Abstract
This review highlights potential molecular targets for treating neuropathic orofacial pain based on current findings in animal models. Preclinical research is currently elucidating the pathophysiology of the disease and identifying the molecular targets for better therapies using animal models that mimic this category of orofacial pain, especially post-traumatic trigeminal neuropathic pain (PTNP) and primary trigeminal neuralgia (PTN). Animal models of PTNP and PTN simulate their etiologies, that is, trauma to the trigeminal nerve branch and compression of the trigeminal root entry zone, respectively. Investigations in these animal models have suggested that biological processes, including inflammation, enhanced neuropeptide-mediated pain signal transmission, axonal ectopic discharges, and enhancement of interactions between neurons and glial cells in the trigeminal pathway, are underlying orofacial pain phenotypes. The molecules associated with biological processes, whose expressions are substantially altered following trigeminal nerve damage or compression of the trigeminal nerve root, are potentially involved in the generation and/or exacerbation of neuropathic orofacial pain and can be potential molecular targets for the discovery of better therapies. Application of therapeutic candidates, which act on the molecular targets and modulate biological processes, attenuates pain-associated behaviors in animal models. Such therapeutic candidates including calcitonin gene-related peptide receptor antagonists that have a reasonable mechanism for ameliorating neuropathic orofacial pain and meet the requirements for safe administration to humans seem worth to be evaluated in clinical trials. Such prospective translation of the efficacy of therapeutic candidates from animal models to human patients would help develop better therapies for neuropathic orofacial pain.
Keywords: neuropathic orofacial pain, molecular targets, therapeutic candidates, trigeminal pathway, post-traumatic trigeminal neuropathic pain, primary trigeminal neuralgia, animal model
1. Introduction
Orofacial pain is defined as pain felt in the face and its associated regions and/or the oral cavity [1]. It is divergent and complex with regard to the source of pain, etiology, and pathophysiology. The International Classification of Orofacial Pain (ICOP) 1st edition classifies orofacial pain as: (1) orofacial pain attributed to disorders of the dentoalveolar and anatomically related structures; (2) myofascial orofacial pain; (3) temporomandibular joint pain; (4) orofacial pain attributed to a lesion or disease of the cranial nerves; (5) orofacial pain resembling presentations of primary headaches; and (6) idiopathic orofacial pain [2]. Among them, neuropathic orofacial pain, including post-traumatic trigeminal neuropathic pain (PTNP) and primary trigeminal neuralgia (PTN) (subclasses of “orofacial pain attributed to lesion or disease of the cranial nerves” in the ICOP [3,4]) is a category of orofacial pain, wherein the mechanism of neuropathic pain is primarily implicated in the etiology and pathophysiology [1]. Because this category of orofacial pain is a substantial burden on patients, is difficult to treat, and has a huge medical unmet need [5,6,7,8], current preclinical research is tackling the elucidation of the disease pathophysiology and the identification of molecular targets for treating it using animal models that simulate neuropathic orofacial pain, especially PTNP and PTN, which are essential research tools to analyze the underlying pathophysiology and explore potential molecular targets [9]. This review highlights the potential molecular targets for treating neuropathic orofacial pain based on the current findings in animal models of PTNP and PTN.
2. Clinical Features of Neuropathic Orofacial Pain
PTNP is a disorder characterized by recurrent orofacial pain in regions innervated by one or more branches of the trigeminal nerve. It is caused by a major or minor trauma in the trigeminal nerve branches that occur as a consequence of maxillofacial surgical procedures and invasive dental treatments, among others [2,10]. Due to trauma, positive and negative somatosensory changes occur within the trigeminal nerve distribution [2]. Pain is usually continuous and was reported to be dull or burning [2,10]. PTNP has a substantially negative impact on the quality of life of patients, and the efficacy of currently available therapeutic options is far from satisfactory [10,11].
PTN is also a neuropathic pain-associated disorder, which is distinct from PTNP in terms of pain and etiology. It is characterized by recurrent, unilateral, excruciating, brief electric shock-like pain in the facial regions, such as in the forehead, cheek, and lower jaw, which are innervated by one or more trigeminal nerve branch(es), and in most cases, by the maxillary or mandibular branch [12,13]. Only paroxysmal pain occurs in a portion of the patient population that experiences this condition, although continuous pain concomitantly occurs in another proportion of the population [14]. Pain can be triggered by innocuous stimuli such as exposure to wind and eating [2]. This characteristic of pain, that is, the brief pain paroxysms, is distinct from that in PTNP [2,10]. Trigeminal neuralgia is classified as PTN and secondary trigeminal neuralgia based on etiology [7]. PTN, the most common type, is associated with the compression of the trigeminal nerve root due to neurovascular contact, mainly at the brainstem [7,15,16,17]. Pain relief in patients with PTN after administration of current treatment options has been unsatisfactory, with a large inter-patient variability [18].
Taken together, neuropathic orofacial pain conditions, such as PTNP and PTN, are associated with recurrent and debilitating orofacial pain symptoms, each with their own characteristic properties in terms of pain and etiology, and they reduce the quality of life of patients [10,19]. Given that consistently effective treatment options are not yet available [10,11,18,20], preclinical research is expected to elucidate the molecular mechanisms underlying these categories of orofacial pain and identify molecular targets for better therapies using animal models that simulate PTNP and PTN.
3. Potential Molecular Targets for Treating PTNP
3.1. Animal Models of PTNP
The animal models used to simulate PTNP are summarized in Table 1. These models commonly use procedures such as surgical injury or venom injection to cause damage at the level of the trigeminal nerve branch (e.g., ION or mental nerve), which is proximate to the etiology of PTNP, that is, major or minor trauma to the trigeminal nerve branch. Chronic constriction injury of the infraorbital nerve (CCI-ION) in rats is a prototype animal model of PTNP associated with damage at the level of the trigeminal nerve branch, and it has been the most widely used model since 1994 [21]. In this model, ligation of the ION (a pure sensory nerve and a branch of the maxillary division of the trigeminal nerve) causes sensory abnormalities in the ION-receptive region (e.g., mystacial vibrissae and its surrounding skin), which can be detected as evoked (e.g., hypersensitivity to mechanical, cold, or heat stimuli) or spontaneous (e.g., increase in face grooming) pain-associated behaviors. Various procedures for triggering damage at varying regions in the trigeminal nerve branch have also been performed, as shown in Table 1. For example, segmental transection of ION branches [22] or a partial ligation of the ION [23] instead of CCI-ION has been employed. A slightly different method, the injection of the biotoxin cobra venom into the trunk of the ION, causes demyelination of the axon and induces evoked [24] and spontaneous (e.g., face-grooming and head shaking) [25,26] pain-associated behaviors. Furthermore, the procedure for constructing malpositioned dental implants induces injury at the level of the inferior alveolar nerve (a branch of the mandibular division of the trigeminal nerve) and prolonged mechanical allodynia in the orofacial regions of rats [27]. Some of these procedures for triggering trigeminal nerve damage have been applied to both rats and mice.
Table 1.
Current findings in animal models of post-traumatic trigeminal neuropathic pain (PTNP).
|
Animal models of PTNP Species/Procedure to injure trigeminal nerve branch/ Year of original report |
|
|
Potential molecular targets Alteration of molecular expressions or biological process occurring in the trigeminal pathway |
Trigeminal neuron (axon) |
| Upregulation: | |
| Downregulation: | |
| Trigeminal ganglion | |
| Upregulation: | |
| |
| Downregulation: | |
| Trigeminal nucleus | |
| Upregulation: | |
| |
| Downregulation: | |
| Upper central nervous system | |
| Upregulation: | |
|
Efficacy of clinically used drugs Name/Administration route/Pain measurement methodology |
Positive effect:
|
Negative effect:
| |
|
Therapeutic candidates which modulate potential molecular targets Name/Administration route/Pain measurement methodology |
Positive effect: |
|
AMPA:α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate, ATF: activating transcription factor, BDNF: brain- derived neurotrophic factor, BrdU: bromodeoxyuridine, Cav: voltage-gated calcium channel, CCL: C-C motif chemokine ligand, CXCL: C-X-C motif chemokine ligand, CXCR: C-X-C motif chemokine receptor, EphA4: ephrin A4 receptor, ErbB3: epidermal growth factor receptor tyrosine kinase, ET: endothelin, GAD: glutamic acid decarboxylase, GDNF: glial derived neurotrophic factor, GRK2: G protein-coupled receptor kinase 2, Iba-1: ionized calcium binding adapter protein 1, ION: infraorbital nerve, JNK: c-Jun N-terminal kinases, KCC2: potassium chloride transporter, Kv: voltage-gated K+ channel, LPA: lysophosphatidic acid, MrgC: mas-related G-protein-coupled receptor subtype C, MAPK: mitogen-activated protein kinase, MDH: medullary dorsal horn, MEK: mitogen-activated protein kinase kinase, MMP: matrix metalloproteinase, mPFC: medial prefrontal cortex, NADP: nicotinamide adenine dinucleotide phosphate, Nav: voltage-gated Na+ channel, NF: nuclear factor, NPY: neuropeptide Y, NGF: nerve growth factor, NR: nuclear receptor, OX-42: a microglial marker, p-ERK: phosphorylation of extracellular-signal regulated kinase, PKCγ: protein kinase C gamma, PPADS: pyridoxal-phosphate-6-azophenyl-2’,4’-disulfonic acid, PPARγ: peroxisome proliferator-activated receptor gamma, R: receptor, RGS: rat grimace scale, TG: trigeminal ganglia, TLR: toll-like receptor, TN: trigeminal nerve, TREZ: trigeminal root entry zone, TrkB: tropomyosin receptor kinase B, TRPM: transient receptor potential melastatin, TRPV transient receptor potential vanilloid, SP: substance P, TSP4: thrombospondin-4, VEGF: vascular endothelial growth factor, Vc: trigeminal spinal subnucleus caudalis, ip: intraperitoneal, it: intrathecal, iv: intravenous, po: per os, sc: subcutaneous, mech.: hypersensitivity to mechanical stimuli, heat: hypersensitivity to heat stimuli, cold: hypersensitivity to cold stimuli, spon.: spontaneous-pain associated behavior.
