Trigeminal Innervation Research Articles

Corneal Denervation Causes Epithelial Apoptosis Through Inhibiting NAD+ Biosynthesis.

To determine if trigeminal innervations of the corneal epithelium maintains its integrity and homeostasis through controlling the nicotinamide adenine dinucleotide (NAD) content of this tissue. Corneal denervation of C57BL/6 mice was induced by squeezing the nerve bundles that derive from the trigeminal ganglion and was confirmed by whole-mount corneal nerve staining and the sensation test. The apoptosis of the corneal epithelium was examined by TUNEL assay and annexin V/propidium iodide staining. NAD biosynthesis-related enzymes were analyzed by quantitative PCR, immunofluorescence staining, and Western blotting. FK866, an inhibitor of nicotinamide phosphoribosyltransferase (NAMPT), exogenous nicotinamide mononucleotide (NMN), and NAD+ were used to evaluate the effect of NAD+ on the apoptosis of cultured corneal epithelial cells and epithelial detachment in denervated mice. Protein expression that related to apoptosis and phosphorylation were analyzed by Western blotting. The denervated mice showed spontaneous corneal epithelial detachment and cell apoptosis accompanied with impaired epithelial NAD+ contents due to low levels of NAMPT. Similarly, inhibition of NAMPT recapitulated epithelial detachment as in denervated mice and induced apoptosis in cultured corneal epithelial cells. The replenishment of NMN or NAD+ partially slowed down corneal nerve fiber degeneration, reduced the epithelial defect in denervated mice, and improved apoptosis induction in FK866-treated cells by restoring the activation levels of SIRT1, AKT, and CREB. Corneal denervation lowered epithelial NAD+ contents through reducing the expression of NAMPT and caused cell apoptosis and epithelial defects, suggesting that corneal innervations contribute to epithelial homeostasis by regulating NAD+ biosynthesis.

Detection of Spicy Compounds Using the Electronic Tongue

The consumption of spicy food products has increased, resulting in an increased demand for these products. The sensory evaluation of foods containing spicy compounds provides challenges due to their trigeminal innervation and associated sensory fatigue. Thus, for the routine evaluation of spices, a need exists for rapid and objective methods of analysis; the electronic tongue (e-tongue) provides a potential solution. The objective of this study was to evaluate the ability of the e-tongue to distinguish among spicy compounds at varying concentrations. Due to the diversity of spicy compounds, seven spicy compounds were selected: capsaicin, thymol, piperine, zingerone, p-cymene, menthol, and eugenol. For each of these compounds, a low concentration (1.427 × 10-5 to 0.85 mg/L), medium concentration (2.854 × 10-5 to 1.49 mg/L), and high concentration (0.0133 to 30.5 mg/L) were analyzed by the e-tongue. For each compound, the e-tongue discriminated among the concentrations with discrimination indices between 72% to 84%. Based on the responses of the e-tongue sensors, the samples formed three clusters. Cluster 1 contained menthol, eugenol, and p-cymene, cluster 2 contained capsaicin and thymol, and cluster 3 contained piperine and zingerone. Same-different sensory testing was completed on a representative sample from each cluster. Untrained consumers (n = 80) distinguished among the three clusters, verifying the clusters identified by the e-tongue. These results demonstrated that the e-tongue could be applicable in product development and the routine evaluation of spicy products. PRACTICAL APPLICATION: As the e-tongue differentiated among spicy compounds in an effective manner, it could be used instead of or alongside sensory evaluation when evaluating spicy compounds to reduce sensory fatigue associated with routine testing. Utilizing the e-tongue for spicy products will be an important area of research as the market for such products continues to grow.

