
in Nav, Cav, voltage-gated potassium channels (Kv), and
TRP channels have yet to be established as causal in TN
transduction (Table 1).17 Furthermore, mutations in iono-
tropic channels are exceedingly rare in the TN popula-
tion. Based on a case report that identified a deleterious
M136V SCN8A mutation in a single patient with TN,23
Sekula et al. screened 123 patients and were unable to
identify the M136V in any other patient in their series.24
Thus, although these recent investigations implicate the
pathological role of ionotropic channels in TN, the fact
remains that germline mutations probably represent a
small proportion of patients with TN. Increased genetic
sequencing and routine screening of these patients for
genetic mutations will clarify the relative contribution of
channelopathies to this disorder.
TN as an Oxidative Stress Disorder
TN has also been evaluated as a dysfunction of cell
signaling and transduction networks. Identifying and
regulating the centers of these key networks may advance
more effective and robust therapies for TN. Oxidative
stress refers to an abnormal balance of ROS—derivatives
of oxygen that have oxidizing potential, such as superox-
ide, hydroxyl radicals, and hydrogen peroxide.25 Normally,
ROS are a product of cellular metabolism and regulate a
range of functions, including cell signaling, survival, and
transcription. However, an excess of ROS can lead to the
oxidation of proteins, nucleic acids, and lipids, disrupt-
ing normal cellular processes. Oxidative stress has been
linked to a spectrum of diseases, such as cancer, diabetes
mellitus, and neurodegenerative diseases.26
Elevated ROS levels have been observed in chronic
neuropathic pain syndromes such as diabetic neuropathy,
chemotherapy-associated neuropathy, spinal cord injury,
and, recently, TN.27 Recently, Vasavda et al. discovered
that CSF from patients with TN had increased 4-hy-
droxynonenal (4-HNE) and malondialdehyde, which are
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TABLE 1. List of human genetic/molecular studies in patients with TN and related studies in animal models
Original
Study, Authors Discovery Genes/Molecules of
& Year Cohort Significance Study Findings Related Animal Study
Vasavda et al., 13 pts w/ TRPA1, NRF2 CSF: pts w/ TN had upregulated ROS ROS signaling through TRPA1 contrib-
202228 primary TN levels mediating noxious, inflammatory utes to trigeminal neuropathic pain,
cascade along TRPA1 axis NRF2 activation alleviates TRPA1-
induced nociception24
Hale et al., 1188 pts w/ TN Genome-wide association 5 single-nucleotide polymorphisms at in- None
202264 study tergenic locus on chromosome 1p22.2,
variant on chromosome 5q35.1
Romero et al., 48 pts w/ SCN8A, BDNF, COMT, GCH1 Polymorphisms in SCN8A, BDNF, COMT, None
202115 classic or & GCH1 were not associated w/ TN
idiopathic TN onset or orofacial pain intensity
Sekula et al., 123 pts w/ clas- SCN8A M136V mutation of SCN8A was not identi- None
202124 sic TN fied in any pts in discovery cohort
Di Stefano et 11 pts w/ SCN2A, SCN3A, SCN5A, Sequencing revealed rare, potentially None
al., 202017 classic or SCN7A, SCN9A, SCN10A, pathogenic mutations of 36 genes
idiopathic TRPA1, TRPC6, TRPM2, encoding voltage-dependent Na+, K+,
familial TN TRPM3, TRPM4, TRPM7, Ca2+, C1–, nonspecific ligand–gated
TRPM8, TRPS1, TRPV4, channels, & gap junction channels
TRPV5, TRPV6, KCNA5,
KCNC3, KCND2, KCNH2,
KCNH7, KCNJ6, KCNK17,
KCNS2, KCNV1, CACNA1A,
CACNA1D, CACNA1G,
CACNA1I, CACNA1S,
CACNB1, CLCN1, CLCN2,
CLIC5, GJB5
Dong et al., 290 pts w/ mul- GABRG1, CACNA1H, TRAK1 Genomic screening of pts w/ TN revealed Mutant GABA AR contributes to me-
202018 timodal TN rare, deleterious GABRG1, CACNA1H, chanical allodynia sensing in mice,14
& TRAK1 variants mutant Cav3.2 contributes to thermal
allodynia sensing in mice15