3.2. Potential Molecular Targets in the Trigeminal Pathway for Treating PTNP
Pain sensations occurring in the orofacial region are conveyed to the brain via the trigeminal pathway. More specifically, the trigeminal nerve axons, whose cell bodies exist in the trigeminal ganglion, deliver the pain signal (occurring at the free nerve endings of the trigeminal branch) to the trigeminal nucleus in the brain stem, which in turn projects to the somatosensory and limbic cortices via the thalamus [110]. Because abnormalities occurring in the trigeminal pathway may underlie chronic pain in PTNP, intensive investigation of the pathophysiology of the trigeminal pathway has been conducted using animal models of PTNP.
The alteration patterns in molecular expression occurring after trigeminal branch damage have provided information about the biological processes, specifically the pathophysiology of pain, occurring in the trigeminal pathway. The current findings in the animal models of PTNP are summarized in Table 1, examples of which are as follows. The increase in immunity/inflammation markers, such as IL-6 [39,49,63,64], IL-1 β [38,63,64], and ATF-3 [33,56], indicate the involvement of inflammation and enhanced immune function at the level of the axon, ganglion, and nucleus in the trigeminal pathway. According to a study using the CCI-ION rat model, proinflammatory cytokine (IL-6 and IL-1 β) levels were significantly elevated in the affected ION. Treatment with the anti-neuropathic pain drug pregabalin attenuates tactile allodynia in the facial region and reduces the elevated levels of such cytokines [64]. The increased expression of neuropeptides, such as SP [38], NPY [42], and CGRP [63], in the axon or the nucleus suggests enhanced pain signal transmission mediated by these neuropeptides in the trigeminal pathway. Constriction injury of the mental nerve, which normally does not express NPY, induces the expression of NPY distal to the site of the injury, suggesting that the induced NPY might modulate pain in the periphery [42]. Overexpression of sodium channels [50] and the calcium channel α2δ1 subunit [54] in the ganglion could be associated with increased ectopic discharges in the axons and enhanced presynaptic excitatory neurotransmitter release, respectively. It has been demonstrated that sensory nerve injury alters the expression and function of voltage-gated sodium channels (Navs), which influences the excitability of neurons and results in neuropathic pain conditions [111]. The increased expression of TRP channels (e.g., TRPV1 [48,53] and TRPA1 [48]) and purinergic P2X receptors (e.g., P2X3-R [51] and P2X4-R [41]) at the level of the axon, ganglion, or nucleus could be associated with an increase in pain signal transduction mediated by these polymodal nociceptor channels at the peripheral and central levels. The increase in glial activity markers, such as BrdU [33], Iba-1 [56], and GFAP [33] in the nucleus, suggests the proliferation and activation of microglia and astrocytes, and the enhancement of interactions between neurons and glial cells in the trigeminal pathway. An investigation of glial cell activity in the trigeminal nucleus following ION ligature in rats showed that microglia and astrocytes are activated under the influence of the chemokine CCL2 at different time points, suggesting that glial cell activation is associated with the development and maintenance of PTNP [62]. Furthermore, neuroplastic changes and hyperexcitability of the central nervous system were suggested to result from substantial alterations in the expression of certain growth factors (e.g., NGF [40] and BDNF [45]) and markers of neuronal activity (e.g., p-p38 [46,51] and p-ERK [34,46,51,52]) in the brain stem and the higher central nervous system such as the mPFC. A study has shown that ERK, p38, and JNK MAPKs are accelerated in the TG of the CCI-ION rat model and that their inhibitors significantly reversed the effect of facial mechanical allodynia, suggesting that MAPKs are therapeutic targets for the treatment of chronic pain in PTNP [46].
These current findings, such as the changes in molecular expression and biological processes occurring in the trigeminal pathway, in animal models demonstrate the potential molecular targets for treating PTNP. The molecules whose expression is substantially altered following trigeminal nerve damage are possibly involved in the generation and/or exacerbation of chronic pain in PTNP, and can be potential molecular targets for treating PTNP. Modulation of these potential molecular targets by therapeutic candidates could attenuate pain phenotypes in animal models and chronic pain in patients with PTNP.
3.3. Efficacy of Clinically Used Drugs
In estimating the clinical analgesic efficacy of therapeutic candidates, it is crucial to understand the mechanisms of the current standard drugs for treating PTNP, using the efficacy of clinically used drugs in animal models as a reference. In the clinical setting, the treatment of PTNP has been conducted with reference to the algorithm for the management of neuropathic pain [112], that is, first-line treatment with tricyclic antidepressants, serotonin norepinephrine reuptake inhibitors, gabapentinoids, topicals, and transdermal substances. Second-line treatments include combination therapies (first-line medications) and tramadol/tapentadol. Third-line treatments include serotonin-specific reuptake inhibitors, anticonvulsants, and NMDA receptor antagonists. The fourth line of treatment for this condition is neurostimulation; fifth-line treatment, low-dose opioids; and sixth-line treatment, targeted drug delivery [113].
Some of these therapies have already been tested in animal models (Table 1). Among the first-line drugs, gabapentinoids, such as gabapentin [29,32,54,87,88,89,95] and pregabalin [26,28,64,88,97] have been assessed as reference drugs. Currently, it seems that gabapentinoids are the most widely used positive control drugs in animal models of PTNP. In contrast, tricyclic antidepressants, such as clomipramine [94] and amitriptyline [83], did not attenuate mechanical allodynia in the CCI-ION rat model, although clomipramine significantly reduced spontaneous pain-associated behavior in a mouse model with a partial ligation of ION [99]. Second-line drugs, such as tapentadol [39] and tramadol [99], have exhibited positive effects in rat and mouse models. Carbamazepine, a third-line drug used for the treatment of neuropathic pain but a first-line drug for trigeminal neuralgia [13], has exhibited a positive effect in some studies [81,94,95] but not in other studies [81,83]. Anti-migraine drugs (e.g., naratriptan [92] and zolmitriptan [85]) and muscle relaxants (e.g., baclofen [82,83,94]) have also shown positive effects in several studies. Although most of the evaluations of clinically used drugs have been conducted using evoked pain assessment paradigms (e.g., mechanical allodynia) in animal models of PTNP, a study has demonstrated that carbamazepine and baclofen attenuated spontaneous pain-associated behavior (face grooming) [94] and that morphine (an opioid) only attenuates evoked pain (mechanical allodynia) but not face grooming [94].
