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.

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.

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.

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.

Macrophages in trigeminal ganglion contribute to ectopic mechanical hypersensitivity following inferior alveolar nerve injury in rats.

BACKGROUND: Accidental mandibular nerve injury may occur during tooth extraction or implant procedures, causing ectopic orofacial pain. The exact mechanisms underlying ectopic orofacial pain following mandibular nerve injury is still unknown. Here, we investigated the role of macrophages and tumor necrosis factor alpha (TNFα) in the trigeminal ganglion (TG) in ectopic orofacial pain following inferior alveolar nerve transection (IANX). METHODS: IANX was performed and the mechanical head-withdrawal threshold (MHWT) in the whisker pad skin ipsilateral to IANX was measured for 15 days. Expression of Iba1 in the TG was examined on day 3 after IANX, and the MHWT in the whisker pad skin ipsilateral to IANX was measured following successive intra-ganglion administration of the macrophage depletion agent liposomal clodronate Clophosome-A (LCCA). TNFα expression in the TG and the MHWT in the whisker pad skin ipsilateral to IANX following successive intra-ganglion administration of the TNFα blocker etanercept were measured on day 3 after IANX, and tumor necrosis factor receptor-1 (TNFR1) immunoreactive (IR) cells in the TG were analyzed immunohistochemically on day 3. RESULTS: The MHWT in the whisker pad skin was significantly decreased for 15 days, and the number of Iba1-IR cells was significantly increased in the TG on day 3 after IANX. Successive intra-ganglion administration of the macrophage depletion agent LCCA significantly reduced the increased number of Iba1-IR cells in the TG and reversed the IANX-induced decrease in MHWT in the whisker pad skin. TNFα expression was increased in the TG on day 3 after IANX and was reduced following successive intra-ganglion administration of the TNFα inhibitor etanercept. The decreased MHWT was also recovered by etanercept administration, and TNFR1-IR cells in the TG were increased on day 3 following IANX. CONCLUSIONS: These findings suggest that signaling cascades resulting from the production of TNFα by infiltrated macrophages in the TG contributes to the development of ectopic mechanical allodynia in whisker pad skin following IANX.

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.

Enophthalmos and Hemifacial Skeletal Atrophy After Trigeminal Nerve Injury.

A 60-year-old woman presented with several years increasing right upper eyelid ptosis. She had undergone surgical decompression of the right trigeminal nerve in the posterior cranial fossa 15 years earlier for trigeminal neuralgia. This left her with permanent numbness in the second and third divisions of the trigeminal nerve. In addition to the ptosis, she was found to have right enophthalmos and a smaller right face. CT scans showed a smaller midfacial skeleton on the right and a depressed orbital floor. The changes were different to those seen in silent sinus syndrome. Photographs taken over many years showed the facial changes were acquired and came on gradually many years after the trigeminal nerve injury. It is possible that trigeminal nerve injury may lead to trophic changes in the facial skeleton, but these have not been previously reported.

Connexin 43 contributes to ectopic orofacial pain following inferior alveolar nerve injury.

BACKGROUND: Clinically, it is well known that injury of mandibular nerve fiber induces persistent ectopic pain which can spread to a wide area of the orofacial region innervated by the uninjured trigeminal nerve branches. However, the exact mechanism of such persistent ectopic orofacial pain is not still known. The present study was undertaken to determine the role of connexin 43 in the trigeminal ganglion on mechanical hypersensitivity in rat whisker pad skin induced by inferior alveolar nerve injury. Here, we examined changes in orofacial mechanical sensitivity following inferior alveolar nerve injury. Furthermore, changes in connexin 43 expression in the trigeminal ganglion and its localization in the trigeminal ganglion were also examined. In addition, we investigated the functional significance of connexin 43 in relation to mechanical allodynia by using a selective gap junction blocker (Gap27). RESULTS: Long-lasting mechanical allodynia in the whisker pad skin and the upper eyelid skin, and activation of satellite glial cells in the trigeminal ganglion, were induced after inferior alveolar nerve injury. Connexin 43 was expressed in the activated satellite glial cells encircling trigeminal ganglion neurons innervating the whisker pad skin, and the connexin 43 protein expression was significantly increased after inferior alveolar nerve injury. Administration of Gap27 in the trigeminal ganglion significantly reduced satellite glial cell activation and mechanical hypersensitivity in the whisker pad skin. Moreover, the marked activation of satellite glial cells encircling trigeminal ganglion neurons innervating the whisker pad skin following inferior alveolar nerve injury implies that the satellite glial cell activation exerts a major influence on the excitability of nociceptive trigeminal ganglion neurons. CONCLUSIONS: These findings indicate that the propagation of satellite glial cell activation throughout the trigeminal ganglion via gap junctions, which are composed of connexin 43, plays a pivotal role in ectopic mechanical hypersensitivity in whisker pad skin following inferior alveolar nerve injury.

