Experimental traumatic occlusion drives immune changes in trigeminal ganglion.

We previously demonstrated that experimental traumatic occlusion (ETO) induces a long-lasting nociceptive response. These findings were associated with altered neuronal patterns and suggestive satellite glial cell activation. This study aimed to elucidate the activation of satellite glial cells following ETO in the trigeminal ganglion. Moreover, we explored the involvement of resident and infiltrating cells in trigeminal ganglion in ETO. Finally, we investigated the overexpression of purinergic signaling and the CX3CL1/CX3CR1 axis. RT-qPCR and electrophoresis showed overexpression of GFAP in the trigeminal ganglion (TG), and immunohistochemistry corroborated these findings, demonstrating SGCs activation. ELISA reveals enhanced levels of TNF-α and IL-1ß in TG after 28 d of ETO. In trigeminal ganglia, ETO groups improved the release of CX3CL1, and immunohistochemistry showed higher CX3CR1+ -immunoreactive cells in ETO groups. Immunohistochemistry and electrophoresis of the P2X7 receptor were found in ETO groups. The mRNA levels of IBA1 are upregulated in the 0.7-mm ETO group, while immunohistochemistry showed higher IBA1+ -immunoreactive cells in both ETO groups. The expression of CD68 by electrophoresis and immunohistochemistry was observed in the ETO groups. For last, ELISA revealed increased levels of IL-6, IL-12, and CCL2 in the TG of ETO groups. Furthermore, the mRNA expression revealed augmented transcription factors and cytokines associated with lymphocyte activation, such as RORγt, IL-17, Tbet, IFNγ, FOXP3, and IL-10. The findings of this study suggested that ETO activates SGCs in TG, and purinergic signaling and CX3CL1/CX3CR1 axis were upregulated. We uncovered the involvement of a distinct subtype of macrophages, named sensory neuron-associated macrophage activation (sNMAs), and detected an expanded number of infiltrated macrophages onto TG. These findings indicate that ETO induces chronic/persistent immune response.

Optogenetic stimulation of the motor cortex alleviates neuropathic pain in rats of infraorbital nerve injury with/without CGRP knock-down.

BACKGROUND: Previous studies have reported that electrical stimulation of the motor cortex is effective in reducing trigeminal neuropathic pain; however, the effects of optical motor cortex stimulation remain unclear. OBJECTIVE: The present study aimed to investigate whether optical stimulation of the primary motor cortex can modulate chronic neuropathic pain in rats with infraorbital nerve constriction injury. METHODS: Animals were randomly divided into a trigeminal neuralgia group, a sham group, and a control group. Trigeminal neuropathic pain was generated via constriction of the infraorbital nerve and animals were treated via selective inhibition of calcitonin gene-related peptide in the trigeminal ganglion. We assessed alterations in behavioral responses in the pre-stimulation, stimulation, and post-stimulation conditions. In vivo extracellular recordings were obtained from the ventral posteromedial nucleus of the thalamus, and viral and α-CGRP expression were investigated in the primary motor cortex and trigeminal ganglion, respectively. RESULTS: We found that optogenetic stimulation significantly improved pain behaviors in the trigeminal neuralgia animals and it provided more significant improvement with inhibited α-CGRP state than active α-CGRP state. Electrophysiological recordings revealed decreases in abnormal thalamic firing during the stimulation-on condition. CONCLUSION: Our findings suggest that optical motor cortex stimulation can alleviate pain behaviors in a rat model of trigeminal neuropathic pain. Transmission of trigeminal pain signals can be modulated via knock-down of α-CGRP and optical motor cortex stimulation.

Calcium Channel α2δ1 Subunit Mediates Secondary Orofacial Hyperalgesia Through PKC-TRPA1/Gap Junction Signaling.

