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To investigate the behavioral and biomolecular similarity between neuralgia and depression, a trigeminal neuralgia (TN) mouse model was established by constriction of the infraorbital nerve (CION) to mimic clinical trigeminal neuropathic pain. A mouse learned helplessness (LH) model was developed to investigate inescapable foot-shock-induced psychiatric disorders like depression in humans. Mass spectrometry was used to assess changes in the biomolecules and signaling pathways in the hippocampus from TN or LH mice. TN mice developed not only significant mechanical allodynia but also depressive-like behaviors (mainly behavioral despair) at 2 weeks after CION, similar to LH mice. MS analysis demonstrated common and distinctive protein changes in the hippocampus between groups. Many protein function families (such as cell-to-cell signaling and interaction, and cell assembly and organization,) and signaling pathways (e.g., the Huntington's disease pathway) were involved in chronic neuralgia and depression. Together, these results demonstrated that the LH and TN models both develop depressive-like behaviors, and revealed the involvement of many psychiatric disorder-related biomolecules/pathways in the pathogenesis of TN and LH.

Aims: To explore the possible relationship between protein kinase C gamma (PKCγ) and phosphorylated forms of extracellular signal-regulated kinases 1/2 (pERK1/2) in the rat medullary dorsal horn and the facial hypersensitivity indicative of dynamic mechanical allodynia (DMA) following chronic constriction of the infraorbital nerve (CCI-IoN)., Methods: A well-established rat model of trigeminal neuropathic pain involving CCI-IoN was used. Facial mechanical hypersensitivity was tested with non-noxious dynamic mechanical stimulation (air-puff), and the medullary dorsal horn was examined immunohistochemically using PKCγ and pERK1/2 as pain markers. Statistical analysis was performed using Student t test or one-way analysis of variance (ANOVA)., Results: Increased PKCγ and pERK1/2 expressions within the medullary dorsal horn were associated with DMA following CCI-IoN. A segmental network composed of PKCγ-positive cells located in medullary dorsal horn laminae II/III, contacting more superficially located pERK1/2-expressing cells, was identified. Ultrastructural analysis confirmed the presence of PKCγ to pERK1/2-positive cells. Moreover, intracisternal administration of the selective PKCγ inhibitor KIG31-I blocked both the DMA and pERK1/2 expression in a dose-dependent manner. Although the number of pERK1/2-positive cells was significantly elevated with air-puff stimulation, DMA rats not receiving air-puff stimulation showed significant pERK1/2 expression, suggesting they were experiencing spontaneous pain., Conclusion: PKCγ cells in the medullary dorsal horn may be involved in DMA following CCI-IoN through the activation of pERK1/2-expressing cells, which then may relay non-nociceptive information to lamina I cells in the medullary dorsal horn.

Animal models are important tools to study the pathophysiology and pharmacology of neuropathic pain. This manuscript describes the surgical and behavioral procedures to study trigeminal neuropathic pain in rats. To meet the specificity of trigeminal neuropathic pain syndromes, the infraorbital nerve (IoN) is subjected to a chronic constriction injury (CCI) by loosely ligating the nerve. An intra-orbital approach is presented here to expose and ligate the IoN in the orbital cavity. After IoN ligation, rats exhibit changes in spontaneous behavior and in response to von Frey hair stimulation that are indicative of persistent pain and mechanical allodynia. Two phases can be defined in the development of the behavioral changes. During the first week following IoN-CCI (phase 1), rats show an increased and asymmetric face grooming activity, i.e., with face wash strokes primarily directed to the nerve-injured IoN territory. A distinction is made between face grooming behavior that is part of a more general body grooming behavior, which remains largely unaffected by IoN-CCI, and face grooming that is neither preceded nor followed by body grooming, which is significantly increased after IoN-CCI. During this period, responsiveness to mechanical stimulation of the IoN territory is reduced. This hyporesponsiveness is abruptly replaced by an extreme hyperresponsiveness whereby even very weak stimulus intensities provoke nocifensive behavior (phase 2). The phenomenological similarities between these behavioral alterations and reported signs of facial pain (i.e., responses to noxious stimulation of the face) suggest the presence of dysesthesia/paresthesia and mechanical allodynia in the ligated IoN territory.