Li et al., 28 pts w/ clas- miR-132-3p, miR-146b-5p,miR-132-3p, miR-146b-5p, miR-155-5p, None
202033 sic TN miR-155-5p, & miR-384 & miR-384 were highly upregulated in
serum of pts w/ TN
Costa et al., 48 pts w/ clas- SCN9A, NTRK1 Polymorphisms in SCN9A & NTRK1 were None
201914 sic TN not associated w/ TN onset or orofacial
pain intensity
Qin et al., 20 pts w/ CGRP, SP, VIP, & β-endorphin Increased levels of CGRP, SP, & VIP & CGRP mRNA was upregulated in rat TG
201647 primary TN lowered levels of β-endorphin in CSF after ION constriction,60 CGRP & SP
of pts w/ TN levels were increased in rat TG after
ION constriction,61 greater no. of SP
immunopositive cells in rat TG after
ION constriction,62 heat hyperalgesia
was reduced after administration of
SP receptor NK1 antagonist63
Cui et al., 280 pts w/ idio- SLC6A4 SLC6A4 short-short alleles were more None
201466 pathic TN expressed in pts w/ TN, & associated
w/ higher levels of pain
Siqueira et al., 10 pts w/ TN SCN3A, SCN9A, SCN10A Increased expressivity of Nav1.3 & Nav1.7 None
2009 65 mRNA in gingival tissue of pts w/ TN
Strittmatter et 16 pts w/ idio- Epinephrine, norepinephrine, Increased levels of SP & lowered levels Same studies regarding SP
al., 199648 pathic TN dopamine, VMA, HVA, SP, of norepinephrine, somatostatin, VMA,
5-HIAA, somatostatin HVA, & 5-HIAA in CSF of pts w/ TN
5-HIAA = 5-hydroxyindoleacetic acid; HVA = homovanillic acid; mRNA = messenger RNA; pts = patients; VMA = vanillylmandelic acid.

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 Dong et al.

FIG. 2. Overview of genetic and molecular pathways implicated in orofacial pain signaling in TG neurons in human and animal
models of TN. NVC or secondary lesions impinge on the trigeminal nerve root, causing mechanical injury to the nerve. Mechanical
injury can cause ROS production, leading to activation of the TRPA1 channels, which are regulated by the NRF2 axis. Neuroin-
flammation, which may be downstream of mechanical injury or secondary to autoimmune disease such as MS, may also increase
neuropathic pain. Rare but damaging mutations of genes encoding T-type low-voltage–gated calcium channel (Cav3.2) and
GABA AR may lower activation potential and cause hyperexcitability in TG neurons. Figure is available in color online only.

ROS products of lipid peroxidation.28 These ROS interact
with the TRP ankyrin 1 (TRPA1) channel, a nonselective
cation channel that is selectively expressed in nociceptive
mammalian small-diameter dorsal root ganglion and TG
neurons, increasing its response to nerve injury in a mouse
model of trigeminal nerve compression.29,30 This work
builds on prior studies by Trevisani et al. and Andersson
et al., who found that application of 4-HNE produced de-
polarizing currents in rat and mouse dorsal root ganglion
neurons and increased their sensitivity to mechanical allo-
dynia; inhibiting TRPA1 attenuated the 4-HNE–induced
depolarization and reduced pain behavior.31,32 Vasavda et
al. further demonstrated that pharmacological or genetic
activation of nuclear factor erythroid 2–related factor 2
(NRF2), a key transcriptional driver of the cellular anti-
oxidant response, was important in decreasing mechanical
and cold allodynia in the mouse maxillary nerve constric-
tion model (Fig. 2).28
Interestingly, an independent transcriptomic study by
Li et al. investigated the miRNA serum profile of patients
with TN and found that 4 miRNAs were expressed at sig-
nificantly higher levels in patients with TN.33 One of these,
miR-155–5p, was shown to target NRF2 transcripts and
downregulate cellular NRF2 levels, indicating a possible
endogenous pathway by which NRF2-driven oxidative re-
sponse is suppressed in TN. However, whether miR-155–
5p signaling is directly related with noxious sensing in an
animal model of TN remains to be tested.