3.4. Therapeutic Candidates Which Modulate Potential Molecular Targets
Therapeutic candidates for PTNP act on potential molecular targets and modulate the biological processes occurring after trigeminal nerve damage. They have shown significant efficacy on the orofacial pain phenotype in animal models of PTNP, as shown in Table 1. Examples of findings in animal models are as follows. While the expression of inflammation-associated substances, such as TNF-α and IL-1β, is upregulated in the trigeminal nucleus [63], their inhibitors attenuate the proinflammatory process and reduce pain in the facial region [58]. Neuropeptides, including CGRP, are overexpressed in the trigeminal pathway [63], and administration of CGRP receptor antagonists attenuates mechanical allodynia by inhibiting neuropeptide-mediated signal transmission at the trigeminal nerve terminal [44]. Navs are considered to be involved in the ectopic discharges in the axons and paroximal pain; hence, preemptive application of inhibitors of Navs prevents both the overexpression of Navs in the trigeminal ganglion and the development of neuropathic pain phenotypes [50]. While cation channels, including TRPA1, function as polymodal nociceptors and are overexpressed in the trigeminal pathway, administration of their antagonists (e.g., TRPA1 antagonist) reduces orofacial pain phenotypes [48]. The activation of glial cells (e.g., microglia and astrocytes) and enhancement of the interaction between neurons and glial cells occur in the trigeminal pathway [33,56]; thus, treatment with glial cell inhibitors produces antiallodynic effects [70]. Upregulation of the expression of growth factors such as NGF [40] and BDNF [45] could cause neuroplastic changes and enhance pain transmission in the trigeminal pathway [40,45]; hence, suppression of the expression of BDNF and its receptor TrkB in the TG inhibits the development of orofacial pain phenotypes [45]. Furthermore, activation of MAP kinase in the TG suggests accelerated pain signal transmission in the trigeminal pathway, thus, administration of MAP kinase inhibitors into the TG reverses facial mechanical allodynia [46]. Given that biological processes similar to those occurring in animal models are also similar to those underlying chronic orofacial pain in patients with PTNP, it is expected that the therapeutic candidates shown in Table 1 act on the potential molecular targets, inhibit the biological processes, and consequently attenuate orofacial neuropathic pain in patients with PTNP. It is challenging to identify which therapeutic candidates in Table 1 are most promising for the treatment of PTNP without evaluation in clinical trials. Thus, therapeutic candidates, such as CGRP receptor antagonists [44,92] and PPARγ agonists [75], that have a reasonable mechanism for ameliorating chronic pain in PTNP and meet the requirements for safe administration to humans seem worth to be evaluated in clinical trials in patients with PTNP.
4. Potential Molecular Targets for Treating PTN
4.1. Animal Models of PTN
The animal models that have simulated PTN are summarized in Table 2. These models employ a procedure to cause compression at the level of the trigeminal root entry zone (TREZ), the transitional zone of the central and peripheral tissue compartments, in the trigeminal nerve root. This procedure specifically simulates the etiology of PTN, that is, the compression of the trigeminal nerve root by blood vessels (e.g., the superior cerebellar artery and the anterior inferior cerebellar artery) [2,114,115]. There have been fewer studies on animal models of PTN compared to those of PTNP. To date, some procedures that cause compression of the trigeminal nerve root have been applied to animals (rats). These animals manifest not only evoked pain-associated behaviors (e.g., hypersensitivity to mechanical and heat stimuli), but also spontaneous pain-associated behaviors (e.g., increased face grooming), that is, pain phenotypes in the orofacial region [116].
Table 2.
Current findings in animal models of primary trigeminal neuralgia (PTN).
|
Animal models of PTN Species/Methods for trigeminal nerve injury/ Year of original report |
|
|
Potential molecular targets Alteration of molecular expressions or biological process occurring in the trigeminal pathway |
Trigeminal ganglion |
Upregulation:
| |
| Downregulation: | |
| |
| Trigeminal root entry zone (TREZ) | |
| Upregulation: | |
| Downregulation: | |
| |
| Trigeminal nucleus | |
| Upregulation: | |
| Downregulation: | |
|
Efficacy of clinically used drugs Name/Administration route/Pain measurement methodology |
Positive effect
|
|
Therapeutic candidates which modulate potential molecular targets Name/Administration route/Pain measurement methodology |
Positive effect
|
AKT: a serine—threonine protein kinase, CGRP: calcitonin gene-related peptide, D-AP5: D-2-amino-5-phosphonopentanoate; ERK: extracellular signal-regulated kinase; GFAP: glial fibrillary acidic protein; IB4: isolectin B4; NMDA: N-methyl-D-aspartate; p75: low-affinity neurotrophin receptor; PPDA: (2S,3R)-1-(phenanthren-2carbonyl)piperazine-2,3-dicarboxylic acid, PPPA: (2R,4S)-4-(3-phosphonopropyl)-2-piperidinecarboxylic acid; SP: substance P, ip: intraperitoneal, it: intrathecal, mech.: hypersensitivity to mechanical stimuli.
4.2. Molecular Expression and Biological Processes Occurring in the Trigeminal Pathway
A recent study has suggested that activation of glial cells, including oligodendrocytes, astrocytes, Schwann cells, and microglia/macrophages, in the TREZ occurs as a biological process (pathophysiology) accompanying the compression of the trigeminal nerve root [121]. Because there have been far fewer studies investigating the alterations in molecular expression in the trigeminal pathway using animal models of PTN compared to those of PTNP, a large number of pathophysiologies underlying chronic orofacial pain in PTN remain to be clarified. Further investigation of the alteration patterns of molecular expression occurring after trigeminal nerve root compression is warranted to elucidate the pathophysiology underlying the pain phenotypes in animal models of PTN. A comparative investigation of the alterations in molecular expression between animal models of PTN and PTNP may suggest the common features and differences between these two neuropathic orofacial pain conditions.
4.3. Efficacy of Clinically Used Drugs
According to a general guideline on the management of trigeminal neuralgia [123], pharmacotherapy using anticonvulsants is usually applied first for the management of PTN. Carbamazepine is used as a first-line drug, and its response rate during initial treatment was reported to be 70% [13]. However, the response rate during its long-term use tends to decrease [9]. Oxcarbazepine is often used instead of carbamazepine, although its comparative efficacy with carbamazepine is not clear. It is currently considered that both drugs inhibit the activity of voltage-gated sodium channels on the trigeminal nerve, reduce the generation of action potentials, and decrease the hyperexcitability of the nerve [38]. Other anticonvulsants, including gabapentin, pregabalin, lamotrigine, and topiramate, have also been used as a monotherapy or in combination with carbamazepine or oxcarbazepine, although there is only low quality evidence supporting their use [20]. In addition, botulinum toxin A, an inhibitor of acetylcholine release at the neuromuscular junction, has been reported to reduce pain symptoms [124]. Despite the variety of available treatment options, relieving pain in patients with PTN has been unsatisfactory, with large inter-patient variability [61].
Unfortunately, there is a limited number of studies that have assessed the effect of clinically used drugs in animal models of PTN. A study using an agar solution on the trigeminal nerve root in rats showed that carbamazepine attenuates facial mechanical allodynia [122]. The lack of information about the efficacy of clinically used drugs makes it difficult to verify the predictive validity of animal models of PTN. Thus, evaluation of more kinds of clinically used drugs in animal models of PTN is warranted. A comparative assessment of the efficacy of currently available drugs between animal models of PTN and PTNP could provide information about the common features and differences in the sensitivities to drug therapies between these two neuropathic orofacial pain conditions.
4.4. Therapeutic Candidates Which Modulate Potential Molecular Targets for Treating PTN
There have been fewer studies investigating the therapeutic candidates for treating PTN than those for PTNP. A study has shown that NMDA receptors play an important role in the central processing of pain signals in a rat model that underwent compression of the trigeminal nerve root with an agar solution, suggesting that the blockade of NMDA receptors is a potential approach for treating patients with PTN [117].
5. Challenges for Developing Better Therapies for Neuropathic Orofacial Pain
Various potential molecular targets have been identified, and their modulators (i.e., therapeutic candidates) have exhibited promising efficacy in animal models of neuropathic orofacial pain, mostly in animal models of PTNP, as shown above. However, prospective translation of the efficacies of such therapeutic candidates from these animal models to patients remains to be achieved. One of the critical points to be considered in clinical trials of therapeutic candidates is as follows. Neuropathic orofacial pain is heterogeneous; for example, PTNP and PTN are different in terms of etiology, underlying pathophysiology, and response to therapies. It would be difficult for a therapeutic candidate with a specific mechanism to exhibit sufficient efficacy in a mixed patient population. If that were the case, it would be important to match the pathophysiology between animal models and patient populations in clinical trials. For example, if a therapeutic candidate showed positive efficacy in an animal model of PTNP, it would be important to limit the target patients to those with PTNP and exclude patients with orofacial pain of other etiologies.
Although studies using animal models of PTNP have identified potential molecular targets and estimated the efficacy of therapeutic candidates, studies using animal models of PTN are lacking. A more intensive analysis of the changes in molecular expression and biological processes accompanying trigeminal root compression is warranted to identify potential molecular targets for treating PTN. Studies using animal models of PTN, but not those of PTNP, would be essential, because PTN has an etiology, pathophysiology, and sensitivity to therapies different from those of PTNP.