Purpose: To discuss an effective surgical treatment of a subtype of trigeminal neuralgia with descending palatine neuralgia of the maxillary division., Method: Nine patients, who suffered from trigeminal neuralgia with descending palatine neuralgia of the maxillary division, received neurotomy and avulsion of the descending palatine nerve in the pterygopalatine fossa via the greater palatine foramen-pterygopalatine canal approach. Seven of the patients had a recurrence of descending palatine neuralgia after they received treatment of maxillary neuralgia with neurotomy and avulsion of the infraorbital nerve; two patients were diagnosed with descending palatine neuralgia of the maxillary division in our department. Postoperative follow-up was conducted., Results: Pain in the palate disappeared; all patients felt numb and paresthetic in the area innervated by the trigeminal nerve, with no pain. During the 3-36 months of follow-up, no recurrence occurred., Conclusions: Descending palatine neurotomy in the pterygopalatine fossa via the greater palatine foramen-pterygopalatine canal approach is a simple, safe and effective way to treat a subtype of trigeminal neuralgia--descending palatine neuralgia., (Copyright © 2014 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.)

Trigeminal neuropathic pain affects millions of people worldwide. Despite decades of study on the neuronal processing of pain, mechanisms underlying enhanced pain states after injury remain unclear. N-methyl-D-aspartate (NMDA) receptor-dependent changes play a critical role in triggering central sensitization in neuropathic pain. These receptors are regulated at the glycine site through a mandatory endogenous co-agonist D-serine, which is synthesized by astrocytes. Therefore, the present study was carried out to determine whether astrocytes are involved, through D-serine secretion, in dynamic mechanical allodynia (DMA) obtained after chronic constriction of the infraorbital nerve (CCI-IoN) in rats. Two weeks after CCI-IoN, an important reaction of astrocytes was present in the medullary dorsal horn (MDH), as revealed by an up-regulation of glial fibrillary acidic protein (GFAP) in allodynic rats. In parallel, an increase in D-serine synthesis, which co-localized with its synthesis enzyme serine racemase, was strictly observed in astrocytes. Blocking astrocyte metabolism by intracisternal delivery of fluorocitrate alleviated DMA. Furthermore, the administration of D-amino-acid oxidase (DAAO), a D-serine-degrading enzyme, or that of L-serine O-sulfate (LSOS), a serine racemase inhibitor, significantly decreased pain behavior in allodynic rats. These results demonstrate that astrocytes are involved in the modulation of orofacial post-traumatic neuropathic pain via the release of the gliotransmitter D-serine.

Aims: To develop a behavioral model in mice that is capable of mimicking some distinctive symptoms of human posttraumatic trigeminal neuropathic pain such as spontaneous pain, cold allodynia, and chemical÷inflammatory hyperalgesia, and to use this model to investigate the antinociceptive effects of clomipramine and tramadol, two drugs used for the treatment of neuropathic pain., Methods: A partial tight ligature of the right infraorbital nerve by an intraoral access or a sham procedure was performed. Fourteen days later, mice were subcutaneously injected with saline or drugs and the spontaneous nociceptive behavior, as well as the responses to topical acetone and to formalin or capsaicin injected into the ipsilateral vibrissal pad, were assessed. Data were analyzed by ANOVA., Results: Neuropathic mice exhibited an increased spontaneous rubbing÷scratching of the ipsilateral vibrissal pad, together with enhanced responses to cooling (acetone) and the chemical irritants (formalin, capsaicin). Clomipramine and tramadol produced an antihyperalgesic effect on most of these nociceptive responses, but tramadol was ineffective on capsaicin-induced hyperalgesia., Conclusion: Nociceptive responses in this neuropathic pain model in mice exhibited a pattern consistent with the pain described by posttraumatic trigeminal neuropathic patients. The selective antihyperalgesic effect obtained with two commonly used drugs for treating neuropathic pain confirms the validity of this preclinical model.

Background: Understanding the mechanism of trigeminal neuralgia may be elucidated by developing laboratory animal models that closely mimic the features of this specific type of neuropathic pain. We have developed an experimental animal model for trigeminal neuralgia using a technique of injecting cobra venom into the infraorbital nerve (ION) trunk., Methods: Male Sprague-Dawley rats were subjected to the administration of cobra venom or saline into the ION trunk. Mechanical stimuli were applied to the ION territory in consecutive days after surgery. Mechanical thresholds were measured over a 90-day period on the bilateral facial region. Vascular permeability in the ION territory was measured using Evans blue dye., Results: The cobra venom-treated rats developed mechanical allodynia 3 days after surgery that lasted for 60 days postoperatively at the ipsilateral side. The mechanical thresholds of the contralateral ION territory also showed a profound decrease but were sustained for only approximately 30 days. There was no change of mechanical thresholds in the control groups. The extravasation of Evans blue increased significantly in the skin after administration of cobra venom to the ION compared with control rats (P < 0.05)., Conclusion: The cobra venom model may provide a reasonable model for investigating the mechanism of trigeminal neuropathic pain.

