Trigeminal Injury Research Articles

Medullary neural circuit regeneration after trigeminal nerve transection.

The inferior alveolar nerve (IAN) comprises several types of sensory fibers. To clarify whether each type of primary afferent is regenerated comparably after injury, we developed a model of complete IAN transection (IANX) in mice. A retrograde tracer, fluoro-gold, injected into the mental skin was transferred to the cell bodies of a subset of isolectin B4 (IB4)-binding (non-peptidergic C) or CGRP-positive (peptidergic C) neurons at 2 weeks post-axotomy, indicating that the injured C afferents had regenerated anatomically. IANX led to a decrease of IB4-binding and CGRP immunoreactivity (IR) in the trigeminal ganglion (TG) and within the trigeminal spinal subnucleus caudalis (Vc) (i.e. terminals of the central branch of TG neurons). Two weeks after IANX, the reduction in IB4-binding activity and CGRP expression in the TG recovered to the control level; however, IB4-binding within the Vc did not, suggesting that central branch non-peptidergic neurons remained impaired. Two weeks after IANX, pinching or heat stimulus-induced extracellular signal-regulated kinase phosphorylation (pERK) was restored to the control level, but in the case of pinch stimulation the distribution pattern of pERK-IR cells was altered in the Vc. Taken together, our results support the possibility that peptidergic neurons regenerate more efficiently than non-peptidergic neurons after trigeminal nerve injury.

Histone deacetylase inhibitors prevent persistent hypersensitivity in an orofacial neuropathic pain model.

Chronic orofacial pain is a significant health problem requiring identification of regulating processes. Involvement of epigenetic modifications that is reported for hindlimb neuropathic pain experimental models, however, is less well studied in cranial nerve pain models. Three independent observations reported here are the (1) epigenetic profile in mouse trigeminal ganglia (TG) after trigeminal inflammatory compression (TIC) nerve injury mouse model determined by gene expression microarray, (2) H3K9 acetylation pattern in TG by immunohistochemistry, and (3) efficacy of histone deacetylase (HDAC) inhibitors to attenuate development of hypersensitivity. After TIC injury, ipsilateral whisker pad mechanical sensitization develops by day 3 and persists well beyond day 21 in contrast to sham surgery. Global acetylation of H3K9 decreases at day 21 in ipsilateral TG . Thirty-four genes are significantly (p < 0.05) overexpressed in the ipsilateral TG by at least two-fold at either 3 or 21 days post-trigeminal inflammatory compression injury. The three genes most overexpressed three days post-trigeminal inflammatory compression nerve injury are nerve regeneration-associated gene ATF3, up 6.8-fold, and two of its regeneration-associated gene effector genes, Sprr1a and Gal, up 174- and 25-fold, respectively. Although transcription levels of 25 of 32 genes significantly overexpressed three days post-trigeminal inflammatory compression return to constitutive levels by day 21, these three regeneration-associated genes remain significantly overexpressed at the later time point. On day 21, when tissues are healed, other differentially expressed genes include 39 of the top 50 upregulated and downregulated genes. Remarkably, preemptive manipulation of gene expression with two HDAC inhibitors (HDACi's), suberanilohydroxamic acid (SAHA) and MS-275, reduces the magnitude and duration of whisker pad mechanical hypersensitivity and prevents the development of a persistent pain state. These findings suggest that trigeminal nerve injury leads to epigenetic modifications favoring overexpression of genes involved in nerve regeneration and that maintaining transcriptional homeostasis with epigenetic modifying drugs could help prevent the development of persistent pain.

Role of MR Neurography for the Diagnosis of Peripheral Trigeminal Nerve Injuries in Patients with Prior Molar Tooth Extraction.