6. Conclusions
Increasing amount of preclinical research has attempted to elucidate the pathophysiology and identify molecular targets for better therapies for neuropathic orofacial pain. Studies using animal models have suggested that biological processes, including inflammation, enhanced neuropeptide-mediated pain signal transmission, axonal ectopic discharges, and enhanced interactions between neurons and glial cells in the trigeminal pathway underlie the chronic orofacial pain phenotypes. The molecules associated with biological processes, whose expression is substantially altered following trigeminal nerve damage or trigeminal nerve root compression, are potentially involved in the generation and/or exacerbation of neuropathic orofacial pain and can be potential molecular targets for the discovery of better therapies. Application of therapeutic candidates, which act on the molecular targets and modulate biological processes, attenuates pain-associated behaviors in animal models. Such therapeutic candidates including CGRP receptor antagonists and PPARγ agonists that have a reasonable mechanism for ameliorating neuropathic orofacial pain and meet the requirements for safe administration to humans seem worth to be evaluated in clinical trials. Such prospective translation of the efficacy of therapeutic candidates from animal models to human patients would help develop better therapies for neuropathic orofacial pain.
Author Contributions
Conceptualization and literature analysis, Y.N., S.N. and T.K.; writing—original draft preparation, Y.N.; writing—review and editing, S.N. and T.K.; preparation of figures and tables, Y.N. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
Not applicable.
Informed Consent Statement
Not applicable.
Conflicts of Interest
The authors declare no conflict of interest.
Footnotes
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.
References
- 1.Zakrzewska J.M., Hamlyn P.J. In: Epidemiology of Pain. Crombie IKCPR L.S., LeResche L., Von Korff M., editors. IASP Press; Seattle, WA, USA: 1999. pp. 171–202. [Google Scholar]
- 2.International Classification of Orofacial Pain, 1st edition (ICOP) Cephalalgia. 2020;40:129–221. doi: 10.1177/0333102419893823. [DOI] [PubMed] [Google Scholar]
- 3.Sukenaga N., Matsuki Y., Maeda L., Nagai T., Hashimoto K., Takao Y., Hirose M. Neuropathic Characteristics In Patients With Persistent Idiopathic Facial Pain. J. Pain Res. 2019;12:2801–2805. doi: 10.2147/JPR.S218332. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Benoliel R., Gaul C. Persistent idiopathic facial pain. Cephalalgia. 2017;37:680–691. doi: 10.1177/0333102417706349. [DOI] [PubMed] [Google Scholar]
- 5.Haviv Y., Zadik Y., Sharav Y., Benoliel R. Painful Traumatic Trigeminal Neuropathy: An Open Study on the Pharmacotherapeutic Response to Stepped Treatment. J. Oral Facial Pain Headache. 2014;28:52–60. doi: 10.11607/jop.1154. [DOI] [PubMed] [Google Scholar]
- 6.Araya E.I., Claudino R.F., Piovesan E.J., Chichorro J.G. Trigeminal Neuralgia: Basic and Clinical Aspects. Curr. Neuropharmacol. 2020;18:109–119. doi: 10.2174/1570159X17666191010094350. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Maarbjerg S., Di Stefano G., Bendtsen L., Cruccu G. Trigeminal neuralgia—diagnosis and treatment. Cephalalgia. 2017;37:648–657. doi: 10.1177/0333102416687280. [DOI] [PubMed] [Google Scholar]
- 8.Kawasaki K., Sugawara S., Watanabe K., Hong C., Tu T.T.H., Watanabe T., Sakamoto J., Yoshino N., Suga T., Mikuzuki L., et al. Differences in the Clinical Characteristics of Persistent Idiopathic Facial Pain (Atypical Odontalgia) Patients with or Without Neurovascular Compression of the Trigeminal Nerve. Pain Med. 2020;21:814–821. doi: 10.1093/pm/pnz300. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Araújo-Filho H.G., Pereira E.W., Campos A.R., Quintans-Júnior L.J., Quintans J.S. Chronic orofacial pain animal models—Progress and challenges. Expert Opin. Drug Discov. 2018;13:949–964. doi: 10.1080/17460441.2018.1524458. [DOI] [PubMed] [Google Scholar]
- 10.Baad-Hansen L., Benoliel R. Neuropathic orofacial pain: Facts and fiction. Cephalalgia. 2017;37:670–679. doi: 10.1177/0333102417706310. [DOI] [PubMed] [Google Scholar]
- 11.Niraj G., Simpson L., Raithatha B. Interventional Management of Refractory Trigeminal Neuropathic Pain: A Prospective Audit of a Novel Management Pathway in 70 Patients. Pain Physician. 2020;23:e525–e534. doi: 10.36076/ppj.2020/23/E525. [DOI] [PubMed] [Google Scholar]
- 12.Headache Classification Committee of the International Headache Society (IHS) The International Classification of Headache Disorders, 3rd edition. Cephalalgia. 2018;38:1–211. doi: 10.1177/0333102417738202. [DOI] [PubMed] [Google Scholar]
- 13.Gambeta E., Chichorro J.G., Zamponi G.W. Trigeminal neuralgia: An overview from pathophysiology to pharmacological treatments. Mol. Pain. 2020;16:1744806920901890. doi: 10.1177/1744806920901890. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Cruccu G., Finnerup N., Jensen T.S., Scholz J., Sindou M., Svensson P., Treede R.-D., Zakrzewska J.M., Nurmikko T. Trigeminal neuralgia: New classification and diagnostic grading for practice and research. Neurology. 2016;87:220–228. doi: 10.1212/WNL.0000000000002840. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Love S. Trigeminal neuralgia: Pathology and pathogenesis. Brain. 2001;124:2347–2360. doi: 10.1093/brain/124.12.2347. [DOI] [PubMed] [Google Scholar]
- 16.Jannetta P.J. Arterial Compression of the Trigeminal Nerve at the Pons in Patients with Trigeminal Neuralgia. J. Neurosurg. 1967;26:159–162. doi: 10.3171/jns.1967.26.1part2.0159. [DOI] [PubMed] [Google Scholar]
- 17.Obermann M. Recent advances in understanding/managing trigeminal neuralgia. F1000Research. 2019;8:505. doi: 10.12688/f1000research.16092.1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.McDonough P., McKenna J.P., McCreary C., Downer E.J. Neuropathic orofacial pain: Cannabinoids as a therapeutic avenue. Int. J. Biochem. Cell Biol. 2014;55:72–78. doi: 10.1016/j.biocel.2014.08.007. [DOI] [PubMed] [Google Scholar]
- 19.Zakrzewska J.M., Wu J., Mon-Williams M., Phillips N., Pavitt S. Evaluating the impact of trigeminal neuralgia. Pain. 2017;158:1166–1174. doi: 10.1097/j.pain.0000000000000853. [DOI] [PubMed] [Google Scholar]
- 20.Bendtsen L., Zakrzewska J.M., Abbott J., Braschinsky M., Di Stefano G., Donnet A., Eide P.K., Leal P.R.L., Maarbjerg S., May A., et al. European Academy of Neurology guideline on trigeminal neuralgia. Eur. J. Neurol. 2019;26:831–849. doi: 10.1111/ene.13950. [DOI] [PubMed] [Google Scholar]
- 21.Vos B.P., Strassman A.M., Maciewicz R.J. Behavioral evidence of trigeminal neuropathic pain following chronic constriction injury to the rat’s infraorbital nerve. J. Neurosci. 1994;14:2708–2723. doi: 10.1523/JNEUROSCI.14-05-02708.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Pozza D.H., Castro-Lopes J.M., Neto F.L., Avelino A. Spared nerve injury model to study orofacial pain. Indian J. Med Res. 2016;143:297–302. doi: 10.4103/0971-5916.182619. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Shinoda M., Kawashima K., Ozaki N., Asai H., Nagamine K., Sugiura Y. P2X3 Receptor Mediates Heat Hyperalgesia in a Rat Model of Trigeminal Neuropathic Pain. J. Pain. 2007;8:588–597. doi: 10.1016/j.jpain.2007.03.001. [DOI] [PubMed] [Google Scholar]