Orofacial pain is characterized by its easy spread to adjacent areas, thus presenting with primary hyperalgesia (hypersensitivity at the site of injury) and secondary hyperalgesia (extraterritorial hypersensitivity outside the injured zone). However, the mechanisms behind the secondary hyperalgesia are poorly understood. In the present study, we used a mouse model of partial transection of the infraorbital nerve (pT-ION) to study whether calcium channel subunit α2δ1 (Cavα2δ1) and its downstream signaling contributes to the development of secondary hyperalgesia in the orofacial area. pT-ION caused primary (V2 skin) and secondary (V3 skin) hyperalgesia, which was reversed by the Cavα2δ1 antagonist gabapentin and by the expression of Cavα2δ1-targeting interfering RNA in trigeminal ganglion (TG)-V3 neurons. pT-ION induced increased expression of PKC and TRPA1, which was reversed by Cavα2δ1-targeting interfering RNA, and PKC inhibition reversed the upregulation of TRPA1 and gap junction (GJ) proteins induced by pT-ION. Cavα2δ1 overexpression in TG-V2 neurons induced the upregulation of PKC, TRPA1, and the GJ proteins in the TG and trigeminal subnucleus caudalis and induced hypersensitivity in the V3 skin area, which was reversed by TRPA1, GJ, or PKC blockade. Thus, we conclude that Cavα2δ1 contributes to the development of secondary hyperalgesia through its downstream PKC-TRPA1/GJ signaling pathways. PERSPECTIVE: This study demonstrates that the activation of Cavα2δ1 and the downstream PKC-TRPA1/GJ signaling pathway contributes greatly to trigeminal nerve injury-induced secondary mechanical and cold hyperalgesia. This suggests that inhibitors of Cavα2δ1, TRPA1, or GJs might be effective treatments for nerve injury-induced spreading of orofacial pain.

Herpes Simplex Reactivation After Surgical Treatment of Trigeminal Neuralgia: A Retrospective Cohort Study.

BACKGROUND: Herpes simplex virus (HSV) reactivation after surgery for trigeminal neuralgia has long been recognized. Only a few studies to date have focused on this complication, and its actual incidence remains unknown. The aim of this study was to investigate the incidence of postoperative herpes labialis (HL) in a cohort of patients treated with either percutaneous balloon compression or microvascular decompression to identify potentially significant differences between different treatments. METHODS: A total of 92 patients who were operated on for TN with microvascular decompression (group A) or percutaneous balloon compression (group B) in the period 2010-2017 were retrospectively evaluated. The 2 subgroups of patients were compared according to history of previous HL and incidence of postoperative HL. RESULTS: The final cohort comprised 56 male and 36 female patients. Average age was 58.50 years; 30 male patients belonged to group A and 26 male patients belonged to group B. Lifetime incidence of episodes of HL before surgery in 18/58 patients in group A (31.0%) and 12/34 patients in group B (35.3%), with no statistically significant difference among subgroups. Postoperatively, 1/56 patients in group A (1.7%) experienced HL compared 5/34 patients in group B (14.7%), with a strongly statistically significant difference between the 2 subgroups. CONCLUSIONS: In our clinical experience, herpes simplex virus reactivation after surgery for trigeminal neuralgia is not so rare and is still not completely understood. Postoperative herpes simplex virus reactivation could be due to a direct mechanical injury on gasserian ganglion neurons, which is more common after percutaneous balloon compression.

Neurochemical effects of photobiostimulation in the trigeminal ganglion after inferior alveolar nerve injury.