Clinical neurosensory testing is an imperfect reference standard to evaluate molar tooth extraction related peripheral trigeminal neuropathy. The purpose was to evaluate the diagnostic accuracy of MR neurography in this domain and correlation with neurosensory testing and surgery. In this retrospective study, nerve caliber, T2 signal intensity ratio, and contrast-to-noise ratios were recorded by 2 observers using MR neurography for bilateral branches of the peripheral trigeminal nerve, the inferior alveolar and lingual nerves. Patient demographics and correlation of the MR neurography findings with the Sunderland classification of nerve injury and intraoperative findings of surgical patients were obtained. Among 42 patients, the mean ± SD age for case and control patients were 35.8 ± 10.2 years and 43.2 ± 11.5 years, respectively, with male-to-female ratios of 1:1.4 and 1:5, respectively. Case subjects (peripheral trigeminal neuropathy or injury) had significantly larger differences in nerve thickness, T2 signal intensity ratio, and contrast-to-noise ratios than control patients for the inferior alveolar nerve and lingual nerve (P = .01 and .0001, .012 and .005, and .01 and .01, respectively). Receiver operating characteristic analysis showed a significant association among differences in nerve thickness, T2 signal intensity ratio, and contrast-to-noise ratios and nerve injury (area under the curve, 0.83-0.84 for the inferior alveolar nerve and 0.77-0.78 for the lingual nerve). Interobserver agreement was good for the inferior alveolar nerve (intraclass correlation coefficient, 0.70-0.79) and good to excellent for the lingual nerve (intraclass correlation coefficient, 0.75-0.85). MR neurography correlations with respect to clinical neurosensory testing and surgical classifications were moderate to good. Pearson correlation coefficients of 0.68 and 0.81 and κ of 0.60 and 0.77 were observed for differences in nerve thickness. MR neurography can be reliably used for the diagnosis of injuries to the peripheral trigeminal nerve related to molar tooth extractions, with good to excellent correlation of imaging with clinical findings and surgical results.

Role of KCNQ2 channels in orofacial cold sensitivity: KCNQ2 upregulation in trigeminal ganglion neurons after infraorbital nerve chronic constrictive injury.

Sensitivity to cooling temperatures often becomes heightened in orofacial regions leading to orofacial cold allodynia/hyperalgesia after chronic trigeminal nerve injury. KCNQ2 channels are involved in controlling excitability of primary afferent neurons and thereby regulate sensory functions under both physiological and pathological conditions. In the present study, we sought to determine whether KCNQ2 channels in trigeminal nerves are involved in regulating orofacial operant behavioral responses to cooling stimulation. We also sought to examine whether chronic trigeminal nerve injury may alter KCNQ2 channel expression in trigeminal ganglions. Using the orofacial operant tests, animals show cold allodynia/hyperalgesia in orofacial regions following infraorbital nerve chronic constrictive injury (ION-CCI), which could be alleviated by subcutaneous administration of retigabine, a KCNQ2 activator. In contrast, subcutaneous administration of the KCNQ2 inhibitor XE991 directly elicits cold allodynia/hyperalgesia in sham animals. Using immunostaining, we show that KCNQ2 channels are primarily expressed in small-sized TG neurons. Interestingly, KCNQ2 channel expression becomes significantly upregulated in TG neurons following the ION-CCI. Our results suggest that KCNQ2 channels are involved in regulating orofacial cold sensitivity. Upregulation of KCNQ2 channels may be a compensatory change in attempting to limit injury-induced trigeminal hyperexcitability.