These studies indicate that TRPA1 may be a potential
therapeutic agent for TN by targeting aberrant oxidative
stress signaling. However, challenges remain in develop-
ing TRPA1-directed therapeutics, given that all TRPA1
antagonists thus far have failed in animal or clinical tri-
als.34–36 For instance, the TRPA1 inhibitors GRC17536
and ODM-108 were terminated at the phase II and phase I
stages, respectively, due to poor pharmacokinetics in both
instances.35,36 Vasavda et al. circumvented these drawbacks
by targeting NRF2 pathways upstream of TRPA1. NRF2
expression levels are strictly regulated at baseline by Kelch-
like ECH–associated protein 1–mediated tagging and
ubiquitination.37 By pretreating mice with sulforaphane,
a Kelch-like ECH–associated protein 1 inhibitor, NRF2
levels were upregulated and 4-HNE and malondialdehyde
levels were diminished in TG neurons, and the intensity
of mechanical and cold allodynia was lessened after max-
illary nerve constriction. Additionally, the authors found
that two compounds, exemestane and JQ-1, could induce
a transcriptional landscape similar to NRF2, possibly by
exemestane activating the canonical NRF2 network and
JQ-1 driving antioxidant signaling parallel to NRF2.37 Ap-
plication of exemestane or JQ-1 again decreased the mag-
nitude of mechanical and cold allodynia in a mouse model

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 Dong et al.
of TN. Importantly, exemestane and JQ-1 are appealing for
TN therapy because exemestane is already approved as a
breast cancer treatment, and analogs to JQ-1 are currently
being investigated in clinical trials for cancer therapy.37
By considering TN as a manifestation of oxidative
stress, at least two potential therapeutic avenues emerge:
inhibiting the direct transduction of ROS nociceptive sig-
nals at the TRPA1 interface, or promoting the antioxidant
response from the global regulator NRF2. Future stud-
ies into the genomic and signaling dynamics of oxidative
stress feedback in pain models may yield more effective
and specific therapies for treating TN.
TN as a Neuroinflammatory Disorder
Orofacial pain in TN may also be affected by inflam-
matory signaling pathways. Multiple sclerosis (MS) is a
well-described autoimmune disease in which central de-
myelination and plaque formation contribute to a range of
motor and sensory neurological deficits.38–40 A small but
well-delineated subgroup of patients with TN, ranging
from 2.4% to 8%, have concomitant MS.41,42 Multiple MRI
studies have indicated that TN secondary to MS is asso-
ciated with demyelinating plaques located in the pontine
region of the primary afferents of the trigeminal nerve be-
tween the root entry zone and the trigeminal nucleus.43,44 It
is still unknown how these central MS-associated plaques
contribute to TN—whether demyelination promotes aber-
rant noxious activity directly (e.g., aberrant firing of nerves
compared to ephaptic coupling), or through indirect, in-
flammatory pathways.