Dental occlusion as one cause of tinnitus

There is large support in literature linking tinnitus to dental occlusion and temporomandibular joint disorders (TMD). However, there is no model to explain such a link. This hypothesis explains how the fusimotor system of the muscles innervated by the trigeminal motor nucleus is affected by inadequacies in the occlusion of the teeth that cause changes in posture and movement of the mandible. Reptile to mammal evolution shows that stomatognathic structures underwent changes related to mastication. Among several changes, there was the appearance of a new articulation between the mandible and skull: the temporomandibular joint. The bones of the old reptile joint, quadrate-articular, have detached from the mandible and are part of the middle ear bone chain. The former becomes the incus and the latter the malleus. This bone change also carried the tensor tympani and its trigeminal motor innervation. Inadequate occlusal contacts give rise to an adapted function of the mandible and the most common compensatory muscular response is hypertonia involving all mandibular muscles, including the tensor tympani. A fundamental clinical feature that demonstrates the involvement of the trigeminal fusimotor system is the characteristic pain by palpation, but no pain on the mandibular movement. Muscle pain is always felt in the dermatome innervated by the mandibular branch of the trigeminal nerve, which carries the motor fibers, reported as tightening, similar to cramp, and has regular behavior in intensity, duration and frequency. In addition, the patient has increased musculature volume, detected by palpation of certain anatomical landmarks, but with loss of functional efficiency. The neuromotor control of the mandibular movements is poor and when asked to make lateral jaw movement touching the teeth, it is common to observe that the patient moves the lips, eyes, and even turns the head in the same direction as the movement. There is also difficulty eating hard foods and talking fast. Tongue biting while chewing is frequent, meaning that these non-physiological events surpass protective reflex circuits. The report of ear pain, tinnitus, blocked ear sensation and sudden hearing loss is common in such patients, compatible with the tonic contraction of the tensor tympani. The fusimotor system hypothesis is able to explain all events related to the symptoms and helps to establish a correct diagnosis for certain types of hearing disorders.

An updated review on pathophysiology and management of burning mouth syndrome with endocrinological, psychological and neuropathic perspectives.

Burning mouth syndrome (BMS) is a chronic oro-facial pain disorder of unknown cause. It is more common in peri- and post-menopausal women, and sex hormone dysregulation is believed to be an important causative factor. Psychosocial events often trigger or exacerbate symptoms, and persons with BMS appear to be predisposed towards anxiety and depression. Atrophy of small nerve fibres in the tongue epithelium has been reported, and potential neuropathic mechanisms for BMS are now widely investigated. Historically, BMS was thought to comprise endocrinological, psychosocial and neuropathic components. Neuroprotective steroids and glial cell line-derived neurotrophic factor family ligands may have pivotal roles in the peripheral mechanisms associated with atrophy of small nerve fibres. Denervation of chorda tympani nerve fibres that innervate fungiform buds leads to alternative trigeminal innervation, which results in dysgeusia and burning pain when eating hot foods. With regard to the central mechanism of BMS, depletion of neuroprotective steroids alters the brain network-related mood and pain modulation. Peripheral mechanistic studies support the use of topical clonazepam and capsaicin for the management of BMS, and some evidence supports the use of cognitive behavioural therapy. Hormone replacement therapy may address the causes of BMS, although adverse effects prevent its use as a first-line treatment. Selective serotonin reuptake inhibitors (SSRIs) and serotonin and noradrenaline reuptake inhibitors (SNRIs) may have important benefits, and well-designed controlled studies are expected. Other treatment options to be investigated include brain stimulation and TSPO (translocator protein 18kDa) ligands.

Post-herpes neurotrophic keratopathy: Aetiopathogenesis, clinical signs and current therapies

Neurotrophic keratopathy (NK) is a degenerative corneal disease caused by damage of trigeminal innervation. This leads to epithelial defects, ulceration and, eventually, perforation. Both herpes simplex and varicella zoster keratitis are reported to be the main causes of NK. Furthermore, prognosis in this type of NK is poor. Classic clinical findings in post-herpes NK are spontaneous epithelial breakdown, round and central epithelial defects with smooth edges, stromal melting and thinning, scarring, and neovascularisation. Although several medical and surgical treatments have been reported, no therapies are currently available to definitely restore corneal sensitivity. Therefore, NK remains a challenging disease to treat. In this review a summary is presented of the pathogenesis, manifestations, and current management of post-herpes NK. The role of antiviral treatment and varicella-zoster vaccination is also discussed. A description is also presented on both medical and surgical novel therapies, such as regenerative drugs and corneal neurotization.

Microvillous cells in the olfactory epithelium express elements of the solitary chemosensory cell transduction signaling cascade.