- 24.An J.-X., He Y., Qian X.-Y., Wu J.-P., Xie Y.-K., Guo Q.-L., Williams J.P., Cope D.K. A New Animal Model of Trigeminal Neuralgia Produced by Administration of Cobra Venom to the Infraorbital Nerve in the Rat. Anesthesia Analg. 2011;113:652–656. doi: 10.1213/ANE.0b013e3182245add. [DOI] [PubMed] [Google Scholar]
- 25.Zhang L., Ding X., Wu Z., Wang M., Tian M. Curcumin alleviates pain and improves cognitive impairment in a rat model of cobra venom-induced trigeminal neuralgia. J. Pain Res. 2018;11:1095–1104. doi: 10.2147/JPR.S162668. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Zhao Q.-Q., Qian X.-Y., An J.-X., Liu C.-C., Fang Q.-W., Wang Y., Jiang Y.-D., Cope D.K., Williams J.P. Rat Model of Trigeminal Neuralgia Using Cobra Venom Mimics the Electron Microscopy, Behavioral, and Anticonvulsant Drug Responses Seen in Patients. Pain Physician. 2015;18:1083–1090. [PubMed] [Google Scholar]
- 27.Han S., Yeo S., Lee M., Bae Y., Ahn D. Early Dexamethasone Relieves Trigeminal Neuropathic Pain. J. Dent. Res. 2010;89:915–920. doi: 10.1177/0022034510374056. [DOI] [PubMed] [Google Scholar]
- 28.Cao Y., Wang H., Chiang C.-Y., Dostrovsky J.O., Sessle B.J. Pregabalin suppresses nociceptive behavior and central sensitization in a rat trigeminal neuropathic pain model. J. Pain. 2013;14:193–204. doi: 10.1016/j.jpain.2012.11.005. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Ding W., You Z., Shen S., Yang J., Lim G., Doheny J.T., Chen L., Zhu S., Mao J. An Improved Rodent Model of Trigeminal Neuropathic Pain by Unilateral Chronic Constriction Injury of Distal Infraorbital Nerve. J. Pain. 2017;18:899–907. doi: 10.1016/j.jpain.2017.02.427. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Grelik C., Bennett G.J., Ribeiro-Da-Silva A. Autonomic fibre sprouting and changes in nociceptive sensory innervation in the rat lower lip skin following chronic constriction injury. Eur. J. Neurosci. 2005;21:2475–2487. doi: 10.1111/j.1460-9568.2005.04089.x. [DOI] [PubMed] [Google Scholar]
- 31.Horie K., Watanabe M., Chanbora C., Awada T., Kunimatsu R., Uchida T., Takata T., Tanimoto K. Bovine lactoferrin reduces extra-territorial facial allodynia/hyperalgesia following a trigeminal nerve injury in the rat. Brain Res. 2017;1669:89–96. doi: 10.1016/j.brainres.2017.04.015. [DOI] [PubMed] [Google Scholar]
- 32.Krzyzanowska A., Pittolo S., Cabrerizo M., Sánchez-López J., Krishnasamy S., Venero C., Avendaño C. Assessing nociceptive sensitivity in mouse models of inflammatory and neuropathic trigeminal pain. J. Neurosci. Methods. 2011;201:46–54. doi: 10.1016/j.jneumeth.2011.07.006. [DOI] [PubMed] [Google Scholar]
- 33.Xu M., Aita M., Chavkin C. Partial Infraorbital Nerve Ligation as a Model of Trigeminal Nerve Injury in the Mouse: Behavioral, Neural, and Glial Reactions. J. Pain. 2008;9:1036–1048. doi: 10.1016/j.jpain.2008.06.006. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34.Miyamoto M., Tsuboi Y., Takamiya K., Huganir R.L., Kondo M., Shinoda M., Oi Y., Iwata K. Involvement of GluR2 and GluR3 subunit C-termini in the trigeminal spinal subnucleus caudalis and C1–C2 neurons in trigeminal neuropathic pain. Neurosci. Lett. 2011;491:8–12. doi: 10.1016/j.neulet.2010.12.060. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35.Ma F., Zhang L., Lyons D., Westlund K.N. Orofacial neuropathic pain mouse model induced by Trigeminal Inflammatory Compression (TIC) of the infraorbital nerve. Mol. Brain. 2012;5:44. doi: 10.1186/1756-6606-5-44. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36.Moreau N., Dieb W., Mauborgne A., Bourgoin S., Villanueva L., Pohl M., Boucher Y. Hedgehog Pathway–Mediated Vascular Alterations Following Trigeminal Nerve Injury. J. Dent. Res. 2016;96:450–457. doi: 10.1177/0022034516679395. [DOI] [PubMed] [Google Scholar]
- 37.Ma P.F., Zhang P.L., Westlund P.K.N. Trigeminal Nerve Injury ErbB3/ErbB2 Promotes Mechanical Hypersensitivity. Anesthesiol. 2012;117:381–388. doi: 10.1097/ALN.0b013e3182604b2b. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38.Costa G.M.F., De Oliveira A.P., Martinelli P.M., Camargos E.R.D.S., Arantes R.M.E., De Almeida-Leite C.M. Demyelination/remyelination and expression of interleukin-1β, substance P, nerve growth factor, and glial-derived neurotrophic factor during trigeminal neuropathic pain in rats. Neurosci. Lett. 2016;612:210–218. doi: 10.1016/j.neulet.2015.12.017. [DOI] [PubMed] [Google Scholar]
- 39.Michot B., Bourgoin S., Kayser V., Hamon M. Effects of tapentadol on mechanical hypersensitivity in rats with ligatures of the infraorbital nerve versus the sciatic nerve. Eur. J. Pain. 2012;17:867–880. doi: 10.1002/j.1532-2149.2012.00259.x. [DOI] [PubMed] [Google Scholar]
- 40.dos Reis R.C., Kopruszinski C.M., Nones C.F., Chichorro J. Nerve growth factor induces facial heat hyperalgesia and plays a role in trigeminal neuropathic pain in rats. Behav. Pharmacol. 2016;27:528–535. doi: 10.1097/FBP.0000000000000246. [DOI] [PubMed] [Google Scholar]
- 41.Nakai K., Nakae A., Oba S., Mashimo T., Ueda K. P2X4 receptor expression in a rat model of trigeminal neuropathic pain. NeuroReport. 2010;21:559–563. doi: 10.1097/WNR.0b013e32833980b2. [DOI] [PubMed] [Google Scholar]
- 42.Magnussen C., Hung S.-P., Ribeiro-Da-Silva A. Novel expression pattern of neuropeptide Y immunoreactivity in the peripheral nervous system in a rat model of neuropathic pain. Mol. Pain. 2015;11 doi: 10.1186/s12990-015-0029-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 43.Trevisan G., Benemei S., Materazzi S., De Logu F., De Siena G., Fusi C., Rossato M.F., Coppi E., Marone I.M., Ferreira J., et al. TRPA1 mediates trigeminal neuropathic pain in mice downstream of monocytes/macrophages and oxidative stress. Brain. 2016;139:1361–1377. doi: 10.1093/brain/aww038. [DOI] [PubMed] [Google Scholar]
- 44.Michot B., Kayser V., Hamon M., Bourgoin S. CGRP receptor blockade by MK-8825 alleviates allodynia in infraorbital nerve-ligated rats. Eur. J. Pain. 2014;19:281–290. doi: 10.1002/ejp.616. [DOI] [PubMed] [Google Scholar]
- 45.Liu L., He L., Yin C., Huang R., Shen W., Ge H., Sun M., Li S., Gao Y., Xiong W. Effects of palmatine on BDNF/TrkB-mediated trigeminal neuralgia. Sci. Rep. 2020;10:1–8. doi: 10.1038/s41598-020-61969-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 46.Liu C.-Y., Lu Z.-Y., Li N., Yu L.-H., Zhao Y.-F., Ma B. The role of large-conductance, calcium-activated potassium channels in a rat model of trigeminal neuropathic pain. Cephalalgia. 2015;35:16–35. doi: 10.1177/0333102414534083. [DOI] [PubMed] [Google Scholar]
- 47.Xiong W., Wu R.-P., Tan M.-X., Tong Z.-J., He L.-K., Guan S., Liu L.-J., Yin C.-C., Shen Y.-L., Ge H.-X., et al. Emodin inhibits the expression of receptor and calcitonin-gene-related peptide release in trigeminal ganglia of trigeminal neuralgia rats. Int J Clin Exp Pathol. 2017;10:11317–11325. [PMC free article] [PubMed] [Google Scholar]
- 48.DeMartini C., Greco R., Zanaboni A.M., Francesconi O., Nativi C., Tassorelli C., Deseure K. Antagonism of Transient Receptor Potential Ankyrin Type-1 Channels as a Potential Target for the Treatment of Trigeminal Neuropathic Pain: Study in an Animal Model. Int. J. Mol. Sci. 2018;19:3320. doi: 10.3390/ijms19113320. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 49.Liu M., Zhong J., Xia L., Dou N., Li S. The expression of voltage-gated sodium channels in trigeminal nerve following chronic constriction injury in rats. Int. J. Neurosci. 2019;129:955–962. doi: 10.1080/00207454.2019.1595616. [DOI] [PubMed] [Google Scholar]