The aim of the present study was to clarify the involvement of protein kinase Cγ (PKCγ) in the facial neuropathic pain following infraorbital nerve injury. We analyzed the change in PKCγ expression in the trigeminal spinal subnucleus caudalis (Vc) and upper cervical spinal cord (C1/C2) following chronic constriction injury of the infraorbital nerve (ION-CCI). We also studied ION-CCI-mediated mechanical nocifensive behavior in rats. The mechanical head-withdrawal threshold significantly decreased 1 to 14 days after ION-CCI compared with that before ION-CCI and in sham rats. The expression of PKCγ was significantly larger in the ipsilateral Vc compared with the contralateral side in ION-CCI rats 3, 7, and 14 days after ION-CCI. Intrathecal (i.t.) administration of the PKCγ inhibitor chelerythrine prevented an increase in the PKCγ expression in the ipsilateral Vc. Moreover, i.t. administration of chelerythrine annulled ION-CCI-mediated reduction in the head-withdrawal threshold. Taken together, these findings suggest that PKCγ expression in the Vc played an important role in the mechanism of orofacial static mechanical allodynia following trigeminal nerve injury.

This retrospective study assessed the effectiveness and complications of peripheral alcohol injections in the management of trigeminal neuralgia (TN). 100 patients were analyzed who received 250 peripheral alcohol injections from June 2004 to January 2010. The duration of effect of alcohol blocks, the effect of repeated administration, and complications associated with alcohol injections were examined. The distal injection technique was applied. The branch of the nerve was identified and confirmed. After carefully anesthetizing the nerve with local anesthesia, 1-1.5 ml of absolute alcohol was injected depending on the nerve involved. Pain relief lasted for a mean of 14.13 ± 8.66 months. There was a fall in the duration of effect with subsequent injections. No serious complications were reported. Only 3% patients presented with non-neuralgic pain, swelling, burning sensation, trismus, dysesthesia, soreness, infection and the expected loss of sensation along the branch involved in TN. The combination of efficacy and reduced morbidity makes this procedure preferable for the treatment of TN. Alcohol injections are useful in those who are refractory to drug therapy, the elderly, medically compromised patients, unwilling to undergo neurosurgical procedures and in whom surgery is delayed for any reason., (Copyright © 2010 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.)

Trigeminal neuralgia is a paroxysmal disorder with severely disabling facial pain and thus continues to be a real therapeutic challenge. At present there are few effective drugs for treatment of this pain. The present study was aimed to explore the involvement of BK(Ca) channels and Kv channels in the mechanical allodynia in a rat model of trigeminal neuropathic pain. Here the effectiveness of drug target injection at the trigeminal ganglion through the infraorbital foramen was first evaluated by immunofluorescence and animal behavior test. Trigeminal neuropathic pain model was established by chronic constriction injury of the infraorbital nerve (ION-CCI) in rats. BK(Ca) channel agonist and Kv channel antagonist were administered into the trigeminal ganglion in ION-CCI rats and sham rats by the above target injection method, and the facial mechanical pain threshold was measured. The results showed that the drug could accurately reach the trigeminal ganglion by target injection which was more effective than that by the normal injection around infraorbital foramen. Rats suffered significant mechanical allodynia in the whisker pad of the operated side from 6 d to 42 d after ION-CCI. BK(Ca) channel agonist NS1619 significantly and dose-dependently attenuated the facial mechanical allodynia and increased the facial mechanical pain threshold in ION-CCI rats 15 d after operation. Kv antagonist 4-AP was able to reduce the threshold in ION-CCI rats when facial mechanical threshold was partly recovered and relatively stable on the 35th day after operation. These results suggest that BK(Ca) channel agonist NS1619 and Kv channel antagonist 4-AP can significantly affect the rats' facial mechanical pain threshold after ION-CCI. Activation of BK(Ca) channels may be related to the depression of the primary afferent neurons in trigeminal neuropathic pain pathways. Activation of Kv channels may exert a tonic inhibition on the trigeminal neuropathic pain.