The interplay between demyelination, inflammatory
cues, and TN is not yet fully characterized; however,
neuroinflammation may play a role in orofacial pain.45
Multiple studies in patients with TN have identified up-
regulated levels of inflammatory biomarkers in CSF and
blood serum, including substance P (SP), calcitonin gene–
related peptide (CGRP), and vasoactive intestinal peptide
(VIP),46–48 as well as endogenous regulators of inflamma-
tion like tumor necrosis factor–α (TNFα) and inflamma-
tory cytokine interleukin-6 (IL-6).49,50 Indeed, enhanced-
activity animal studies show that overexpression of TNFα
in rat TG neurons increased sensitivity to mechanical no-
ciception,51 and a rat ION constriction model showed up-
regulated levels of IL-6.52 Manipulation of these key con-
trollers of neuroinflammation may be leveraged to treat
TN. For instance, downregulation of long noncoding RNA
Gm14461, an endogenous positive regulator of TNFα,
IL-6, and another inflammatory cytokine (IL-1β) in TG
neurons decreased mechanical nociception sensitivity in
a mouse model of TN, whereas overexpressing Gm14461
showed the opposite effect.53
Mechanistically, inflammatory mediators have also
been shown to regulate expression of channels implicated
in noxious signaling, with TNFα contributing to an up-
regulation in noxious mechanosensitive receptors P2X
purinoceptor 3 (P2X3) and P2X purinoceptor 4 (P2X4) in
TG neurons, among others.54,55 Likewise, IL-6 increases
TG expression of Nav 1.3 and mechanosensitive chan-
nel Piezo2 in the TG neurons in rodent models of TN.52,56
Thus, identifying and mediating critical pathway elements
downstream of TNFα, IL-6, and similar neuroinflam-
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matory regulators may provide an alternative strategy in
treating TN. Still, despite many clinical and basic research
studies linking inflammatory signaling and TN, more re-
search is needed to delineate the causes and interactions of
inflammation in different TN subtypes.
Shortcomings of Animal Models of TN
Although rare historical experiments have assessed
physiological features of trigeminal nerve tissue from pa-
tients with TN and found gliosis and demyelination,57,58
there have been no modern molecular studies character-
izing the dynamics of inflammation in neuronal tissue
from patients with TN, due to the ethical limitations of
procuring trigeminal nerve samples from live patients.
This paucity of trigeminal nerve tissue from patients with
TN represents a major hurdle in identifying the role of
intracellular/molecular mediators of pain signal transduc-
tion. Thus, to further interrogate the role of inflammation
and/or other cellular mechanisms in TN, improved trans-
lational animal models are necessary to establish causal
relationships between human correlative studies and true
TN pathophysiology.
Current animal models that attempt to characterize TN
have numerous drawbacks, complicating efforts to bridge
TN from bench to bedside. A majority of rodent models
of TN apply mechanical ligation to the ION or suborbital
branches of the V2 branch of the trigeminal nerve to stim-
ulate the painful features of TN.59 However, these constric-
tion injury models are more similar to painful trigeminal
neuropathy, representing a continuous mechanical noxious
stimulus and failing to capture the paroxysms common in
TN. Additionally, ligation studies do not represent the full
spectrum of pathological agents precipitating TN, given
that idiopathic TN occurs independently of any physical
injury. Furthermore, modeling TN with only mechanical
insults fails to capture the deleterious cellular intrinsic and
extrinsic signaling evidenced in genetic TN studies.
Fundamentally, ligation of V2 subbranches may not ac-
curately depict the underlying determinant of primary TN,
which occurs due to compression at the trigeminal nerve
root entry zone. Indeed, constriction of trigeminal nerve
branches more distal to TG neurons may overlook central
transduction and integration aberrations present in TN.
Recent studies in rats have attempted to address this short-
coming by compressing the trigeminal nerve at the root
entry zone,60,61 representing a more facile model compared
to mice, given the larger animal model. However, unlike
corresponding human studies,46–48 trigeminal nerve root
compression in rats resulted in reduced levels of SP and
CGRP in the medullary dorsal horn,60 again indicating the
possible insufficiency of neurocompressive animal models
in accurately capturing TN etiology. Thus, basic research
models of TN are currently insufficient in replicating the
full breadth of etiological factors driving this disease. Mo-
lecular TN studies that use ION or suborbital nerve liga-
tion as their disease model cannot be directly translated to
clinical application without careful consideration, because
these frameworks may only address neuropathic pain that
is parallel to but ultimately not TN. Ultimately, more com-
prehensive and global models of TN need to be developed
to provide greater translational advantages.