The nasal cavity hosts an array of chemoresponsive cells, including the extended olfactory system and several other cells involved in detection of and responses to irritants. Solitary chemosensory cells (SCCs), which respond to irritants and bacteria, express the transient receptor potential channel TRPM5 an essential element of the taste transduction-signaling cascade. Microvillous cells (MVCs), non-neuronal cells situated in the apical layer of the main olfactory epithelium, also express TRPM5, but their function has not yet been clarified. TRPM5-positive MVCs, like SCCs, show a cholinergic phenotype expressing choline acetyl transferase (ChAT), but none of the other elements of the bitter taste transduction cascade could be detected. We reexamined TRPM5-positive MVCs with more sensitive gene expression and staining techniques to clarify whether they rely only on TRPM5 and ChAT or express other elements of the taste/SCC transduction cascade. Analyzing existing RNA sequencing data from whole olfactory mucosa and isolated olfactory sensory neurons, we determined that several elements of the taste/SCC transduction cascade, including taste receptors, are expressed in the olfactory mucosa in cells other than olfactory sensory neurons. Immunostaining confirmed the presence TRPM5 and ChAT in a subset of cells of the olfactory mucosa, which also showed the expression of PLCB2, gustducin, and T1R3. Specifically, these cells were identified as TRPM5-positive MVCs. Furthermore, we examined whether MVCs are innervated by trigeminal fibers, similarly to SCCs. Using antibodies against trigeminal nerve markers calcitonin gene-related peptide and substance P, we determined that, despite the cholinergic phenotype, most MVCs in the olfactory mucosa lacked consistent trigeminal innervation. Our findings indicate that MVCs, like SCCs, express all the elements of the bitter taste transduction cascade but that, unlike SCCs, they possess only sparse trigeminal innervation. The cholinergic phenotype of MVCs suggests a modulatory function of the surrounding olfactory epithelium, through the release of acetylcholine.

Neurotrophic keratitis: current challenges and future prospects.

Neurotrophic keratitis (NK) is a degenerative corneal disease caused by damage of trigeminal corneal innervation, which leads to spontaneous epithelial breakdown and corneal ulceration. The impairment of corneal sensory innervation causes the reduction of both protective reflexes and trophic neuromodulators that are essential for the vitality, metabolism, and wound healing of ocular surface tissues. A wide range of ocular and systemic conditions, including herpetic keratitis, ocular chemical burns, corneal surgery, diabetes, multiple sclerosis, and neurosurgical procedures, can cause NK by damaging trigeminal innervation. Diagnosis of NK requires careful investigation of any ocular and systemic condition associated with the disease, complete ocular surface examination, and quantitative measurement of corneal sensitivity. The clinical stages of NK range from corneal epithelial alterations (stage 1) to persistent epithelial defect (stage 2) and ulcer (stage 3), which may progress to corneal perforation. Management of NK is based on clinical severity, and the aim of the therapy is to halt the progression of corneal damage and promote epithelial healing. Although several medical and surgical treatments have been proposed, no therapies are currently available to restore corneal sensitivity, and thus, NK remains difficult and challenging to treat. The purpose of this review is to summarize available evidence on the pathogenesis, diagnosis, and treatment of NK. Novel medical and surgical therapies including the topical administration of nerve growth factor and corneal neurotization are also described.

Neurogenic inflammation and its role in migraine.

The etiology of migraine pain involves sensitized meningeal afferents that densely innervate the dural vasculature. These afferents, with their cell bodies located in the trigeminal ganglion, project to the nucleus caudalis, which in turn transmits signals to higher brain centers. Factors such as chronic stress, diet, hormonal fluctuations, or events like cortical spreading depression can generate a state of "sterile inflammation" in the intracranial meninges resulting in the sensitization and activation of trigeminal meningeal nociceptors. This sterile inflammatory phenotype also referred to as neurogenic inflammation is characterized by the release of neuropeptides (such as substance P, calcitonin gene related peptide) from the trigeminal innervation. This release leads to vasodilation, plasma extravasation secondary to capillary leakage, edema, and mast cell degranulation. Although neurogenic inflammation has been observed and extensively studied in peripheral tissues, its role has been primarily investigated in the genesis and maintenance of migraine pain. While some aspects of neurogenic inflammation has been disregarded in the occurrence of migraine pain, targeted analysis of factors have opened up the possibilities of a dialogue between the neurons and immune cells in driving such a sterile neuroinflammatory state in migraine pathophysiology.