Orofacial pain is associated with peripheral and central sensitization of trigeminal nociceptive neurons. Nerve injury results in release of chemical mediators that contribute to persistent pain conditions. The activation of the transient receptor potential vanilloid 1 (TRPV1), promotes release of calcitonin gene-related peptide (CGRP) and substance P (SP) from trigeminal nerve terminals. CGRP and SP contribute to the development of peripheral hyperalgesia. The expression of SP and CGRP by primary afferent neurons is rapidly increased in response to peripheral inflammation. CGRP receptor activation promotes activation of AMPA receptors, leading to increased firing of neurons which is reflected as central sensitization. In this study we investigated whether inferior alveolar nerve (IAN) injury influences AMPA receptors, CGRP, SP and TRPV1 expression in the trigeminal ganglion (TG). The relative expression of the protein of interest from naive rats was compared to those from injured rats and animals that received low level laser therapy (LLLT). IAN-injury did not change expression of GluA1, GluA2 and CGRP, but increased the expression of TRPV1 and SP. LLLT increases GluA1 and GluA2 expression and decreases TVPV1, SP and CGRP. These results, together with previous behavioral data, suggest that IAN-injury induced changes in the proteins analyzed, which could impact on nociceptive threshold. These data may help to understand the molecular mechanisms of pain sensitization in the TG.

Low-intensity pulsed ultrasound accelerates nerve regeneration following inferior alveolar nerve transection in rats.

Inferior alveolar nerve (IAN) injury, which is frequently caused by orofacial surgery or trauma, induces sensory loss in orofacial regions innervated by the IAN. However, no effective treatment for orofacial sensory loss currently exists. We determined whether sensory loss in facial skin above the mental foramen following IAN transection was recovered by exposure of the transected IAN to low-intensity pulsed ultrasound (LIPUS). Inferior alveolar nerve transection (IANX) was performed in 7-wk-old male Sprague-Dawley rats. On day 7 after IANX, the effect of daily LIPUS (from day 0) on the transected IAN, in terms of sensitivity to mechanical stimulation of the facial skin above the mental foramen, was examined. Moreover, the number of trigeminal ganglion (TG) neurons innervating the facial skin above the mental foramen of rats with IANX treated daily with LIPUS was counted using the retrograde neurotracing technique. Daily exposure of the transected IAN to LIPUS significantly promoted recovery of the head-withdrawal threshold in response to mechanical stimulation of the facial skin above the mental foramen, and the number of TG neurons innervating the facial skin above mental foramen was significantly increased in rats with IANX treated daily with LIPUS compared with sham or LIPUS-unexposed rats. Daily treatment of stumps of the transected IAN with LIPUS facilitated morphological and functional regeneration, suggesting that LIPUS is an effective and novel therapy for IAN injury.

Hypoxia-induced changes in Ca(2+) mobilization and protein phosphorylation implicated in impaired wound healing.

The process of wound healing must be tightly regulated to achieve successful restoration of injured tissue. Previously, we demonstrated that when corneal epithelium is injured, nucleotides and neuronal factors are released to the extracellular milieu, generating a Ca(2+) wave from the origin of the wound to neighboring cells. In the present study we sought to determine how the communication between epithelial cells in the presence or absence of neuronal wound media is affected by hypoxia. A signal-sorting algorithm was developed to determine the dynamics of Ca(2+) signaling between neuronal and epithelial cells. The cross talk between activated corneal epithelial cells in response to neuronal wound media demonstrated that injury-induced Ca(2+) dynamic patterns were altered in response to decreased O2 levels. These alterations were associated with an overall decrease in ATP and changes in purinergic receptor-mediated Ca(2+) mobilization and localization of N-methyl-d-aspartate receptors. In addition, we used the cornea in an organ culture wound model to examine how hypoxia impedes reepithelialization after injury. There was a change in the recruitment of paxillin to the cell membrane and deposition of fibronectin along the basal lamina, both factors in cell migration. Our results provide evidence that complex Ca(2+)-mediated signaling occurs between sensory neurons and epithelial cells after injury and is critical to wound healing. Information revealed by these studies will contribute to an enhanced understanding of wound repair under compromised conditions and provide insight into ways to effectively stimulate proper epithelial repair.

Eugenol reverses mechanical allodynia after peripheral nerve injury by inhibiting hyperpolarization-activated cyclic nucleotide-gated (HCN) channels.