Classification of Post-Traumatic Trigeminal Nerve Injuries Comparing MR Neurography with Clinical Neurosensory Tests and Surgical Findings

Classification of Post-Traumatic Trigeminal Nerve Injuries Comparing MR Neurography with Clinical Neurosensory Tests and Surgical Findings

Patulous Eustachian Tube and Otitis Media With Effusion as Complications After Trigeminal Nerve Injury

To describe three patients of patulous Eustachian tube (pET) after trigeminal nerve injury and to demonstrate for the first time their magnetic resonance imaging (MRI) findings to hypothesize the mechanism of the pET after trigeminal nerve injury. Three patients presented with autophony after trigeminal nerve injury caused by the removal of intracranial tumors. Clinical patient records, audiological data, and MRI. Each patient initially developed transient otitis media with effusion (OME) within a few months after surgery and subsequently developed pET. The MRI of the three patients when they developed pET demonstrated atrophy and fat infiltration of the muscles innervated by the mandibular branch of the trigeminal nerve. All three patients transiently manifested OME before pET was diagnosed. Based on the MRI findings and anatomical considerations, this chronological transition from OME to pET was speculated as an initial motor paralysis of the tensor veli palatini muscle, followed by volume decrease of the muscles in the vicinity of the ET due to denervation atrophy and fat infiltration, which resulted in ET closing failure.

Phenotypic change in trigeminal ganglion neurons associated with satellite cell activation via extracellular signal-regulated kinase phosphorylation is involved in lingual neuropathic pain.

Iatrogenic trigeminal nerve injuries remain a common and complex clinical problem. Satellite glial cell (SGC) activation, associated phosphorylation of extracellular signal-regulated kinase (ERK), and neuropeptide expression in the trigeminal ganglion (TG) are known to be involved in trigeminal neuropathic pain related to trigeminal nerve injury. However, the involvement of these molecules in orofacial neuropathic pain mechanisms is still unknown. Phosphorylation of ERK1/2 in lingual nerve crush (LNC) rats was observed in SGCs. To evaluate the role of neuron-SGC interactions under neuropathic pain, calcitonin gene-related peptide (CGRP)-immunoreactive (IR), phosphorylated ERK1/2 (pERK1/2)-IR and glial fibrillary acidic protein (GFAP)-IR cells in the TG were studied in LNC rats. The number of CGRP-IR neurons and neurons encircled with pERK1/2-IR SGCs was significantly larger in LNC rats compared with sham rats. The percentage of large-sized CGRP-IR neurons was significantly higher in LNC rats. The number of CGRP-IR neurons, neurons encircled with pERK1/2-IR SGCs, and neurons encircled with GFAP-IR SGCs was decreased following CGRP receptor blocker CGRP8-37 or mitogen-activated protein kinase/ERK kinase 1 inhibitor PD98059 administration into the TG after LNC. Reduced thresholds to mechanical and heat stimulation to the tongue in LNC rats were also significantly recovered following CGRP8-37 or PD98059 administration. The present findings suggest that CGRP released from TG neurons activates SGCs through ERK1/2 phosphorylation and TG neuronal activity is enhanced, resulting in the tongue hypersensitivity associated with lingual nerve injury. The phenotypic switching of large myelinated TG neurons expressing CGRP may account for the pathogenesis of tongue neuropathic pain.

A Survey of the Opinion and Experience of UK Dentists Part 3: An Evidence-Based Protocol of Surgical Risk Management Strategies in the Mandible.

Implant surgery in the mandible can cause serious complications that can be life threatening. The incidence and cause of iatrogenic trigeminal nerve injury (TNI) related to dental implant surgery was investigated in a survey of the opinion and experience of the UK dentists and reported by the authors in part 1 of this series of articles. Part 2 reported on the risk assessment and management of implant-related inferior alveolar nerve (IAN), mental nerve (MN), and lingual nerve (LN) injuries. This article evaluates the significance of these findings and recommends an evidence-based protocol of risk management strategies to reduce the risk of TNI related to dental implant surgery. A survey was distributed among 405 dentists attending an Association of Dental Implantology (ADI) congress, of which 187 completed the survey. In this study, the strategies to manage the risk of TNI included unilateral staging of implant placement (57%) and identification the MN when placing implants (43%). Twelve percent used drill stops when operating in the mandible. Nineteen dentists used steroids (eg, dexamethasone) routinely preoperatively and postoperatively. Twenty-six dentists used basic cone beam computed tomography minimally invasive techniques, and 70% encountered a large anterior loop of the IAN. Most dentists (76%) allowed a 2- to 4-mm safety zone radiologically above the IAN when placing implants, and over half of the responders (56%) used implants that were 10 mm in length. Given the elective nature of implant surgery, TNI should be fully avoidable. The evidence suggest that TNI can be minimized with meticulous attention to accurate assessment and surgical planning as well as carrying out the surgery with a high degree of precision. In part 3 of their series of articles, the authors presented an evidence-based protocol that comprises preoperative, intraoperative, and postoperative risk management strategies for dental implant surgical procedures in the mandible.