Vitamin B12 Deficiency as a Cause of Neurotrophic Keratopathy

Introduction: Neurotrophic keratitis is a rare degenerative corneal disease caused by an impairment of trigeminal corneal innervation, leading to a decrease or absence of corneal sensation. Here, we present a case of neurotrophic keratopathy caused by B12 deficiency in a 34 years old man who had a progressive decrease in visual acuity and corneal involvement since 3 months before being referred to our ophthalmology clinic. Result and Discussion: Based on our clinical findings and with the diagnosis of B12 deficiency we started B12 treatment for the patient. After 3 weeks the patient showed a dramatic response with corneal sensation reversal, an increase of visual acuity, improved neurotrophic keratopathy and significantly improved neurological findings. To the best of our knowledge, there is no report regarding vitamin B12 deficiency induced keratopathy and this is the first report that describes this aspect of vitamin B12 deficiency.

Evolution of facial innervation in anomodont therapsids (Synapsida): Insights from X-ray computerized microtomography.

Anomodontia was the most successful herbivorous clade of the mammalian stem lineage (non-mammalian synapsids) during the late Permian and Early Triassic. Among anomodonts, Dicynodontia stands apart because of the presence of an osseous beak that shows evidence of the insertion of a cornified sheath, the ramphotheca. In this study, fourteen anomodont specimens were microCT-scanned and their trigeminal canals reconstructed digitally to understand the origin and evolution of trigeminal nerve innervation of the ramphotheca. We show that the pattern of innervation of the anomodont "beak" is more similar to that in chelonians (the nasopalatine branch is enlarged and innervates the premaxillary part of the ramphotheca) than in birds (where the nasopalatine and maxillary branches play minor roles). The nasopalatine branch is noticeably enlarged in the beak-less basal anomodont Patranomodon, suggesting that this could be an anomodont or chainosaur synapomorphy. Our analyses suggest that the presence or absence of tusks and postcanine teeth are often accompanied by corresponding variations of the rami innervating the caniniform process and the alveolar region, respectively. The degree of ossification of the canal for the nasal ramus of the ophthalmic branch also appears to correlate with the presence of a nasal boss. The nasopalatine canal is absent from the premaxilla in the Bidentalia as they uniquely show a large plexus formed by the internal nasal branch of the maxillary canal instead. The elongated shape of this plexus in Lystrosaurus supports the hypothesis that the rostrum evolved as an elongation of the subnarial region of the snout. Finally, the atrophied and variable aspect of the trigeminal canals in Myosaurus supports the hypothesis that this genus had a reduced upper ramphotheca.

Experimental evidence for weaker endogenous inhibition of trigeminal pain than extra-trigeminal pain in healthy individuals.

Background and objectives The prevalence of pain syndromes that affect the territories innervated by the trigeminal nerve, such as headaches, is one of the highest and ranks second only to low back pain. A potential mechanism underlying this high prevalence may be a relatively weak endogenous pain modulation of trigeminal pain. Here, we sought to systematically compare endogenous pain modulation capabilities in the trigeminal region to those of extra-trigeminal regions in healthy subjects. Methods Healthy, pain free subjects (n = 17) underwent a battery of quantitative sensory testing to assess endogenous pain inhibition and pain enhancement efficiencies within and outside the trigeminal innervated region. Measurements included conditioned pain modulation (CPM), temporal summation of pain (TSP) and spatial summation of pain (SSP). Results Testing configurations that included trigeminal-innervated body regions displayed significantly weaker CPM when compared to extra-trigeminal innervated areas. SSP magnitude was smaller in the ophthalmic trigeminal innervation when compared to other body regions. TSP magnitude was not different between the different body regions tested. Conclusions Our findings point to regional differences in endogenous pain inhibition and suggest that in otherwise healthy individuals, the trigeminal innervation is subjected to a weaker inhibitory pain control than other body regions. Such weaker endogenous pain control could play, at least in part, a role in mediating the high prevalence of trigeminal-related pain syndromes, including primary headaches and TMD pain.

Archosauriform endocranial morphology and osteological evidence for semiaquatic sensory adaptations in phytosaurs.

