Is it possible to predict neurosensory alterations in impacted lower third molar removal based on preoperative imaging procedures? A prospective cohort study / ¿Es posible predecir alteraciones neurosensoriales en la extracción del tercer molar inferior impactado basándose en procedimientos de imagen preoperatorios? Un estudio de cohorte prospectivo

Background: Surgical extraction of the lower third molar (LTM) may trigger neurosensory injury of the inferioralveolar nerve, making extraction a real challenge. This study set out to assess whether is it possible to predictneurosensory alterations from preoperative imaging.Material and Methods: A total of 99 patients underwent 124 impacted lower third molar (ILTM) surgeries. Priorto surgery, panoramic and CBCT images were evaluated in an attempt to predict a neurosensory disturbance.Preoperative data (ILTM position, panoramic radiograph signs, inferior alveolar nerve (IAN) location and its con-tact with the ILTM roots) and intra/postoperative findings (extraction difficulty and sensitivity alterations) wererecorded. Descriptive and bivariate data analysis was performed. Statistical comparison applied the chi-squaretest, Fisher test, and one-way ANOVA test. Statistical significance was established with a confidence interval (CI)of 95%.Results: In 4.03% of cases, patients experienced neurosensory alterations. Of 124 ILTM positions in panoramicradiographs, 76 cases were considered to exhibit a potential neurosensory risk as they presented two or more typesof superimposed relationships between ILTM and mandibular canal. Of these, alterations were reported in onlythree cases (3.95%). Of the 48 remaining ILTM images presenting only one sign, neurosensory alterations wereobserved in two cases (4.17%). No permanent alterations were recorded in any of the five cases observed.Conclusions: Within the limitations of the present study, prediction of neurosensory alterations prior to ILTMextraction by means of preoperative imaging did not show a significant statistical correlation with post-surgicalincidence. Nevertheless, interruption of the canal´s white line (ICWL) or a diversion of the canal (DC) may predictan increased risk of IAN injury.(AU)

Outcomes of Coronectomy and Total Odontectomy of Impacted Mandibular Third Molars.

OBJECTIVE: The aim of this research was to evaluate the surgical complications and neurosensory deficits after coronectomy and the complete removal of mandibular third molars. METHODS: The study sample included patients requiring surgical removal of mandibular third molars. A coronectomy was conducted on 220 teeth showing signs of close proximity to the inferior alveolar canal. A complete extraction was performed on 218 teeth with no risk signs. The patients were evaluated at 1 week and 1, 3, 6, 12, and 24 months after surgery for pain, swelling, neurologic deficit, dry socket, postoperative bleeding, infection, root migration, and eruption. RESULTS: No significant difference was noted in pain and swelling; however, bleeding and dry socket were significantly higher in the odontectomy group (P = .017). The inferior alveolar nerve deficit was higher in the odontectomy group (3.7%) than the coronectomy group (0.5%) (P = .017). The percentage and distance of root migration of coronectomised teeth at 3, 6, and 12 months were 60% (2.37 ± 0.96 mm), 66% (3.35 ± 0.86 mm), and 74% (3.85 ± 0.93 mm), respectively. CONCLUSIONS: Coronectomy is a safe procedure and should be performed when the roots are closely associated with the mandibular canal. Although root migration is common, the likelihood of root exposure is low and roots rarely need removal.

Involvement of interferon gamma signaling in spinal trigeminal caudal subnucleus astrocyte in orofacial neuropathic pain in rats with infraorbital nerve injury.