- 50.Yoon J.-H., Son J.-Y., Kim M.-J., Kang S.-H., Ju J.-S., Bae Y.-C., Ahn D.-K. Preemptive application of QX-314 attenuates trigeminal neuropathic mechanical allodynia in rats. Korean J. Physiol. Pharmacol. 2018;22:331–341. doi: 10.4196/kjpp.2018.22.3.331. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 51.Xiong W., Tan M., He L., Ou X., Jin Y., Yang G., Huang L., Shen Y., Guan S., Xu C., et al. Inhibitory effects of tetramethylpyrazine on pain transmission of trigeminal neuralgia in CCI-ION rats. Brain Res. Bull. 2017;134:72–78. doi: 10.1016/j.brainresbull.2017.07.005. [DOI] [PubMed] [Google Scholar]
- 52.Xiong W., Tan M., Tong Z., Yin C., He L., Liu L., Shen Y., Guan S., Ge H., Li G., et al. Effects of long non-coding RNA uc.48+ on pain transmission in trigeminal neuralgia. Brain Res. Bull. 2019;147:92–100. doi: 10.1016/j.brainresbull.2019.02.009. [DOI] [PubMed] [Google Scholar]
- 53.Urano H., Ara T., Fujinami Y., Hiraoka B.Y. Aberrant TRPV1 Expression in Heat Hyperalgesia Associated with Trigeminal Neuropathic Pain. Int. J. Med Sci. 2012;9:690–697. doi: 10.7150/ijms.4706. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 54.Li K.-W., Yu Y.P., Zhou C., Kim D.-S., Lin B., Sharp K., Steward O., Luo Z.D. Calcium Channel α2δ1 Proteins Mediate Trigeminal Neuropathic Pain States Associated with Aberrant Excitatory Synaptogenesis. J. Biol. Chem. 2014;289:7025–7037. doi: 10.1074/jbc.M114.548990. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 55.Yang K., Kim M., Ju J., Park S., Lee C., Kim S., Bae Y., Ahn D. Antinociceptive Effects of Botulinum Toxin Type A on Trigeminal Neuropathic Pain. J. Dent. Res. 2016;95:1183–1190. doi: 10.1177/0022034516659278. [DOI] [PubMed] [Google Scholar]
- 56.Lynds R., Lyu C., Lyu G.-W., Shi X.-Q., Rosen A., Mustafa K., Shi T.-J.S. Neuronal plasticity of trigeminal ganglia in mice following nerve injury. J. Pain Res. 2017;10:349–357. doi: 10.2147/JPR.S120092. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 57.Ju Y.-Y., Jiang M., Xu F., Wang D., Ding B., Ma L.-J., Wu H. CXCL10 and CXCR3 in the Trigeminal Ganglion Contribute to Trigeminal Neuropathic Pain in Mice. J. Pain Res. 2021;14:41–51. doi: 10.2147/JPR.S288292. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 58.Zhang Q., Cao D.-L., Zhang Z.-J., Jiang B.-C., Gao Y.-J. Chemokine CXCL13 mediates orofacial neuropathic pain via CXCR5/ERK pathway in the trigeminal ganglion of mice. J. Neuroinflammation. 2016;13:1–13. doi: 10.1186/s12974-016-0652-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 59.Zhao L.-X., Jiang M., Bai X.-Q., Cao D.-L., Wu X.-B., Zhang J., Guo J.-S., Chen T.-T., Wang J., Wu H., et al. TLR8 in the Trigeminal Ganglion Contributes to the Maintenance of Trigeminal Neuropathic Pain in Mice. Neurosci. Bull. 2021;37:550–562. doi: 10.1007/s12264-020-00621-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 60.Kanda H., Ling J., Chang Y.-T., Erol F., Viatchenko-Karpinski V., Yamada A., Noguchi K., Gu J.G. Kv4.3 Channel Dysfunction Contributes to Trigeminal Neuropathic Pain Manifested with Orofacial Cold Hypersensitivity in Rats. J. Neurosci. 2021;41:2091–2105. doi: 10.1523/JNEUROSCI.2036-20.2021. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 61.Liu M.-X., Zhong J., Xia L., Dou N.-N., Li S.-T. IL-6 contributes to Nav1.3 up-regulation in trigeminal nerve following chronic constriction injury. Neurol. Res. 2020;42:504–514. doi: 10.1080/01616412.2020.1747719. [DOI] [PubMed] [Google Scholar]
- 62.Kubíčková L., Klusáková I., Dubový P. Bilateral activation of glial cells and cellular distribution of the chemokine CCL2 and its receptor CCR2 in the trigeminal subnucleus caudalis of trigeminal neuropathic pain model. Histochem. Cell Biol. 2020;153:239–255. doi: 10.1007/s00418-020-01850-4. [DOI] [PubMed] [Google Scholar]
- 63.Yang Y.-J., Chun-Yi J., Xia Y.-P., Jiang C.-Y., Miao C., Yang C.-Q., Yuan M., Wang L. Resveratrol suppresses glial activation and alleviates trigeminal neuralgia via activation of AMPK. J. Neuroinflammation. 2016;13:1–11. doi: 10.1186/s12974-016-0550-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 64.Khan J., Noboru N., Imamura Y., Eliav E. Effect of Pregabalin and Diclofenac on tactile allodynia, mechanical hyperalgesia and pro inflammatory cytokine levels (IL-6, IL-1β) induced by chronic constriction injury of the infraorbital nerve in rats. Cytokine. 2018;104:124–129. doi: 10.1016/j.cyto.2017.10.003. [DOI] [PubMed] [Google Scholar]
- 65.Dieb W., Alvarez P., Hafidi A. PKCγ-Positive Neurons Gate Light Tactile Inputs to Pain Pathway Through pERK1/2 Neuronal Network in Trigeminal Neuropathic Pain Model. J. Oral Facial Pain Headache. 2015;29:70–82. doi: 10.11607/ofph.1353. [DOI] [PubMed] [Google Scholar]
- 66.Zhang Y., Su Q., Lian Y., Chen Y. Botulinum toxin type A reduces the expression of transient receptor potential melastatin 3 and transient receptor potential vanilloid type 4 in the trigeminal subnucleus caudalis of a rat model of trigeminal neuralgia. NeuroReport. 2019;30:735–740. doi: 10.1097/WNR.0000000000001268. [DOI] [PubMed] [Google Scholar]
- 67.Li K.-W., Kim O.-S., Zaucke F., Luo Z.D. Trigeminal nerve injury-induced thrombospondin-4 up-regulation contributes to orofacial neuropathic pain states in a rat model. Eur. J. Pain. 2013;18:489–495. doi: 10.1002/j.1532-2149.2013.00396.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 68.Boucher Y., Carstens M.I., Sawyer C.M., Zanotto K.L., Merrill A.W., Carstens E. Capsaicin avoidance as a measure of chemical hyperalgesia in orofacial nerve injury models. Neurosci. Lett. 2013;543:37–41. doi: 10.1016/j.neulet.2013.02.060. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 69.Kim M.-J., Son J.-Y., Ju J.-S., Ahn D.-K. Early Blockade of EphA4 Pathway Reduces Trigeminal Neuropathic Pain. J. Pain Res. 2020;13:1173–1183. doi: 10.2147/JPR.S249185. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 70.Won K.A., Kim M.J., Yang K.Y., Park J.S., Lee M.K., Park M.K., Bae Y.C., Ahn N.K. The Glial–Neuronal GRK2 Pathway Participates in the Development of Trigeminal Neuropathic Pain in Rats. J. Pain. 2014;15:250–261. doi: 10.1016/j.jpain.2013.10.013. [DOI] [PubMed] [Google Scholar]
- 71.Li L., Yao L., Wang F., Zhang Z. Knock-down of JAK2 and PTEN on pain behavior in rat model of trigeminal neuropathic pain. Gene. 2019;719:144080. doi: 10.1016/j.gene.2019.144080. [DOI] [PubMed] [Google Scholar]