Future Directions and Unanswered Questions
The most effective current surgical treatment for TN re-
mains microvascular decompression, which is predicated
on resolving the offending NVC.1,3,7 However, it remains
unclear whether the analgesic effect of decompression
results from the removal of physical contact between the
vessel and nerve or from molecular mechanisms second-
ary to NVC. Indeed, approximately one-quarter of patients
with TN still experience persistent pain years after micro-
vascular decompression,62 suggesting that nonmechanical
pathways may still be significant in compressive forms
of TN. Thus, when considering the possible molecular
mechanisms of TN, it is important to consider the types of
TN being investigated. It is unknown whether the differ-
ent molecular mechanisms discussed above each leads to
a distinct form of TN, or if a combination of these mecha-
nisms generates all forms of TN. For instance, Vasavda et
al.’s study only investigated ROS levels in CSF of patients
with classic TN.28 Whether the noxious ROS/TRPA1 sig-
naling axis is present in all forms of TN, or only where
there is NVC remains unclear. Additionally, although
it is plausible that a subset of secondary TN arises from
inflammation underlying pathologies such as MS,63 no
conclusive studies have shown that TN is mechanistically
downstream of MS. Finally, idiopathic TN may arise from
exceedingly rare channel mutations in singular cases,23 but
the inconsistency of such findings poses a challenge for
effective therapeutic management.24 Future studies of TN
need to address the differing pathological mechanisms re-
garding the mode of TN.
Conclusions
TN is classically described as a neuropathic pain condi-
tion arising from the compression of the trigeminal nerve.
We have summarized the current literature on genetic
studies and basic research models of TN in which the like-
ly role of various molecular systems associated with and/
or precipitating TN is implicated. Although a wealth of
evidence points to germline mutations in causing a sub-
set of TN, challenges remain in effective, channel-based
therapeutics because the true prevalence of these rare but
damaging mutations remains unclear. Thus, focusing on
inflammation, oxidative stress, and other downstream
molecular pathways that give rise to TN may provide an
alternative translational approach. Further molecular in-
vestigations are integral in uncovering the underlying fac-
tors of TN and laying the groundwork for developing novel
remedies for this disease.
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Disclosures
Dr. Lim reported grants from Biohaven outside the submit-
ted work; in addition, he has a patent for NRF2 Pathway for
TN pending. He also received research support from Arbor,
BMS, Accuray, Biohaven, and Urogen; he is a consultant for
VBI, InCephalo Therapeutics, Merck, Pyramid Bio, Insightec,
Biohaven, Sanianoia, Hemispherian, Novocure, Noxxon, InCando,
Century Therapeutics, CraniUs, MediFlix, Stryker, and XSense;
he is a shareholder in Egret Therapeutics; has a patent for Focused
radiation + checkpoint inhibitors, Local chemotherapy + check-
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Dong et al.
point inhibitors, and Checkpoints for Neuro-Inflammation; and is
a nonresearch consultant for Stryker’s Data and Safety Monitoring
Board—Cellularity.
Author Contributions
Conception and design: all authors. Analysis and interpretation of
data: all authors. Drafting the article: all authors. Critically revis-
ing the article: all authors. Reviewed submitted version of manu-
script: all authors. Approved the final version of the manuscript
on behalf of all authors: Lim. Statistical analysis: all authors.
Administrative/technical/material support: all authors.
Correspondence
Michael Lim: Stanford University School of Medicine, Palo Alto,
CA. mklim@stanford.edu.
J Neurosurg Volume 139 • November 2023 1479