Background: Trigeminal nerve injury causes orofacial pain that can interfere with activities of daily life. However, the underlying mechanism remains unknown, and the appropriate treatment has not been established yet. This study aimed to examine the involvement of interferon gamma (IFN-γ) signaling in the spinal trigeminal caudal subnucleus (Vc) in orofacial neuropathic pain. Methods: Infraorbital nerve (ION) injury (IONI) was performed in rats by partial ION ligation. The head-withdrawal reflex threshold (HWT) to mechanical stimulation of the whisker pad skin was measured in IONI or sham rats, as well as following a continuous intracisterna magna administration of IFN-γ and a mixture of IFN-γ and fluorocitrate (inhibitor of astrocytes activation) in naïve rats, or an IFN-γ antagonist in IONI rats. The IFN-γ receptor immunohistochemistry and IFN-γ Western blotting were analyzed in the Vc after IONI or sham treatment. The glial fibrillary acid protein (GFAP) immunohistochemistry and Western blotting were also analyzed after administration of IFN-γ and the mixture of IFN-γ and fluorocitrate. Moreover, the change in single neuronal activity in the Vc was examined in the IONI, sham, and IONI group administered IFN-γ antagonist. Results: The HWT decreased after IONI. The IFN-γ and IFN-γ receptor were upregulated after IONI, and the IFN-γ receptor was expressed in Vc astrocytes. IFN-γ administration decreased the HWT, whereas the mixture of IFN-γ and fluorocitrate recovered the decrement of HWT. IFN-γ administration upregulated GFAP expression, while the mixture of IFN-γ and fluorocitrate recovered the upregulation of GFAP expression. IONI significantly enhanced the neuronal activity of the mechanical-evoked responses, and administration of an IFN-γ antagonist significantly inhibited these enhancements. Conclusions: IFN-γ signaling through the receptor in astrocytes is a key mechanism underlying orofacial neuropathic pain associated with trigeminal nerve injury. These findings will aid in the development of therapeutics for orofacial neuropathic pain.

Complicación en la colocación de implante dental con compromiso de nervio dentario inferior reporte de caso clínico, seguimiento de 3 años / Complication in the placement of dental implants with compromise of the inferior dental nerve clinical case report, 3-year follow-up

Introducción: Los accidentes o complicaciones durante la colocación de implantes dentales a pesar de la planeación quirúrgica deben ser manejados de manera inmediata y oportuna. Objetivo: Recomendar el mejor protocolo para manejar la lesión del nervio dentario inferior consecuencia de la colocación de implante dentario. Caso Clínico: Paciente asiste a clínica privada pararecibir atención odontológica de especialidad, edad 67 años, sexo femenino, presenta hipertensión arterial, resistencia a la insulina, premedicada con Hidronorol T y Metformina. Paciente informa deexodoncia de cuatro molares, colocaron inmediata de cuatro implantes dentales, sintió un adormecimiento del mentón con la perdida de efecto del anestèsico; 72 horas posterior se procedió a realizar tomografía Cone Bean, observándose implante contactando el nervio dentario inferior, planificándose de forma inmediata el retiro del implante dental. Resultados: Control a 3, 6, 9 meses, 1 , 2 y 3 años posterior a retiro de implante, aplicación de terapia farmacológica a base de corticoides, aines y vitamina B , con resultados favorables en el tratamiento de la parestesia. Conclusiones: La extracción del implante dental antes de las 72 horas y la terapia farmacológica adecuada resulto exitosa en el tratamiento de la lesión del nervio dentario inferior. (AU)

Introduction: Accidents or complications during the placement of dental implants despite surgical planning should be handled immediately and in a timely manner. Objective: To recommend the best protocol to manage the injury of the inferior dental nerve resulting from the placement of dental implant. Clinical Case: Patient attends private clinic to receive specialty dental care, age 67 years, female, presents arterial hypertension, insulin resistance, premedicated with Hydronorol T and Metformin. Pacientereports exodontics of four molars, immediate placement of four dental implants, felt a numbness of the chin with the loss of effct of the anesthetic; 72 hours later proceeded to perform Tomography Cone Bean, observing implant contacting the inferior dental nerve, immediately planning the removal of the dental implant. Results: Control at 3, 6, 9 months, 1, 2 and 3 years after implant removal, application of pharmacological therapy based on corticosteroids, NSAIDs and vitamin B, with favorable results in the treatment of paresthesia. Conclusions: The extraction of the dental implant before 72 hours and the appropriate pharmacological therapy was successful in the treatment of the lesion of the inferior dental nerve. (AU)

Age-related Changes in Trigeminal Ganglion Macrophages Enhance Orofacial Ectopic Pain After Inferior Alveolar Nerve Injury.