Objective: We report the case of a seemingly rare variation of a branch of the trigeminal nerve. This unusual finding is of practical importance to the neurosurgeon because ablation of this nerve(s) in such a case would require modification of technique. The existence of a bifurcated infraorbital nerve is also relevant for application of local anesthesia to portions of the face innervated by the maxillary nerve., Clinical Presentation: During cadaveric dissection of the face of a male specimen, 2 branches of the infraorbital nerve were identified emanating onto the face. The 2 branches entered separate osseous canals within the orbit to emerge via 2 infraorbital foramina., Intervention: The unusual variation of the trigeminal nerve branch in the reported case necessitates a change in the way in which the nerve is blocked clinically. A common practice involves blocking the infraorbital nerve as it emerges from the infraorbital foramen. The needle is aimed superiorly, posteriorly, and slightly laterally; however, to provide adequate anesthesia to both branches of the infraorbital nerve, as reported here, a needle can be inserted between the zygomatic arch and the notch of the mandible in the pterygopalatine fossa. After the needle contacts the lateral pterygoid plate, it is withdrawn slightly and angled both superiorly and anteriorly to pass into the pterygopalatine fossa., Conclusion: Although apparently uncommon, such derangement of the infraorbital nerve should be kept in mind by surgeons during surgical procedures in the region for treatment of various disorders including trigeminal neuralgia.

Purpose: First-division trigeminal neuralgia, or tic douloureux refractory to medications, presents problems to the surgeon because of the desirability of preserving corneal sensation. A new operation is described that may provide longer duration of pain relief than conventional supraorbital neurectomy, with preservation of the corneal reflex., Methods: Four patients underwent resection of the supratrochlear and supraorbital nerves within the orbit accessed from an upper eyelid skin crease incision., Results: Three patients with typical idiopathic trigeminal neuralgia involving branches of the frontal nerve are without pain 22 to 25 months after surgery. The final patient with atypical pain had no improvement after the procedure. Frontal nerve distribution anesthesia is present in all patients. Postoperative ptosis resolved in all patients within 4 months of surgery., Conclusions: This procedure should be added to the treatment options for patients with first-division trigeminal neuralgia. By avoiding injury to the trigeminal root and ganglion, this surgery carries no risk of facial motor dysfunction, dysthesia, and/or anesthesia in the other trigeminal branches including corneal anesthesia.

Surgical treatment of mechanical trigeminal nerve injuries resulting in neuropathic pain varies with the type of injury (i.e., amputation or compression), presence of painful neuromas, and adjacent hard/soft tissues. Microsurgical principles that include access, preparation, and repair of the various nerve injuries are recommended for surgical treatment. The choice of surgical repair depends on the microscopic pathology and the presence or absence of adequate distal nerve tissue.

Neuronal activities of the somatosensory (Sm1) vibrissa cortex were explored bilaterally under moderate gaseous anaesthesia in rats with a chronic constriction injury (CCI) of an infraorbital nerve (IoN). The CCI-IoN rats exhibited abnormal pain-related reactions to mechanical stimuli directed to the territory of the injured nerve, just prior to the recording session. The responsiveness, laminar localisation, and somatotopic organisation of 388 neurones were recorded in the pad vibrissa cortex contralateral (Cc, n=249) and ipsilateral (Ci, n=139) to the injured nerve, analysed, and compared with 223 neurones recorded in a parallel study of the Sm1 cortex in normal rats (Cn). The mean background activity of all the recorded neurones was relatively low, whether they were located in the Cn, Cc or Ci. The responsive neurones occurred in similar proportions in the Cc and Ci (approximately 55%) and significantly more frequently than in the Cn (35%). They consisted mainly of vibrissa neurones (100% in Cn, 85% in Cc, and 93% in Ci). The ratio [vibrissa neurones/(vibrissa+unresponsive) neurones] was enhanced in all the cortical layers of the Cc and Ci, except in the Cc layer IV. The receptive field (RF) size of the vibrissa neurones also differed greatly. It was limited to one vibrissa for 88% of the Cn neurones, but expanded to two or more vibrissae for 72% of the Cc and 52% of the Ci neurones. These multivibrissa units, mostly located in layers V and VIa for the few Cn neurones, were scattered in the different layers in CCI-IoN rats, with the largest RFs occurring in the deepest layers. In parallel, the cortical somatotopy of the vibrissae, roughly comparable with that initially described in pioneer studies of normal rats, was dramatically disturbed not only in the Cc, but also in the Ci of CCI-IoN rats. Contrasting with the results previously obtained in the ventro-postero-median thalamic nucleus of CCI-IoN rats, no neurones were driven by pinches or pinpricks applied to the cutaneous part of the vibrissa pad. It is questioned whether the disorganisation within the cortical map of the whisker pad, and the expanded RFs of vibrissa neurones could account for the abnormal pain-related reactions elicited from the massively deafferented trigeminal area.