Neurocutaneous disease: Neurocutaneous dysesthesias.

Dysesthesia is a generic term for a cutaneous symptom--such as pruritus, burning, tingling, stinging, anesthesia, hypoesthesia, tickling, crawling, cold sensation, or even pain--without a primary cutaneous condition in a well-defined location that is often caused by nerve trauma, impingement, or irritation. There are multiple types of dysesthesias depending on the body location and the nerves involved. While location, exact symptoms, and etiologies might vary, the underlying theme is that these conditions are of neurologic origin and have dermatologic consequences. For many of these conditions, the symptoms are localized to the skin, and patients frequently present to the dermatologist; it is important for dermatologists to be knowledgeable about these symptoms and their underlying causes. In part II of this continuing medical education review, the primary diagnoses associated with underlying cutaneous dysesthesias will be explored, including scalp dysesthesia, trigeminal trophic syndrome, meralgia paresthetica, notalgia paresthetica, and brachioradial pruritus. The typical demographics in terms of symptoms, location, and patient populations will be discussed in addition to the specific etiologies, workups, and possible treatment options.

Calcium channel α2δ1 proteins mediate trigeminal neuropathic pain states associated with aberrant excitatory synaptogenesis.

To investigate a potential mechanism underlying trigeminal nerve injury-induced orofacial hypersensitivity, we used a rat model of chronic constriction injury to the infraorbital nerve (CCI-ION) to study whether CCI-ION caused calcium channel α2δ1 (Cavα2δ1) protein dysregulation in trigeminal ganglia and associated spinal subnucleus caudalis and C1/C2 cervical dorsal spinal cord (Vc/C2). Furthermore, we studied whether this neuroplasticity contributed to spinal neuron sensitization and neuropathic pain states. CCI-ION caused orofacial hypersensitivity that correlated with Cavα2δ1 up-regulation in trigeminal ganglion neurons and Vc/C2. Blocking Cavα2δ1 with gabapentin, a ligand for the Cavα2δ1 proteins, or Cavα2δ1 antisense oligodeoxynucleotides led to a reversal of orofacial hypersensitivity, supporting an important role of Cavα2δ1 in orofacial pain processing. Importantly, increased Cavα2δ1 in Vc/C2 superficial dorsal horn was associated with increased excitatory synaptogenesis and increased frequency, but not the amplitude, of miniature excitatory postsynaptic currents in dorsal horn neurons that could be blocked by gabapentin. Thus, CCI-ION-induced Cavα2δ1 up-regulation may contribute to orofacial neuropathic pain states through abnormal excitatory synapse formation and enhanced presynaptic excitatory neurotransmitter release in Vc/C2.

Posttraumatic Midface Pain: Clinical Significance of the Anterior Superior Alveolar Nerve and Canalis Sinuosus.