BACKGROUND/AIM: The ectopic pain associated with inferior alveolar nerve (IAN) injury has been reported to involve macrophage expression in the trigeminal ganglion (TG). However, the effect of age-related changes on this abnormal pain conditions are still unknown. This study sought to clarify the involvement of age-related changes in macrophage expression and phenotypic conversion in the TG and how these changes enhance ectopic mechanical allodynia after IAN transection (IANX). MATERIALS AND METHODS: We used senescence-accelerated mouse (SAM)-prone 8 (SAMP8) and SAM-resistance 1 (SAMR1) mice, which are commonly used to study ageing-related changes. Mechanical stimulation was applied to the whisker pad skin under light anaesthesia; the mechanical head withdrawal threshold (MHWT) was measured for 21 d post-IANX. We subsequently counted the numbers of Iba1 (macrophage marker)-immunoreactive (IR) cells, Iba1/CD11c (M1-like inflammatory macrophage marker)-co-IR cells, and Iba1/CD206 (M2-like anti-inflammatory macrophage marker)-co-IR cells in the TG innervating the whisker pad skin. After continuous intra-TG administration of liposomal clodronate Clophosome®-A (LCCA) to IANX-treated SAMP8-mice, the MHWT values of the whisker pad skin were examined. RESULTS: Five days post-IANX, the MHWT had significantly decreased in SAMP8 mice compared to SAMR1-mice. Iba1-IR and Iba1/CD11c-co-IR cell counts were significantly increased in SAMP8 mice compared to SAMR1 mice 5 d post-IANX. LCCA administration significantly restored MHWT compared to control-LCCA administration. CONCLUSION: Ectopic mechanical allodynia of whisker pad skin after IANX is exacerbated by ageing, which involves increases in M1-like inflammatory macrophages in the TG.

Pathophysiology of Post-Traumatic Trigeminal Neuropathic Pain.

Trigeminal nerve injury is one of the causes of chronic orofacial pain. Patients suffering from this condition have a significantly reduced quality of life. The currently available management modalities are associated with limited success. This article reviews some of the common causes and clinical features associated with post-traumatic trigeminal neuropathic pain (PTNP). A cascade of events in the peripheral and central nervous system function is involved in the pathophysiology of pain following nerve injuries. Central and peripheral processes occur in tandem and may often be co-dependent. Due to the complexity of central mechanisms, only peripheral events contributing to the pathophysiology have been reviewed in this article. Future investigations will hopefully help gain insight into trigeminal-specific events in the pathophysiology of the development and maintenance of neuropathic pain secondary to nerve injury and enable the development of new therapeutic modalities.

Mirogabalin alleviates nociceptive hypersensitivity without causing sedation in a mouse model of post-traumatic trigeminal neuropathy.

Post-traumatic trigeminal neuropathy (PTTN) is a chronic sensory disorder that afflicts patients with nerve injury caused by orofacial and dental surgery or cervicofacial trauma. Currently, effective treatment strategies for PTTN are lacking, and patients treated with conventional drugs for PTTN experience adverse effects such as drowsiness and drug addiction. In the present study, we investigated whether mirogabalin, a novel gabapentinoid, could be an effective treatment for PTTN induced by distal infraorbital nerve chronic constriction injury (dIoN-CCI) in the mouse. Increased facial grooming time and hyper-responsiveness to acetone were observed in dIoN-CCI mice. These pain-related behaviors were attenuated by intraperitoneal injection of mirogabalin. In particular, mirogabalin significantly diminished the increase in facial grooming time. The analgesic effect of mirogabalin injection started 45 min after the injection and persisted for 6 h. Additionally, 10 mg/kg mirogabalin did not affect locomotor activity in the open field test, suggesting that it does not cause sedation. Together, the current findings suggest that mirogabalin could be a valuable therapeutic drug for PTTN following orofacial surgeries without sedative side effects.