The examination of endocranial data of archosauriforms has led to advances on the evolution of body size, nerve pathways, and sensory abilities. However, much of that research has focused on bird-line archosaurs, resulting in a skewed view of Archosauria. Phytosauria, a hypothesized sister taxon to or early-branching member of Archosauria, provides a potential outgroup condition. Most previous phytosaur endocranial studies were executed without the use of modern technology and focused on derived members of Phytosauria. We present a comparative CT examination of the internal cranial anatomy of Wannia scurriensis, the most basal known parasuchid phytosaur. Wannia scurriensis shows some overall similarity with extant crocodylians and derived phytosaurs in general endocranial shape, a large hypophyseal fossa, and trigeminal (CN V) innervation, but as a whole, the endocast has noticeable differences to crocodylians and other phytosaurs. The pineal region is expanded dorsally as in other phytosaurs but also laterally (previously unrecognized). CN V exits the pons in a more dorsal position than in Parasuchus hislopi, Machaeroprosopus mccauleyi, or Smilosuchus gregorii. Wannia scurriensis also exhibits a larger hypophyseal fossa relative to brain size than observed in P.hislopi or S.gregorii, which may indicate more rapid growth. The well-preserved semicircular canals have lateral canals that are angled more anteroventrally than in derived phytosaurs. Extensive facial innervation from the large CN V indicates increased rostrum sensitivity and mechanoreceptive abilities as in Alligator mississippiensis. These endocranial similarities among phytosaurs and with Alligator indicate conserved ecological and functional results of an aquatic lifestyle, and highlight a need for further exploration of endocranial anatomy among Archosauriformes.

Burning Mouth Syndrome and Acupuncture

Abstract Background: Burning mouth syndrome (BMS) is described as a sudden bilateral orofacial pain characterized as burning, scalding, tingling, or numbness. Diagnosis remains challenging and therapeutics are equally difficult. Complete spontaneous remission is rare. This article reports a case of BMS managed successfully with acupuncture. Case: A 53-year-old woman presented with a 3-year history of orofacial pain described as “burning, tingling, pins, scalded, numbness and electric shock” sensations, with a profound impact on her daily activities. A physical examination showed no visible lesions and examinations yielded unremarkable results. She was diagnosed with BMS and prescribed pregabalin and tramadol, as she had no benefits from rescue therapy after 6 months. She was then offered 8 acupuncture treatment sessions with a weekly frequency. Points used were local points of the trigeminal innervation (ST 5, ST 6, ST 7, SI 18, GB 2, and TE 21) and systemic action points (GV 24, LI 4, ST 44, and ST 36). ...

Possible role of calcitonin gene-related peptide in trigeminal modulation of glomerular microcircuits of the rodent olfactory bulb.

Chemosensation in the mammalian nose comprises detection of odorants, irritants and pheromones. While the traditional view assigned one distinct sub-system to each stimulus type, recent research has produced a more complex picture. Odorants are not only detected by olfactory sensory neurons but also by the trigeminal system. Irritants, in turn, may have a distinct odor, and some pheromones are detected by the olfactory epithelium. Moreover, it is well established that irritants change odor perception and vice versa. A wealth of psychophysical evidence on olfactory-trigeminal interactions in humans contrasts with a paucity of structural insight. In particular, it is unclear whether the two systems communicate just by sharing stimuli, or whether neuronal connections mediate cross-modal signaling. One connection could exist in the olfactory bulb that performs the primary processing of olfactory signals and receives trigeminal innervation. In the present study, neuroanatomical tracing of the mouse ethmoid system illustrates how peptidergic fibers enter the glomerular layer of the olfactory bulb, where local microcircuits process and filter the afferent signal. Biochemical assays reveal release of calcitonin gene-related peptide from olfactory bulb slices and attenuation of cAMP signaling by the neuropeptide. In the non-stimulated tissue, the neuropeptide specifically inhibited the basal activity of calbindin-expressing periglomerular interneurons, but did not affect the basal activity of neurons expressing calretinin, parvalbumin, or tyrosine hydroxylase, nor the activity of astrocytes. This study represents a first step towards understanding trigeminal neuromodulation of olfactory-bulb microcircuits and provides a working hypothesis for trigeminal inhibition of olfactory signal processing. This article is protected by copyright. All rights reserved.