Mechanical allodynia is a common symptom found in neuropathic patients. Hyperpolarization-activated cyclic nucleotide-gated channels and their current, I(h), have been suggested to play an important role in neuropathic pain, especially in mechanical allodynia and spontaneous pain, by involvement in spontaneous ectopic discharges after peripheral nerve injury. Thus, I(h) blockers may hold therapeutic potential for the intervention of mechanical allodynia under diverse neuropathic conditions. Here we show that eugenol blocks I(h) and abolishes mechanical allodynia in the trigeminal system. Eugenol produced robust inhibition of I(h) with IC(50) of 157 µM in trigeminal ganglion (TG) neurons, which is lower than the dose of eugenol that inhibits voltage-gated Na channels. Eugenol-induced I(h) inhibition was not mediated by G(i/o)-protein activation, but was gradually diminished by an increase in intracellular cAMP concentration. Eugenol also inhibited I(h) from injured TG neurons which were identified by retrograde labeling with DiI and reversed mechanical allodynia in the orofacial area after chronic constriction injury of infraorbital nerve. We propose that eugenol could be potentially useful for reversing mechanical allodynia in neuropathic pain patients.

Trigeminal trophic syndrome with features of oral CMV disease.

Trigeminal trophic syndrome (TTS) is an exceedingly rare complication following injury to the trigeminal ganglion, characterized by painless ulcerations, which has only rarely been reported with intraoral features. We present a patient with multiple intraoral ulcerations of the right buccal and alveolar mucosa that had previously been treated with nerve ablation therapy for trigeminal neuralgia. Positive immunohistochemistry staining of a biopsy specimen for cytomegalovirus suggested a viral etiology; however, lesions persisted despite antiviral therapy, and immunohistochemistry was negative on follow-up biopsy. Diagnosis of TTS is one of exclusion as it can mimic many other conditions, and should be considered in patients with unilateral painless ulcerations with a history of trigeminal nerve damage.

Eye dryness sensations after refractive surgery: impaired tear secretion or "phantom" cornea?

The cornea is richly innervated by various functional types of sensory nerve fibers. When stimulated, these fibers evoke conscious sensations of different quality including ocular dryness, discomfort, and pain. Refractive surgery involves a variable degree of damage to corneal nerves. This leads to an altered expression of membrane ion channels at the injured and regenerating nerve fibers, giving rise to aberrant spontaneous and stimulus-evoked nerve impulse firing. It is speculated that these abnormal sensory discharges are read by the brain as ocular surface dryness. This would explain the high incidence of eye dryness sensations after photorefractive surgery, which are experienced by a large number of patients despite the often modest disturbance of tear secretion. Therefore, drugs that reduce abnormal activity in injured nerves may represent a therapeutic alternative for eye dryness sensations after refractive surgery.

Radiología simple en la microcompresión del ganglio de Gasser. Un método alternativo y económico / Simple radiology in the microcompressión of Gasserian ganglion. An alternative and economic method

Considerado uno de los dolores más intensos que puede soportar el ser humano, la neuralgia trigeminal ha sido tratada con innumerables métodos. Entre ellos, los percutáneos surgieron como variantes poco agresivas e igualmente eficaces que aquellos métodos a cielo abierto. El más reciente de los métodos percutáneos: la compresión de las fibras del ganglio trigeminal de Gasser, se utiliza en el Servicio de Neurocirugía del Hospital Universitario "General Calixto García", guiado por radiología simple(AU)

Considered one of the most intense pains that the human being, the neuralgia trigeminal can support has been treated with countless methods. Among them, the percutáneos arose as not very aggressive and equally effective variants that those methods to open sky. The most recent in the methods percutáneos: the compression of the fibers of the ganglion trigeminal of Gasser, is used in the Service of Neurosurgery of the General University Hospital Calixto García", guided by simple radiology(AU)

Isolated trigeminal neuropathy due to trigeminal nerve root hemorrhage.