Anti-calcitonin gene-related peptide antibody attenuates orofacial mechanical and heat hypersensitivities induced by infraorbital nerve injury.

Currently, limited information regarding the role of calcitonin gene-related peptide (CGRP) in neuropathic pain is available. Intracerebroventricular administrations of an anti-CGRP antibody were performed in rats with infraorbital nerve ligation. Anti-CGRP antibody administration attenuated mechanical and heat hypersensitivities induced by nerve ligation and decreased the phosphorylated extracellular signal-regulated kinase expression levels in the trigeminal spinal subnucleus caudalis (Vc) following mechanical or heat stimulation. An increased CGRP immunoreactivity in the Vc appeared after nerve ligation. A decreased CGRP immunoreactivity resulted from anti-CGRP antibody administration. Our findings suggest that anti-CGRP antibody administration attenuates the symptoms of trigeminal neuropathic pain by acting on CGRP in the Vc.

Profiling thermal pain using quantitative sensory testing in patients with trigeminal nerve injury.

OBJECTIVES: To investigate the thermal pain phenotypes using QST in patients with unilateral trigeminal nerve injury and to explore whether these different thermal pain phenotypes are associated with clinical and psychophysical characteristics. METHODS: This retrospective study included 84 patients diagnosed with posttraumatic trigeminal neuropathy involving inferior alveolar nerve (IAN) and lingual nerve (LN). Data on clinical characteristics, subjective symptoms including hypoesthesia, dysesthesia, and allodynia, and objective signs using thermal QST were collected and explored. RESULTS: Three heat (heat hypoalgesia, heat hyperalgesia, and within normal range) and cold pain phenotypes (cold hypoalgesia, cold hyperalgesia, and within normal ranges) were identified, respectively. Thermal hypoalgesia was more frequently observed than thermal hyperalgesia. Heat hypoalgesia regardless of cold pain abnormalities appears to be associated with subjective negative symptoms, while thermal hyperalgesia seems to have little relationship with negative and positive symptoms. Thermal pain phenotypes were associated with loss of innocuous thermal sensation. Unlike heat pain phenotypes, cold pain phenotypes differed between IAN injury and LN injury. CONCLUSION: The thermal pain phenotypes identified in this study seem to be related to clinical and psychophysical findings differently. These results would be a good starting point for assessing posttraumatic trigeminal neuropathy and interpreting the thermal QST results.

Signs and symptoms, quality of life and psychosocial data in 1331 post-traumatic trigeminal neuropathy patients seen in two tertiary referral centres in two countries.

BACKGROUND: Post-traumatic trigeminal neuropathy (PTN) is a disturbance of function or pathological change of the trigeminal nerve branches following trauma and has an important impact on patient's quality of life (QoL). OBJECTIVES: To provide diagnostic data on PTN and illustrate differences in aetiology, injured nerve, pain distribution, sensory profile and QoL between PTN subgroups. METHODS: 1331 patients with painful or non-painful PTN were retrospectively reviewed in two centres, extracting demographic data, time and cause of trauma, clinical findings including signs and symptoms, basic neurosensory testing, imaging modalities, treatments, and QoL or psychosocial assessment. RESULTS: More females were represented (70%) than males. The inferior alveolar nerve was most frequently damaged (60%) followed by the lingual nerve (28%). Wisdom teeth removal was considered the main cause (48%). Pain was reported in 63% of patients and pain frequency increased with age without clinically significant gender differences. Numbness was reported in 50% of PTN patients. Neurosensory testing showed larger affected dermatome involvement in persistent injuries, with no differences between the non-painful and painful PTN groups. Patient clustering indicated different sensory profile distributions when stratified according to aetiology or affected nerve branch. High interference with lifestyle was reported (78%), and patients suffering from painful PTN had worse QoL and psychosocial outcomes. CONCLUSION: Patients with painful PTN had different clinical profiles and lower QoL scores than those with non-painful PTN. Sensory profiles may provide important prognostic and therapeutic information; however, more research is needed to assess the clustering procedure and link these clusters to therapeutic guidelines.