Mandibular division trigeminal nerve injuries following primary endodontic treatment. A case series.

The aim of this study is to report a series of patients with mandibular division trigeminal nerve (V3 ) injuries secondary to endodontic treatment, evaluate presentation characteristics and identify prevention strategies. This article describes a retrospective review of patients referred to a tertiary clinic 2007-2015 with V3 injury following endodontic treatment. The sample included 12 male and 16 female patients with a mean age of 41.5years. Sixteen cases presented following endodontic treatment of the first and second molar, premolar teeth in eight cases and canine in two cases.Fifteen patients reported immediate post-operative symptoms, in eleven cases there was a 24-48h asymptomatic period. The average referral delay was 23.1months. Twenty patients had permanent neuropathy. Four patients experienced resolution of symptoms within 8weeks. V3 injury following endodontic treatment is rare but can result in permanent neuropathy and functional impairment. This can be avoided through comprehensive pre-operative radiographic examination, identification and referral of high-risk cases.

Bovine lactoferrin reduces extra-territorial facial allodynia/hyperalgesia following a trigeminal nerve injury in the rat

There is an urgent clinical need for an effective therapeutic agent to treat neuropathic pain. This study explored whether intrathecal administration of bovine lactoferrin (bLF), in combination with signal transduction pathway inhibition or an inflammatory cytokine production, results in reduced allodynia/hyperalgesia in the whisker pad area following mental nerve transection (MNT) in rats. Rats were intrathecally infused with bLF, lipopolysaccharide from Rhodobacter sphaeroides (LPS-RS), an antagonist of Toll-like receptor 4 (TLR4), or interleukin (IL)-18 binding protein (BP). bLF attenuated allodynia/hyperalgesia and blocked upregulation of phosphorylated (p)-p38 mitogen-activated protein kinase (MAPK), p-nuclear factor (NF)-κB p65, p-IκB kinase, and IL-18 in the trigeminal subnucleus caudalis (Vc). Microglia expressed p-p38 and astrocytes expressed p-NF-κB p65 in the Vc following MNT. LPS-RS had the same effects as bLF, except for attenuation of p-NF-κB p65. IL-18BP attenuated allodynia/hyperalgesia and IL-18 upregulation in the Vc. These results suggest that bLF suppresses IL-18 production, which is involved in allodynia/hyperalgesia following MNT, by inhibiting TLR4-derived p38 MAPK activation in microglia. Additionally, binding of bLF to tumor necrosis factor receptor-associated factor 6 might result in inhibition of p38 MAPK and NF-κB activation. The findings suggest that bLF could serve as a potent therapeutic agent for neuropathic pain.

Neuropathic orofacial pain: Facts and fiction.