BACKGROUND: Posttraumatic midface pain secondary to injury of the anterior superior alveolar nerve (ASAN) is characterized as pain localized to the central and lateral incisors, canines, and maxilla. This nerve is susceptible to injury and subsequent formation of neuromas after midface trauma. Surgical intervention requires an accurate and precise understanding of the course of the ASAN. METHODS: Dissections of 12 human cadaver heads were conducted to identify the course of the ASAN through the canalis sinuosus (CS). Fifty 1-mm slice face computed tomographic scans were evaluated to document the dimensions and course of the CS. RESULTS: The ASAN branched laterally from the infraorbital nerve before reaching the infraorbital rim in all cadavers. The bifurcation occurred 18 mm posterior to the infraorbital rim (range, 10-30 mm). At a point 25 mm inferior to the infraorbital rim, the ASAN is found 3.4 mm lateral to the piriform aperture (range, 3-4 mm). Radiographic analysis demonstrated a 12.9-mm horizontal length of the CS across the anterior maxilla (SD, 2.2 mm), a distance of 4.8 mm between the piriform aperture and the CS (SD, 1.2 mm), and 11.7 mm vertical length of the CS along the piriform aperture (SD, 3.0 mm). CONCLUSIONS: The ASAN maintains consistent coordinates at specific points along its course through the midface. An improved understanding of the course of the ASAN will guide future diagnosis of injury to this nerve and surgical intervention for patients with posttraumatic midface pain secondary to ASAN injury.

A rare case of trigeminal trophic syndrome with an extensive scalp, forehead, and upper eyelid ulceration in a patient with undiagnosed Alzheimer disease.

BACKGROUND: Trigeminal Trophic Syndrome (TTS) is a rare presentation of facial ulceration, which is characterized by the triad of anesthesia, paraesthesia, and damage of trigeminal sensory branches. MAIN OBSERVATIONS: We report a unique case of TTS as an extensive forehead and scalp ulceration in a patient with undiagnosed Alzheimer disease. CONCLUSIONS: Treatment options for trigeminal trophic syndrome are limited and disappointing especially in older patients with dementia. Family education and behavioral modification therapies may be well tolerated option in this population.

Dural neurogenic inflammation induced by neuropathic pain is specific to cranial region.

Up to now, dural neurogenic inflammation (DNI) has been studied primarily as a part of migraine pain pathophysiology. A recent study from our laboratory demonstrated the occurrence of DNI in response to peripheral trigeminal nerve injury. In this report, we characterize the occurrence of DNI after different peripheral nerve injuries in and outside of the trigeminal region. We have used the infraorbital nerve constriction injury model (IoNC) as a model of trigeminal neuropathic pain. Greater occipital nerve constriction injury (GoNC), partial transection of the sciatic nerve (ScNT) and sciatic nerve constriction injury (SCI) were employed to characterize the occurrence of DNI in response to nerve injury outside of the trigeminal region. DNI was measured as colorimetric absorbance of Evans blue plasma protein complexes. In addition, cellular inflammatory response in dural tissue was histologically examined in IoNC and SCI models. In comparison to the strong DNI evoked by IoNC, a smaller but significant DNI has been observed following the GoNC. However, DNI has not been observed either in cranial or in lumbar dura following ScNT and SCI. Histological evidence has demonstrated a dural proinflammatory cell infiltration in the IoNC model, which is in contrast to the SCI model. Inflammatory cell types (lymphocytes, plasma cells, and monocytes) have indicated the presence of sterile cellular inflammatory response in the IoNC model. To our knowledge, this is the first observation that the DNI evoked by peripheral neuropathic pain is specific to the trigeminal area and the adjacent occipital area. DNI after peripheral nerve injury consists of both plasma protein extravasation and proinflammatory cell infiltration.

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.

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.

Peripheral painful traumatic trigeminal neuropathies.

The aim of this article is to review the clinical, pathophysiological, and therapeutic aspects of traumatically induced trigeminal nerve pain. We introduce a new and, in our view, more accurate terminology: peripheral painful traumatic trigeminal neuropathy (PPTTN) to define this patient group. The proposed pathophysiology of PPTTN is largely based on studies in spinal nerve injury models. However, trigeminal nerve injury studies have shown some subtle differences in response to physical and inflammatory insults, and these are discussed. The treatment of painful neuropathies is difficult and carries a poor prognosis. Based on the available literature on efficacy and side effects, we propose a treatment algorithm for traumatic trigeminal neuropathies.

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.