Distal infraorbital nerve injury: a model for persistent facial pain in mice.

Inflammation or injuries of the trigeminal nerve are often associated with persistent facial pain and its sequelae. A number of models have been described to study trigeminal pain in rodents, but the long-lasting behavioral consequences are unknown. This study characterizes the impact of a distal infraorbital nerve injury, called DIONI, which consists of ligature and transection of distal fibers of the infraorbital nerve. We assessed nociception using a conflict paradigm and optogenetics, and a set of reward, aversion, spatial, temporal, and competition tasks in the IntelliCage to study multiple aspects of cognition, circadian rhythms, and social interactions in groups of mice in home cage environments. Mice with DIONI developed cold and mechanical allodynia, and hypersensitivity towards blue light stimulation. They maintained a long-lasting memory of aversive stimuli (airpuff from above), but had no difficulty in learning appetitive tasks, which consisted in developing a preference for a rewarding corner in the IntelliCage. Indeed, they were more strongly "addicted" to sugar than sham mice but temporarily failed to relearn the location of rewarding sites after corner switching (reversal learning). They were mildly overactive in some tasks but without disruptions of circadian rhythms or impact on social structure. They adopted a strategy to maintain licking with fewer nosepokes, presumably trying to avoid mechanical stimulation of the snout. The results suggest that mice with DIONI develop strong aversive memories and some cognitive inflexibility, but create adaptive strategies to cope with the persistent trigeminal hypersensitivity.

Mental nerve injury induces novelty seeking behaviour leading to increasing ethanol intake in Wistar rats.

OBJECTIVE: Dental treatment and orofacial surgeries may induce chronic neuropathic orofacial pain (CNOP). This kind of pain affects adaptability to environmental changes in both model animals and humans. Part of the adaptation process depends on the ability to distinguish between familiar and novel stimuli. CNOP induces novelty seeking behaviour as a deficit in environmental adaptation. Alternatively, novelty seeking is a sign for susceptibility to the development of substance abuse. Evidence shows that CNOP leads to alcoholism in animal models. The behavioural relationship between CNOP, novelty seeking behaviour and substance abuse is unknown. In this article, we investigate if CNOP produces an increase in novelty seeking and leads to increasing ethanol intake. DESIGN: Firstly, we used mental nerve injury as a neuropathic orofacial pain model to evaluate both thermal and mechanical allodynia. We used the novel recognition task to determine novelty seeking behaviour and the drink in darkness protocol to assess ethanol intake. RESULTS: Our results show that mental nerve constriction increases novelty seeking behaviour (p = 0.01) and correlates with ethanol binge consumption (r2 = 0.68, p = 0.0008). CONCLUSIONS: The present study demonstrates, for the first time, that trigeminal nerve injury, which induces CNOP, is enough to provide novelty seeking behaviour and lead to increasing ethanol intake. The increase of novelty seeking behaviour can serve as a predictor of risk of developing substance abuse. The treatment of CNOP involves a high risk of producing addiction. The level of novelty seeking evaluation in patients with neuropathic pain before treatment is critical.

Topical insulin in neurotrophic keratopathy after resection of acoustic neuroma. / Insulina tópica en queratopatía neurotrófica tras resección de neurinoma del acústico.

CASE REPORT: A patient with a history of surgical resection of an acoustic neuroma presented with involvement of both the left facial nerve and the left trigeminal nerve. She initially consulted for exposure keratitis, but two weeks later presented with an infectious keratitis. After taking the corneal sample, she presented with persistent epithelial defect, which did not respond to medical management. Topical insulin was indicated, and a decrease in the area of the lesion was seen in the following 5 days. A therapeutic contact lens was also placed at that time and finally, two weeks after the initiation of insulin, the epithelial defect completely closed. DISCUSSION: This was a complex case due to the confluence of facial paralysis, neurotrophic keratitis, and infectious keratitis, which finally had a successful outcome. Topical insulin can be an effective adjuvant therapy in cases of neurotrophic ulcers that do not respond to standard therapy.