Trigeminal neuralgia and cluster headache syndrome are complex pain conditions of the craniofacial region. Both diseases can coexist in the same patient, comprising the cluster-tic syndrome. This article reviews the literature on this condition and reports a new case who responded well to peripheral streptomycin-lidocaine injections.

Many etiologies have been postulated to explain the pathogenesis of Trigeminal Neuralgia (TN). Most theories focus on a demyelinating process resulting in ephaptic transmission and recruitment of small pain fibers or a restrictive relationship of the superior cerebellar arteries and the trigeminal nerve roots at the level of the pons which may lead to demyelination. It is postulated that vasodilation or constriction of these vessels in a confined bony canal can create localized regions of demyelination and restrictive relationships creating painful stimuli. It is the purpose of this study to grossly investigate the relationship of the infraorbital nerve and vessels passing through the infraorbital canal to discuss whether their relationship may play a role in the pathogenesis of idiopathic TN. Patterns of relationship have been elucidated and will be described. This preliminary gross anatomical study should set the framework from which to base further microscopic and clinical studies.

The intensity of clinical manifestations (rubbing of the oro-facial area with skin injury), bioelectric activity of the somatosensory cortex and microcirculatory disturbances were studied for 6 weeks in Wistar rats with partial infraorbital nerve compression. These parameters were compared among rats of the following groups: without skin rubbing (1), with them (2), with repaired skin (3) after nerve compression and sham-operated rats (4). A correlation between the intensity of clinical manifestations and microcirculatory disturbances was shown. Epileptiform cortex activity was observed in 100% and 75% rats of the 2nd and 3rd groups, respectively, while in group 1 this per cent decreased time. These results are discussed with regard to the formation of pathologic algic system which underlies the pain syndrome and affects peripheral target organs.

Bioelectrical activity of the somatosensory cortex was studied in the Wistar rats with chronic (1.5-2 months) compression of the infraorbital nerve produced by two partial ligations. In 20% of rats spike-slow wave complex and slow waves were observed. Electrostimulation of the skin on the injured nerve side resulted in a considerable increase in the amplitude of early components of the contralaterally evoked potentials in comparison with the non-injured side stimulation in 75% of rats. A decrease in the evoked potential thresholds on the injured nerve stimulation was shown in both hemispheres. In most of the animals a hypersynchronous late component of the evoked potential was observed.

A new tool in neurophysiological exploration of the trigeminal nerve has recently been introduced. It has been demonstrated that stimulation of the infraorbital nerve trunk gives rise to very reliable scalp responses reflecting the activity of the afferent pathway between the maximally nerve and the brain stem. The authors demonstrate that alterations of such trigeminal evoked responses fit with documented pathological processes at various locations along the trigeminal pathway (maxillary sinus, parasellar region, and within the brain-stem parenchyma). They report the findings in 68 patients suffering from "idiopathic" trigeminal neuralgia. Alterations of the response were detected in 33 cases, suggesting that some damage of the nerve had taken place either at the root entry zone into the pons (23 cases) or slightly distal to it (10 cases). Such results support the hypothesis that trigeminal neuralgia may be due to a compression of the trigeminal root at the pons entry zone.

Paroxysmal trigeminal neuralgia still remains a difficult condition to treat. Carbamazepine (Tegretol) has been a first line treatment, failing this surgery becomes necessary. However, many surgical procedures result in permanent sensory loss. Peripheral cryotherapy, along with the recently described Jannetta (1976) and Hakanson (1981) techniques, attempt to preserve sensation. Cryotherapy to 53 branches of the trigeminal nerve in 39 patients, who were followed up for 4 years, resulted in pain relief out-lasting return of sensation. These cases show that cryotherapy applied to the correctly located affected nerve branches can produce results which are unobtainable by other methods of pain control in paroxysmal trigeminal neuralgia.

In 55 patients with trigeminal pain syndromes of different genesis a study of the state of the orbit-pupillar innervation was undertaken judging by the response to sympathomimetic drugs (adrenalin and cocaine solutions) administered into the conjunctival sack. The obtained data were evaluated by way of pupillography. The disorders in sympathetic orbit-pupillary innervation were found to be independent of a prevailing lesion of any of the three peripheral branches of the trigeminal nerve. Trigeminal neuralgias develop without any disorders in the sympathetic orbit-pupillary innervation. In the presence of a neuritic component in trigeminal pains the disorders in the sympathetic orbit-pupillary innervation are noted invariably. In anaesthesia dolorosa of the face an important place in the genesis of the pain syndrome belongs to the cranial portion of the sympathetic nervous system.