Definition and taxonomy This review deals with neuropathic pain of traumatic origin affecting the trigeminal nerve, i.e. painful post-traumatic trigeminal neuropathy (PTTN). Symptomatology The clinical characteristics of PTTN vary considerably, partly due to the type and extent of injury. Symptoms involve combinations of spontaneous and evoked pain and of positive and negative somatosensory signs. These patients are at risk of going through unnecessary dental/surgical procedures in the attempt to eradicate the cause of the pain, due to the fact that most dentists only rarely encounter PTTN. Epidemiology Overall, approximately 3% of patients with trigeminal nerve injuries develop PTTN. Patients are most often female above the age of 45 years, and both physical and psychological comorbidities are common. Pathophysiology PTTN shares many pathophysiological mechanisms with other peripheral neuropathic pain conditions. Diagnostic considerations PTTN may be confused with one of the regional neuralgias or other orofacial pain conditions. For intraoral PTTN, early stages are often misdiagnosed as odontogenic pain. Pain management Management of PTTN generally follows recommendations for peripheral neuropathic pain. Expert opinion International consensus on classification and taxonomy is urgently needed in order to advance the field related to this condition.

Thermal Perception as a Key Factor for Assessing Effects of Trigeminal Nerve Injury.

To conduct a functional examination using multimodal exploration of a sample of patients with iatrogenic trigeminal nerve injury to understand the underlying mechanisms of neuropathic pain following trigeminal nerve injury. Subjective and objective symptoms and responses to thermal and electrical quantitative sensory testing (QST) were evaluated in 85 patients with unilateral trigeminal nerve injury. Objective symptoms were measured by seven clinical sensory tests. Thermal QST included cold detection threshold (CDT), warm detection threshold (WDT), and heat pain threshold (HPT). Electrical current perception threshold was performed with electrical stimuli of 2,000, 250, and 5 Hz. The time since injury was included as a possible independent variable. The data were analyzed using chi-square test, independent t test, Mann Whitney U test, one-way analysis of variance (ANOVA), and Kruskal-Wallis test. Further analyses with Pearson correlation analysis, Spearman rank correlation analysis, and cluster analysis were applied. Unlike objective symptoms, thermal and electrical QST values and subjective symptoms did not improve in patients with an old injury. Thermal QST, particularly WDT, showed the highest positive correlation with subjective symptoms in all tests. Cluster analysis of the thermal QST values identified three subgroups: cluster 1, which was characterized by prominent cold and warm hypoesthesia; cluster 2, which presented elevated WDT; and cluster 3, which showed the smallest thermal differences for all thermal variables but had the highest proportion of neuropathic pain. These findings have demonstrated that thermal QST is a suitable tool for evaluating and characterizing the sensory effects of trigeminal nerve injury. Three subgroups with different thermosensory profiles showed that the less the damage, the more neuropathic pain occurs. The loss of warm perception in particular might play a pivotal role in the chronicity and severity of subjective sensory symptoms.

A Survey of the Opinion and Experience of UK Dentists: Part 2: Risk Assessment Strategies and the Management of Iatrogenic Trigeminal Nerve Injuries Related to Dental Implant Surgery.

Dental implant-related iatrogenic injuries are proportionally increasing with dental implant surgery. This study assessed the experience of implant-related trigeminal nerve (TG) injuries among UK dentists. Risk management strategies and management of implant-related inferior alveolar nerve (IAN), mental nerve (MN), and lingual nerve injuries were investigated. A survey was distributed among 405 dentists attending an Association of Dental Implantology (ADI) congress, of which 187 completed the survey. Most dentists (76% of 134 responses) allowed a 2 to 4 mm safety zone radiologically above the IAN when placing implants, and over half of the responders (56%) used implants that were 10 mm in length. The most frequent precautionary measure used by 73 (80%) responders was antibiotic coverage routinely to reduce the risk of infection when placing grafts in the posterior mandible. Other precautionary measures included unilateral staging of implant placement (57%), and 43% always identified the MN when placing implants. Nineteen dentists used steroids (eg, dexamethasone) routinely preoperatively and postoperatively. Twenty-six dentists used basic cone-beam CT (CBCT) minimally invasive techniques, and drill stops during implant placement were used by 14 responders. Although it is not highly recommended, steroids were used to manage the neuropathic pain and discomfort experienced by patients with IAN injuries in 40% of cases. Further training of dentists undertaking implant surgery is required so that they acquire up-to-date and evidence-based knowledge and skills in the prevention, diagnosis, and management of dental implant-related TG injuries. This training should also involve the justification and interpretation of CBCTs.