- 72.Lee M.K., Han S.R., Park M.K., Kim M.J., Bae Y.C., Kim S.K., Park J.S., Ahn D.K. Behavioral Evidence for the Differential Regulation of p-p38 MAPK and p-NF-κB in Rats with Trigeminal Neuropathic Pain. Mol. Pain. 2011;7:57. doi: 10.1186/1744-8069-7-57. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 73.Lee G.W., Son J.Y., Lee A.R., Ju J.S., Bae Y.C., Ahn D.K. Central VEGF-A pathway plays a key role in the development of trigeminal neuropathic pain in rats. Mol. Pain. 2019;15:1744806919872602. doi: 10.1177/1744806919872602. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 74.Ma F., Zhang L., Oz H.S., Mashni M., Westlund K.N. Dysregulated TNFα promotes cytokine proteome profile increases and bilateral orofacial hypersensitivity. Neuroscience. 2015;300:493–507. doi: 10.1016/j.neuroscience.2015.05.046. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 75.Lyons D.N., Zhang L., Danaher R.J., Miller C.S., Westlund K.N. PPARγ Agonists Attenuate Trigeminal Neuropathic Pain. Clin. J. Pain. 2017;33:1071–1080. doi: 10.1097/AJP.0000000000000509. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 76.Luo X., He T., Wang Y., Wang J.-L., Yan X.-B., Zhou H.-C., Wang R.-R., Du R., Wang X.-L., Chen J., et al. Ceftriaxone Relieves Trigeminal Neuropathic Pain Through Suppression of Spatiotemporal Synaptic Plasticity via Restoration of Glutamate Transporter 1 in the Medullary Dorsal Horn. Front. Cell. Neurosci. 2020;14:199. doi: 10.3389/fncel.2020.00199. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 77.Castro A., Li Y., Raver C., Chandra R., Masri R., Lobo M.K., Keller A. Neuropathic pain after chronic nerve constriction may not correlate with chloride dysregulation in mouse trigeminal nucleus caudalis neurons. Pain. 2017;158:1366–1372. doi: 10.1097/j.pain.0000000000000926. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 78.Martin Y., Malmierca E., Avendaño C., Nuñez A. Neuronal disinhibition in the trigeminal nucleus caudalis in a model of chronic neuropathic pain. Eur. J. Neurosci. 2010;32:399–408. doi: 10.1111/j.1460-9568.2010.07302.x. [DOI] [PubMed] [Google Scholar]
- 79.Devoizel L., Alvarezl P., Monconduitl L., Dallel R. Representation of dynamic mechanical allodynia in the ventral medial prefrontal cortex of trigeminal neuropathic rats. Eur. J. Pain. 2011;15:676–682. doi: 10.1016/j.ejpain.2010.11.017. [DOI] [PubMed] [Google Scholar]
- 80.Wang Y., Cao P., Mei L., Yin W., Mao Y., Niu C., Zhang Z., Tao W. Microglia in the Primary Somatosensory Barrel Cortex Mediate Trigeminal Neuropathic Pain. Neuroscience. 2019;414:299–310. doi: 10.1016/j.neuroscience.2019.05.034. [DOI] [PubMed] [Google Scholar]
- 81.Kopruszinski C.M., Reis R.C., Chichorro J.G. B vitamins relieve neuropathic pain behaviors induced by infraorbital nerve constriction in rats. Life Sci. 2012;91:1187–1195. doi: 10.1016/j.lfs.2012.08.025. [DOI] [PubMed] [Google Scholar]
- 82.Deseure K., Koek W., Colpaert F.C., Adriaensen H. The 5-HT1A receptor agonist F 13640 attenuates mechanical allodynia in a rat model of trigeminal neuropathic pain. Eur. J. Pharmacol. 2002;456:51–57. doi: 10.1016/S0014-2999(02)02640-7. [DOI] [PubMed] [Google Scholar]
- 83.Idänpään-Heikkilä J.J., Guilbaud G. Pharmacological studies on a rat model of trigeminal neuropathic pain: Baclofen, but not carbamazepine, morphine or tricyclic antidepressants, attenuates the allodynia-like behaviour. Pain. 1999;79:281–290. doi: 10.1016/S0304-3959(98)00172-9. [DOI] [PubMed] [Google Scholar]
- 84.Chichorro J., Zampronio A., Souza G.E.P., Rae G.A. Orofacial cold hyperalgesia due to infraorbital nerve constriction injury in rats: Reversal by endothelin receptor antagonists but not non-steroidal anti-inflammatory drugs. Pain. 2006;123:64–74. doi: 10.1016/j.pain.2006.02.010. [DOI] [PubMed] [Google Scholar]
- 85.Kayserl V., Latrémolièrel A., Hamonl M., Bourgoinl S. N-methyl-d -aspartate receptor-mediated modulations of the anti-allodynic effects of 5-HT1B/1D receptor stimulation in a rat model of trigeminal neuropathic pain. Eur. J. Pain. 2011;15:451–458. doi: 10.1016/j.ejpain.2010.09.012. [DOI] [PubMed] [Google Scholar]
- 86.Akintola T., Raver C., Studlack P., Uddin O., Masri R., Keller A. The grimace scale reliably assesses chronic pain in a rodent model of trigeminal neuropathic pain. Neurobiol. Pain. 2017;2:13–17. doi: 10.1016/j.ynpai.2017.10.001. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 87.Christensen D., Gautron M., Guilbaud G., Kayser V. Effect of gabapentin and lamotrigine on mechanical allodynia-like behaviour in a rat model of trigeminal neuropathic pain. Pain. 2001;93:147–153. doi: 10.1016/S0304-3959(01)00305-0. [DOI] [PubMed] [Google Scholar]
- 88.Nakai K., Nakae A., Hashimoto R., Mashimo T., Hosokawa K. Antinociceptive effects of mirtazapine, pregabalin, and gabapentin after chronic constriction injury of the infraorbital nerve in rats. J. Oral Facial Pain Headache. 2014;28:61–67. doi: 10.11607/jop.1105. [DOI] [PubMed] [Google Scholar]
- 89.Milosevic N., Nikolic N., Djordjevic I., Todorović A., Lazić V., Milašin J., Henry M.A., Fairchild D.D., Patil M.J., Hanania T., et al. Association of Functional Polymorphisms in Matrix Metalloproteinase-9 and Glutathione S-Transferase T1 Genes with Temporomandibular Disorders. J. Oral Facial Pain Headache. 2015;29:286–296. doi: 10.11607/ofph.1350. [DOI] [PubMed] [Google Scholar]
- 90.Chichorro J.G., Zampronio A., Rae G.A. Endothelin ET(B) receptor antagonist reduces mechanical allodynia in rats with trigeminal neuropathic pain. Exp. Biol. Med. 2006;231:1136–1140. [PubMed] [Google Scholar]
- 91.Cha M., Kohan K.J., Zuo X., Ling J.X., Gu J.G. Assessment of chronic trigeminal neuropathic pain by the orofacial operant test in rats. Behav. Brain Res. 2012;234:82–90. doi: 10.1016/j.bbr.2012.06.020. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 92.Michot B., Bourgoin S., Viguier F., Hamon M., Kayser V. Differential effects of calcitonin gene-related peptide receptor blockade by olcegepant on mechanical allodynia induced by ligation of the infraorbital nerve vs the sciatic nerve in the rat. Pain. 2012;153:1939–1948. doi: 10.1016/j.pain.2012.06.009. [DOI] [PubMed] [Google Scholar]
- 93.A Abd-Elsayed A., Ikeda R., Jia Z., Ling J., Zuo X., Li M., Gu J.G. KCNQ channels in nociceptive cold-sensing trigeminal ganglion neurons as therapeutic targets for treating orofacial cold hyperalgesia. Mol. Pain. 2015;11 doi: 10.1186/s12990-015-0048-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 94.Deseure K., Hans G. Differential drug effects on spontaneous and evoked pain behavior in a model of trigeminal neuropathic pain. J. Pain Res. 2017;10:279–286. doi: 10.2147/JPR.S124526. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 95.Zhang M., Hu M., A Montera M., Westlund K.N. Sustained relief of trigeminal neuropathic pain by a blood–brain barrier penetrable PPAR gamma agonist. Mol. Pain. 2019;15:1744806919884498. doi: 10.1177/1744806919884498. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 96.Zhang L., Ma Z., Wu Z., Jin M., An L., Xue F. Curcumin Improves Chronic Pain Induced Depression Through Regulating Serum Metabolomics in a Rat Model of Trigeminal Neuralgia. J. Pain Res. 2020;13:3479–3492. doi: 10.2147/JPR.S283782. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 97.Chen R.-W., Liu H., An J.-X., Qian X.-Y., Jiang Y.-D., Cope D.K., Williams J.P., Zhang R., Sun L.-N. Cognitive effects of electro-acupuncture and pregabalin in a trigeminal neuralgia rat model induced by cobra venom. J. Pain Res. 2017;10:1887–1897. doi: 10.2147/JPR.S140840. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 98.Park J., Trinh V.N., Sears-Kraxberger I., Li K.-W., Steward O., Luo Z.D. Synaptic ultrastructure changes in trigeminocervical complex posttrigeminal nerve injury. J. Comp. Neurol. 2016;524:309–322. doi: 10.1002/cne.23844. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 99.Alvarez P., Brun A., Labertrandie A., Lopez J., Correa A., Constandil L., Hernández A., Pelissier T. Antihyperalgesic effects of clomipramine and tramadol in a model of posttraumatic trigeminal neuropathic pain in mice. J. Orofac. Pain. 2011;25:354–363. [PubMed] [Google Scholar]