Trigeminal trophic syndrome: an updated review.

Trigeminal trophic syndrome (TTS) is a rare disease process that is thought to occur after insult to the trigeminal nerve. The earliest descriptions of this condition were provided in the early 20th century, yet it remains relatively unknown, with approximately 200 cases since described. Most commonly seen in older women, TTS characteristically involves persistent facial ulceration with loss of sensation and paresthesia along the distribution of the trigeminal dermatome. Ulceration often occurs in the alar region, following self-manipulation in response to paresthesias. Time of onset of TTS after trigeminal insult may vary from weeks to decades, and emergence of ulceration may be associated with psychiatric disorders. Diagnosis is clinical and made by exclusion of similarly presenting conditions. Histology is nonspecific yet necessary to exclude other causes of facial ulceration. Although there is not yet a standard management strategy, a number of successful approaches have been reported including pharmaceutical and surgical interventions, installation of a protector, and transcutaneous nerve stimulation. However, because of the self-inflicted manifestations of this disorder, behavioral modifications remain of the utmost importance. This review serves to address the history, epidemiology, pathogenesis, clinical presentation, histology, diagnosis, differential diagnosis, and management options for TTS.

Corneal neurotisation by great auricular nerve transfer and scleral-corneal tunnel incisions for neurotrophic keratopathy.

BACKGROUND/AIMS: Medical management of neurotrophickeratopathy is challenging and costly. Supra-orbital nerve transfer to thecornea has proven effective for management of keratopathy, but yieldsconsiderable donor site morbidity. Herein, a novel technique for reinnervationof the anaesthetic cornea is presented and early results characterised. METHODS: Sensory fibres of the ipsilateral greatauricular nerve were directed via an interposition graft to the anteriorcorneal stroma using scleral-corneal tunnel incisions in two patients withgrade III neurotrophic keratopathy. RESULTS: Improvements in visual acuity, cornealpachymetry, corneal esthesiometry, and corneal neurotisation as assessed by invivo confocal microscopy were observed within nine months of surgery in bothpatients. CONCLUSION: Corneal neurotisation by interposition grafttransfer of great auricular nerve fibres via scleral-corneal tunnel incisionsappears effective in the management of neurotrophic keratopathy.

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.

Sleep quality and psychosocial characteristics of patients with painful post-traumatic trigeminal neuropathies.

OBJECTIVES: The aim of this study was to explore how pain and psychological distress influence the sleep quality of patients with painful post-traumatic trigeminal neuropathy (PPTN). STUDY DESIGN: Thirty-two patients with a diagnosis of PPTN according to the International Classification for Headache Disorders of the International Headache Society were enrolled. All patients completed a number of questionnaires that examined sleep quality, psychological distress, and quality of life. RESULTS: The global Pittsburg Sleep Quality Index (PSQI) score was "5" or greater in 75% of the patients. Additionally, the Symptom Check List-90-Revised (SCL-90-R) global severity index (GSI) revealed that 71.9% of the study sample reported values of psychological distress over the level of clinical significance. Sleep quality was analyzed through a linear regression model of global PSQI (dependent variable) that included gender, age, pain intensity, and pain duration (independent variables). This model revealed a significant positive association between the PSQI global score and the SCL-90-R GSI that was independent of age, gender, pain intensity, and duration. CONCLUSIONS: Patients with PPTN present higher levels of sleep disturbance and psychological distress compared with the general population. Sleep quality disturbances and levels of psychological distress are strongly associated and seem to be independent of age, gender, medication use, pain intensity and duration.

Lipopolysaccharide-mediated inflammatory priming potentiates painful post-traumatic trigeminal neuropathy.