A case series of trigeminal nerve injuries caused by periapical lesions of mandibular teeth.

Aims Periapical lesions have been implicated in mandibular trigeminal sensory neuropathy. This study aimed to report on a case series of consecutive patients presenting with mandibular division trigeminal nerve injuries (TNI) caused by periapical lesions. Common presenting characteristics and possible strategies for management were also investigated.Materials and methods A retrospective study of 22 patients with TNI caused by periapical lesions. Data were extracted from patient records and analysed using Microsoft Excel and SPSS. Factors associated with TNI resolution were assessed using Student's t-Tests and one-way Analysis of Variance (ANOVA), where P <0.05 indicated statistical significance.Results Twenty-one patients had inferior alveolar nerve injuries (IANI) and one had a lingual nerve injury (LNI). The most commonly affected teeth were the first molars (11 patients; 50%). TNI symptoms included numbness, pain and/or paraesthesia. IANI resolved completely among five patients within a mean time of 4.7 months (range 1.5-12 months). Patients who showed complete resolution had the affected teeth extracted or primary endodontic treatment with antibiotics.Conclusions Patients with TNI caused by periapical lesions can suffer significantly from combined numbness, pain and paraesthesia. Resolution of these injuries may be maximised upon early diagnosis and treatment of the periapical lesion by tooth extraction or primary endodontic treatment.

Longitudinal treatment outcomes of microsurgical repair of trigeminal nerve injury from lower third molar surgery

Longitudinal treatment outcomes of microsurgical repair of trigeminal nerve injury from lower third molar surgery

Efficacy of Acellular Nerve Allografts in Trigeminal Nerve Reconstruction

During trigeminal nerve repair, a gap is sometimes encountered that prevents the tension-free apposition of nerve endings. The use of a processed acellular nerve allograft is a novel technique that shows promise in overcoming this problem. The goal of the present study was to support the slowly evolving body of evidence that acellular processed nerve allografts (Avance; Axogen, Alachua, FL) are a viable alternative to autogenous nerve grafting and the use of conduits for reconstructing defects of the trigeminal nerve. The study design consisted of a retrospective review of the medical records of patients referred to Rutgers School of Dental Medicine for management of trigeminal nerve injuries from July 2008 to August 2014. Sixteen patients met the inclusion criteria for the present study. All patients underwent nerve grafting using a processed nerve allograft. All operations were performed by the same surgeon (V.Z.). Serial neurosensory testing was performed by 1 clinician (V.Z.) in a standardized fashion. The primary outcome variable was the interval to functional sensory recovery as defined by the Medical Research Council Scale. The participants ranged in age from 16 to 62years (mean 32). Of the 16 patients, 12 were female (75%) and 4 were male (25%), and 3 were smokers (18.75%) and 13 were nonsmokers (81.25%). One half of the patients (n= 8; 50%) underwent surgery on the inferior alveolar nerve, and 8 (50%) underwent surgery on the lingual nerve. The most common mechanism of injury was impacted third molar removal (n= 9; 56.25%) Of the 16 patients, 15 (93.75%) achieved functional sensory recovery during the study period. The results of the present study support the hypothesis that processed nerve allografts are effective in reconstructing small (<2-cm) trigeminal nerve defects.

An Improved Rodent Model of Trigeminal Neuropathic Pain by Unilateral Chronic Constriction Injury of Distal Infraorbital Nerve.

The orofacial pain caused by trigeminal nerve damage is severe and perhaps more debilitating than other types of neuropathic pain. However, studies on trigeminal neuropathic pain remain limited. This is largely because of the lack of proper animal models because of the complexity of the existing surgical procedures required to induce trigeminal nerve injury. Our improved dIoN-CCI model is likely to make it more accessible to study the cellular and molecular mechanisms of neuropathic pain caused by trigeminal nerve damage.