Understanding the Pathogenesis of Neurotrophic Keratitis: The Role of Corneal Nerves.

Neurotrophic keratitis (NK) is a rare degenerative disease of the cornea caused by trigeminal nerve damage, which leads to loss of corneal sensitivity, corneal epithelium breakdown, and poor healing. Though extremely uncommon, NK is increasingly recognized for its characteristics as a distinct and well-defined clinical entity rather than a rare complication of various diseases that can disrupt trigeminal innervation. Indeed, the defining feature of NK is loss of corneal sensitivity, and its clinical findings do not correlate with the wide range of systemic or ocular conditions that underlie trigeminal nerve damage. Despite increasing awareness of NK as a distinct condition, its management continues to be challenged by the lack of treatments that target nerve regeneration. This review focuses on the role of corneal nerves in maintaining ocular surface homeostasis, the consequences (such as alterations in neuromediators and corneal cell morphology/function) of impaired innervation, and advances in NK diagnosis and management. Novel therapeutic strategies should aim to improve corneal innervation in order support corneal renewal and healing. J. Cell. Physiol. 232: 717-724, 2017. © 2016 Wiley Periodicals, Inc.

Immunocytochemical organization and sour taste activation in the rostral nucleus of the solitary tract of mice.

Sensory inputs from the oropharynx terminate in both the trigeminal brainstem complex and the rostral part of the nucleus of the solitary tract (nTS). Taste information is conveyed via the facial and glossopharyngeal nerves, while general mucosal innervation is carried by the trigeminal and glossopharyngeal nerves. In contrast, the caudal nTS receives general visceral information largely from the vagus nerve. Although the caudal nTS shows clear morphological and molecularly delimited subdivisions, the rostral part does not. Thus, linking taste-induced patterns of activity to morphological subdivisions in the nTS is challenging. To test whether molecularly defined features of the rostral nTS correlate with patterns of taste-induced activity, we combined immunohistochemistry for markers of various visceral afferent and efferent systems with c-Fos-based activity maps generated by stimulation with a sour tastant, 30 mM citric acid. We further dissociated taste-related activity from activity arising from acid-sensitive general mucosal innervation by comparing acid-evoked c-Fos in wild-type and "taste blind" P2X2 /P2X3 double knockout (P2X-dbl KO) mice. In wild-type mice, citric acid stimulation evoked significant c-Fos activation in the central part of the rostral nTS-activity that was largely absent in the P2X-dbl KO mice. P2X-dbl KO mice, like wild-type mice, did exhibit acid-induced c-Fos activity in the dorsomedial trigeminal brainstem nucleus situated laterally adjacent to the rostral nTS. This dorsomedial nucleus also showed substantial innervation by trigeminal nerve fibers immunoreactive for calcitonin gene-related peptide (CGRP), a marker for polymodal nociceptors, suggesting that trigeminal general mucosal innervation carries information about acids in the oral cavity. J. Comp. Neurol. 525:271-290, 2017. © 2016 Wiley Periodicals, Inc.

GABA-A receptor activity in the noradrenergic locus coeruleus drives trigeminal neuropathic pain in the rat; contribution of NAα1 receptors in the medial prefrontal cortex

Trigeminal neuropathic pain is described as constant excruciating facial pain. The study goal was to investigate the role of nucleus locus coeruleus (LC) in a model of chronic orofacial neuropathic pain (CCI-ION). The study examines LC’s relationship to both the medullary dorsal horn receiving trigeminal nerve sensory innervation and the medial prefrontal cortex (mPFC). LC is a major source of CNS noradrenaline (NA) and a primary nucleus involved in pain modulation. Although descending inhibition of acute pain by LC is well established, contribution of the LC to facilitation of chronic neuropathic pain is also reported. In the present study, a rat orofacial pain model of trigeminal neuropathy was induced by chronic constrictive injury of the infraorbital nerve (CCI-ION). Orofacial neuropathic pain was indicated by development of whisker pad mechanical hypersensitivity. Hypersensitivity was alleviated by selective elimination of NA neurons, including LC (A6 cell group), with the neurotoxin anti-dopamine-β-hydroxylase saporin (anti-DβH-saporin) microinjected either intracerebroventricularly (i.c.v.) or into trigeminal spinal nucleus caudalis (spVc). The GABAA receptor antagonist, bicuculline, administered directly into LC (week 8) inhibited hypersensitivity. This indicates a valence shift in which increased GABAA signaling ongoing in LC after trigeminal nerve injury paradoxically produces excitatory facilitation of the chronic pain state. Microinjection of NAα1 receptor antagonist, benoxathian, into mPFC attenuated whisker pad hypersensitivity, while NAα2 receptor antagonist, idazoxan, was ineffective. Thus, GABAA-mediated activation of NA neurons during CCI-ION can facilitate hypersensitivity through NAα1 receptors in the mPFC. These data indicate LC is a chronic pain generator.