We explored the molecular and behavioral effects of a perineural Lipopolysaccharide (LPS)-mediated inflammatory priming on the development and maintenance of painful post-traumatic trigeminal neuropathy (PPTTN) following infra-orbital nerve chronic constriction injury (CCI-IoN) in rats. Rats were pretreated with repetitive perineural injections in the vicinity of the IoN of either LPS or vehicle (Vhcl) before being submitted to CCI-IoN. Orofacial pain-like behaviors (response to Von Frey Filament testing and spontaneous isolated face grooming) were measured during the period of LPS injections (three weeks) and following CCI-IoN surgery (two weeks). Local LPS administration induced an early pain-like behavior (i.e. an increase in spontaneous pain [SP] or mechanical static allodynia [MSA]) in both conditions, and following CCI-IoN, MSA and SP developed earlier and more severely in LPS-pretreated rats than in the control group. Ipsilateral increases of key neuropathic pain mRNA markers in the IoN parenchyma, trigeminal ganglia (TG) and spinal trigeminal nucleus caudalis (Sp5C) were observed in CCI-IoN injured animals as compared to controls. Although no significant molecular differences could be observed within the IoN parenchyma between LPS and Vhcl-pretreated animals, a significant increase of key inflammatory cytokine Interleukin 1 beta (IL - 1ß) could be found in the TG of LPS-pretreated CCI-injured animals versus controls. Finally, a higher increase of inducible nitric oxide synthase (iNOS) in ipsilateral Sp5C of LPS-pretreated animals was observed as compared to Sp5C of Vhcl-pretreated animals. These results suggest a key role of inflammatory priming in the development and maintenance of PPTTN implicating IL-1ß/iNOS-dependent central sensitization mechanisms.

Inhibition of 2-arachydonoylgycerol degradation attenuates orofacial neuropathic pain in trigeminal nerve-injured mice.

Current therapeutics are not effective for orofacial neuropathic pain, and better options are needed. The present study used inferior orbital nerve (ION)-injured mice to investigate the effect of inhibiting monoacylglycerol lipase (MAGL), an enzyme that degrades the major endocannabinoid 2-arachydonoylgycerol (2-AG) in orofacial neuropathic pain. The head-withdrawal threshold to mechanical stimulation of the whisker pad was reduced on days 3, 5, and 7 after ION injury. Injection of JZL184, a selective inhibitor of MAGL, on day 7 after ION injury attenuated the reduction in head-withdrawal threshold at 2 h after administration. Moreover, the numbers of MAGL-immunoreactive neurons in the trigeminal subnucleus caudalis (Vc) and upper cervical spinal cord (C1-C2) were significantly greater in ION-injured mice than in sham-operated mice but were reduced after administration of JZL184. The increase in MAGL immunoreactivity suggests that increased 2-AG production is followed by rapid enzymatic degradation of 2-AG. JZL184 inhibited this degradation and thus increased 2-AG concentration in the brain, particularly in the Vc and C1-C2 regions, thus attenuating pain. Our findings suggest that inhibition of 2-AG degradation by MAGL inhibitors is a promising therapeutic option for treatment of orofacial neuropathic pain.

Development of mirror pain following trigeminal nerve injury: a case report and review of neuropathic mechanisms.

Following injury to a peripheral nerve, patients may complain of pain over the distribution of the same contralateral nerve, a phenomenon referred to as contralateral pain or mirror pain (MP). Symptoms of MP usually begin after the neuropathic pain from the original nerve injury has become chronic. Chronic neuropathic pain can lead to sensitization and spread of pain. Because the diagnosis of MP can be missed, patients may undergo multiple treatment procedures that prove to be ineffective in relieving the pain. This article presents a case of MP that appeared approximately 20 months following inferior alveolar nerve injury that occurred during placement of a dental implant in the region of the first molar. Acutely painful nerve injuries must be aggressively treated to prevent changeover to a chronic pain state characterized by sensitization and spread of pain beyond the initial injury. Consequently, clinicians need to begin effective, early pain management to prevent the changeover to chronic pain that has become centralized and refractive to treatment.