Neuronal plasticity of trigeminal ganglia in mice following nerve injury.

BackgroundNerve injury may induce neuropathic pain. In studying the mechanisms of orofacial neuropathic pain, attention has been paid to the plastic changes that occur in the trigeminal ganglia (TGs) and nucleus in response to an injury of the trigeminal nerve branches. Previous studies have explored the impact of sciatic nerve injury on dorsal root ganglia (DRGs) and it has shown dramatic changes in the expression of multiple biomarkers. In large, the changes in biomarker expression in TGs after trigeminal nerve injury are similar to that in DRGs after sciatic nerve injury. However, important differences exist. Therefore, there is a need to study the plasticity of biomarkers in TGs after nerve injury in the context of the development of neuropathic pain-like behaviors.AimThe aim of this study was to investigate the plasticity of biomarkers associated with chronic persistent pain in TGs after trigeminal nerve injury.Materials and methodsTo mimic the chronic nature of the disorder, we used an intraoral procedure to access the infraorbital nerve (ION) and induced a nerve injury in mice. Immunohistochemistry and quantification were used for revealing the expression level of each biomarker in TGs after nerve injury.ResultsTwo weeks after partial ION injury, immunohistochemistry results showed strongly upregulated expressions of activating transcription factor 3 and neuropeptide Y (NPY) in the ipsilateral TGs. Microglial cells were also activated after nerve injury. In regard to positive neuronal profile counting, however, no significant difference in expression was observed in galanin, substance P, calcitonin gene-related peptide, neuronal nitric oxide synthase, phosphorylated AKT, or P2X3 in ipsilateral TGs when compared to contralateral TGs.ConclusionIn this study, the expression and regulation of biomarkers in TGs have been observed in response to trigeminal nerve injury. Our results suggest that NPY and Iba1 might play crucial roles in the pathogenesis of orofacial neuropathic pain following this type of injury. Further investigations on the relevance of these changes may help to target suitable treatment possibilities for trigeminal neuralgia.

Pathophysiology and treatment of orofacial pain.

"Pain" is one of body defense mechanisms and crucial for the life support. However, orofacial pain such as myofascial pain syndrome, burning mouth syndrome and trigeminal neuralgia plays no part in body defense mechanisms and requires therapeutic intervention. Recent studies have indicated that plastic changes in the activities of trigeminal neurons, satellite glial cells in trigeminal ganglion, secondary neurons, microglia and astrocytes in trigeminal spinal subnucleus following orofacial inflammation and trigeminal nerve injury are responsible for orofacial pain mechanisms. Clinically, it is well known that the etiologic differential diagnosis which consists of careful history-taking and physical examination is essential for therapeutic decision in patients with orofacial pain. This report outlines the current knowledge on the pathophysiology, diagnosis, treatment of orofacial pain.

Neuron-glia interaction is a key mechanism underlying persistent orofacial pain.

Excitability of neurons in the trigeminal ganglion (TG), trigeminal spinal subnucleus caudalis (Vc), and upper cervical spinal cord (C1-C2) is greatly enhanced after orofacial inflammation and trigeminal nerve injury, and TG, Vc, and C1-C2 neurons remain sensitized long after such episodes. Sensitized neurons generate various molecules, which are released from nociceptive neurons in these areas and are involved in modulating the excitability of TG, Vc, and C1-C2 nociceptive neurons. Hyperexcitable nociceptive neurons also activate satellite glial cells in the TG and microglial cells and astrocytes in the Vc and C1-C2. Glial cell activation spreads throughout the TG, Vc, and C1-C2 and triggers the release of various molecules involved in modulating nociceptive neurons in TG, Vc, and C1-C2 neurons. These findings suggest that functional interaction between neurons and glial cells is critical in persistent orofacial pain associated with orofacial inflammation and trigeminal nerve injury.