BACKGROUND: Isolated trigeminal neuropathy is uncommon; causes include trauma, inflammation, or neoplasm. METHODS: We report a patient who fell and struck his head during a myocardial infarction, was treated with streptokinase, and developed symptoms and signs of an isolated trigeminal sensory neuropathy. RESULTS: Imaging showed hemorrhage in the trigeminal nerve root; follow-up imaging showed resolution of the hemorrhage, but no underlying structural lesion. CONCLUSION: A combination of head trauma plus thrombolysis resulted in an isolated trigeminal neuropathy.

Experimental trigeminal nerve injury.

The successful reinnervation of peripheral targets after injury varies with the axonal population of the nerve that is injured and the extent of the dislocation of its central component from the peripheral endoneurial tube. Larger-diameter axons such as those supplying mechanoreceptors recover more readily than narrower axons such as those supplying taste. A complex, bi-directional interaction between lingual epithelium and sprouting nerve results in the redifferentiation of taste buds after denervation. Dentin and the dental pulp provide a strong attraction to sprouting nerves and will become reinnervated from collateral sources if recovery of the original innervation is blocked. The most effective repair technique for transected lingual nerves is one which brings the cut ends together rather than one that provides a temporary bridge. Injuries can result in cell death in the trigeminal ganglion but only if the injury is severe and recovery is prevented. Lesser damage results in chromatolysis and the increased expression of neuropeptides. All nerve injuries bring about changes in the trigeminal nucleus. These occur as changes in receptive field and the incidence of spontaneously active neurons, effects which are consistent with the unmasking of existing afferents. These functional changes are short-lived and reversible. Morphologically, nerve injury results in terminal degeneration in the nuclei and an increased expression of the c-Fos gene and some neuropeptides. Only a chronic constriction injury induces behavioral changes. The adult trigeminal system retains considerable plasticity that permits it to respond successfully to nerve injury. Much remains to be learned about this response, particularly of the trophic factors that control peripheral recovery and the central response to more severe injuries.

Appearance of neuropeptide Y-like immunoreactive cells in the rat trigeminal ganglion following dental injuries.

The effects of these injuries on the presence and distribution of neuropeptide Y (NPY)-immunoreactive (-IR) neurones were examined immunohistochemically. In the normal trigeminal ganglion: some perivascular nerves displayed NPY-IR but there were no NPY-IR ganglionic cells. Fourteen days after extraction or pulp exposure of the upper first molar, NPY-IR cells appeared in the maxillary region of the trigeminal ganglion. About 90% of the injury-evoked NPY-IR cells had medium to large diameters (more than 300 microns2 in cross-sectional area). Shallow cavity preparation, however, did not induce the appearance of NPY-IR cells in the trigeminal ganglion. These results indicate the dental injuries alter the primary sensory neurones in the trigeminal ganglion.

The effect of trigeminal nerve and ganglion manipulation on recurrence of ocular herpes simplex in rabbits.

Latent herpes simplex virus (HSV) has been demonstrated in the trigeminal ganglia of experimentally infected rabbits between episodes of spontaneous ocular recurrence. In three experiments reported here, the normal pattern of recurrence was modified by manipulation of the trigeminal nerve and ganglion. Temporary retrobulbar disruption of trigeminal nerve function in chronically infected animals significantly decreased the number of ocular HSV isolations obtained during the 20 weeks immediately following surgery. Stereotaxic interruption of intracranial trigeminal nerve function prior to initial HSV infection dramatically reduced the incidence of peripheral recurrence of HSV. In chronically infected animals, stereotaxic stimulation of the trigeminal ganglion caused a marked increase in positive cultures within 2 days. These studies provide additional evidence for the theory that the reservoir for latent ocular HSV in rabbits is the trigeminal ganglion. Moreover, the studies suggest that the transmission of latent HSV from the trigeminal ganglion to its infectious form in the peripheral tissues involves the trigeminal nerve. We have shown that mechanical and stereotaxic stimulation of the trigeminal ganglion is a reliable and rapid means of precipitating peripheral ocular shedding of HSV on command, a finding which should prove most productive in future research.