- 100.Latrémolière A., Mauborgne A., Masson J., Bourgoin S., Kayser V., Hamon M., Pohl M. Differential Implication of Proinflammatory Cytokine Interleukin-6 in the Development of Cephalic versus Extracephalic Neuropathic Pain in Rats. J. Neurosci. 2008;28:8489–8501. doi: 10.1523/JNEUROSCI.2552-08.2008. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 101.Vasovic D., Divović B., Treven M., Knutson D.E., Steudle F., Scholze P., Obradović A., Fabjan J., Brković B., Sieghart W., et al. Trigeminal neuropathic pain development and maintenance in rats are suppressed by a positive modulator of α6 GABA A receptors. Eur. J. Pain. 2019;23:973–984. doi: 10.1002/ejp.1365. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 102.Liang Y.-C., Huang C.-C., Hsu K.-S. The synthetic cannabinoids attenuate allodynia and hyperalgesia in a rat model of trigeminal neuropathic pain. Neuropharmacology. 2007;53:169–177. doi: 10.1016/j.neuropharm.2007.04.019. [DOI] [PubMed] [Google Scholar]
- 103.Nakai K., Nakae A., Oba S., Mashimo T., Ueda K. 5-HT2C receptor agonists attenuate pain-related behaviour in a rat model of trigeminal neuropathic pain. Eur. J. Pain. 2010;14:999–1006. doi: 10.1016/j.ejpain.2010.04.008. [DOI] [PubMed] [Google Scholar]
- 104.dos Reis R.C., Kopruszinski C.M., Nones C.F.M., Aguiar D.A., Chichorro J.G. The opposing contribution of neurotrophin-3 and nerve growth factor to orofacial heat hyperalgesia in rats. Behav. Pharmacol. 2020;31:27–33. doi: 10.1097/FBP.0000000000000503. [DOI] [PubMed] [Google Scholar]
- 105.Lim E.J., Jeon H.J., Yang G.Y., Lee M.K., Ju J.S., Han S.R., Ahn D.K. Intracisternal administration of mitogen-activated protein kinase inhibitors reduced mechanical allodynia following chronic constriction injury of infraorbital nerve in rats. Prog. Neuro-Psychopharmacol. Biol. Psychiatry. 2007;31:1322–1329. doi: 10.1016/j.pnpbp.2007.05.016. [DOI] [PubMed] [Google Scholar]
- 106.Melo L., Panchalingam V., Cherkas P., Campos A., Avivi-Arber L., Sessle B. (−)-α-Bisabolol reduces nociception and trigeminal central sensitisation in acute orofacial neuropathic pain induced by infraorbital nerve injury. Life Sci. 2019;227:122–128. doi: 10.1016/j.lfs.2019.04.032. [DOI] [PubMed] [Google Scholar]
- 107.Constandil L., Goich M., Hernández A., Bourgeais L., Cazorla M., Hamon M., Villanueva L., Pelissier T. Cyclotraxin-B, a New TrkB Antagonist, and Glial Blockade by Propentofylline, Equally Prevent and Reverse Cold Allodynia Induced by BDNF or Partial Infraorbital Nerve Constriction in Mice. J. Pain. 2012;13:579–589. doi: 10.1016/j.jpain.2012.03.008. [DOI] [PubMed] [Google Scholar]
- 108.Luiz A., Schroeder S., Rae G., Calixto J., Chichorro J. Contribution and interaction of kinin receptors and dynorphin A in a model of trigeminal neuropathic pain in mice. Neuroscience. 2015;300:189–200. doi: 10.1016/j.neuroscience.2015.05.015. [DOI] [PubMed] [Google Scholar]
- 109.He S.-Q., Li Z., Chu Y.-X., Han L., Xu Q., Li M., Yang F., Liu Q., Tang Z., Wang Y., et al. MrgC agonism at central terminals of primary sensory neurons inhibits neuropathic pain. Pain. 2014;155:534–544. doi: 10.1016/j.pain.2013.12.008. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 110.Bista P., Imlach W.L. Pathological Mechanisms and Therapeutic Targets for Trigeminal Neuropathic Pain. Medicines. 2019;6:91. doi: 10.3390/medicines6030091. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 111.Dib-Hajj S.D., Black J.A., Waxman S.G. Voltage-Gated Sodium Channels: Therapeutic Targets for Pain. Pain Med. 2009;10:1260–1269. doi: 10.1111/j.1526-4637.2009.00719.x. [DOI] [PubMed] [Google Scholar]
- 112.Zakrzewska J.M. Medical management of trigeminal neuropathic pains. Expert Opin. Pharmacother. 2010;11:1239–1254. doi: 10.1517/14656561003767449. [DOI] [PubMed] [Google Scholar]
- 113.Bates D., Schultheis B.C., Hanes M.C., Jolly S.M., Chakravarthy K.V., Deer T.R., Levy R.M., Hunter C.W. A Comprehensive Algorithm for Management of Neuropathic Pain. Pain Med. 2019;20:S2–S12. doi: 10.1093/pm/pnz075. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 114.Fried K., Hansson P.T. Animal models of trigeminal neuralgia: A commentary. Mol. Pain. 2020;16:1744806920980538. doi: 10.1177/1744806920980538. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 115.Leal P.R.L., Hermier M., Souza M.A., Cristino-Filho G., Froment J.C., Sindou M. Visualization of Vascular Compression of the Trigeminal Nerve with High-Resolution 3T MRI: A Prospective Study Comparing Preoperative Imaging Analysis to Surgical Findings in 40 Consecutive Patients Who Underwent Microvascular Decompression for Trigeminal Neuralgia. Neurosurgery. 2011;69:15–26. doi: 10.1227/neu.0b013e318212bafa. [DOI] [PubMed] [Google Scholar]
- 116.Luo D., Zhang T., Zuo C.-X., Zuo Z.-F., Li H., Wu S.-X., Wang W., Li Y.-Q. An animal model for trigeminal neuralgia by compression of the trigeminal nerve root. Pain Physician. 2012;15:187–196. [PubMed] [Google Scholar]
- 117.Jeon H.J., Han S.R., Lim K.H., A Won K., Bae Y.C., Ahn D.K. Intracisternal Administration of NR2 Subunit Antagonists Attenuates the Nociceptive Behavior and p-p38 MAPK Expression Produced by Compression of the Trigeminal Nerve Root. Mol. Pain. 2011;7 doi: 10.1186/1744-8069-7-46. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 118.Yeomans D.C., Klukinov M. A Rodent Model of Trigeminal Neuralgia. Adv. Struct. Safety Stud. 2012;851:121–131. doi: 10.1007/978-1-61779-561-9_8. [DOI] [PubMed] [Google Scholar]
- 119.Luo D., Luo L., Lin R., Lin L., Lin Q. Brain-derived neurotrophic factor and Glial cell line-derived neurotrophic factor expressions in the trigeminal root entry zone and trigeminal ganglion neurons of a trigeminal neuralgia rat model. Anat. Rec. Adv. Integr. Anat. Evol. Biol. 2020;303:3014–3023. doi: 10.1002/ar.24364. [DOI] [PubMed] [Google Scholar]
- 120.Lin R., Luo L., Gong Y., Zheng J., Wang S., Du J., Luo D. Immunohistochemical analysis of histone H3 acetylation in the trigeminal root entry zone in an animal model of trigeminal neuralgia. J. Neurosurg. 2019;131:828–838. doi: 10.3171/2018.5.JNS172948. [DOI] [PubMed] [Google Scholar]
- 121.Luo D., Lin R., Luo L., Li Q., Chen T., Qiu R., Li Y. Glial Plasticity in the Trigeminal Root Entry Zone of a Rat Trigeminal Neuralgia Animal Model. Neurochem. Res. 2019;44:1893–1902. doi: 10.1007/s11064-019-02824-2. [DOI] [PubMed] [Google Scholar]
- 122.Jeon H.J., Han S.R., Park M.K., Yang K.Y., Bae Y.C., Ahn D.K. A novel trigeminal neuropathic pain model: Compression of the trigeminal nerve root produces prolonged nociception in rats. Prog. Neuro-Psychopharmacol. Biol. Psychiatry. 2012;38:149–158. doi: 10.1016/j.pnpbp.2012.03.002. [DOI] [PubMed] [Google Scholar]
- 123.Cruccu G., Gronseth G., Alksne J., Argoff C., Brainin M., Burchiel K., Nurmikko T., Zakrzewska J.M. AAN-EFNS guidelines on trigeminal neuralgia management. Eur. J. Neurol. 2008;15:1013–1028. doi: 10.1111/j.1468-1331.2008.02185.x. [DOI] [PubMed] [Google Scholar]
- 124.Do T.M., Unis G.D., Ba N.K., Ananth A., McCoul E.D. Neuromodulators for Atypical Facial Pain and Neuralgias: A Systematic Review and Meta-Analysis. Laryngoscope. 2021;131:1235–1253. doi: 10.1002/lary.29162. [DOI] [PubMed] [Google Scholar]