Pain. Part 7: Trigeminal Neuralgia.

Trigeminal neuralgia (TN) is also known as 'tic douloureux' (in French, 'painful twitch'). It is a rare chronic facial pain syndrome, characterized by severe, brief, stabbing, 'electric shock-like 'recurrent pain attacks felt in one or more divisions of trigeminal nerve innervation areas. So intense is the elicited pain that TN has a significant effect on a sufferer's quality of life, rendering many patients unable to consider a future with the ongoing threat of recurrent pain. The aim of this article is to discuss the diagnosis and management of this disabling facial pain condition. CPD/Clinical Relevance: As general medical practitioners may struggle differentiating TN from toothache, primary care dentists have an important role in excluding odontogenic cause of pain, diagnosing TN and referring patients to a facial pain clinic for further investigations and multidisciplinary team management.

Facial Mechanosensory Influence on Forelimb Movement in Newborn Opossums, Monodelphis domestica.

The opossum, Monodelphis domestica, is born very immature but crawls, unaided, with its forelimbs (FL) from the mother's birth canal to a nipple where it attaches to pursue its development. What sensory cues guide the newborn to the nipple and trigger its attachment to it? Previous experiments showed that low intensity electrical stimulation of the trigeminal ganglion induces FL movement in in vitro preparations and that trigeminal innervation of the facial skin is well developed in the newborn. The skin does not contain Vater-Pacini or Meissner touch corpuscles at this age, but it contains cells which appear to be Merkel cells (MC). We sought to determine if touch perceived by MC could exert an influence on FL movements. Application of the fluorescent dye AM1-43, which labels sensory cells such as MC, revealed the presence of a large number of labeled cells in the facial epidermis, especially in the snout skin, in newborn opossums. Moreover, calibrated pressure applied to the snout induced bilateral and simultaneous electromyographic responses of the triceps muscle in in vitro preparations of the neuraxis and FL from newborn. These responses increase with stimulation intensity and tend to decrease over time. Removing the facial skin nearly abolished these responses. Metabotropic glutamate 1 receptors being involved in MC neurotransmission, an antagonist of these receptors was applied to the bath, which decreased the EMG responses in a reversible manner. Likewise, bath application of the purinergic type 2 receptors, used by AM1-43 to penetrate sensory cells, also decreased the triceps EMG responses. The combined results support a strong influence of facial mechanosensation on FL movement in newborn opossums, and suggest that this influence could be exerted via MC.

New insights into pathophysiology of vestibular migraine.

Vestibular migraine (VM) is a common disorder in which genetic, epigenetic, and environmental factors probably contribute to its development. The pathophysiology of VM is unknown; nevertheless in the last few years, several studies are contributing to understand the neurophysiological pathways involved in VM. The current hypotheses are mostly based on the knowledge of migraine itself. The evidence of trigeminal innervation of the labyrinth vessels and the localization of vasoactive neuropeptides in the perivascular afferent terminals of these trigeminal fibers support the involvement of the trigemino-vascular system. The neurogenic inflammation triggered by activation of the trigeminal-vestibulocochlear reflex, with the subsequent inner ear plasma protein extravasation and the release of inflammatory mediators, can contribute to a sustained activation and sensitization of the trigeminal primary afferent neurons explaining VM symptoms. The reciprocal connections between brainstem vestibular nuclei and the structures that modulate trigeminal nociceptive inputs (rostral ventromedial medulla, ventrolateral periaqueductal gray, locus coeruleus, and nucleus raphe magnus) are critical to understand the pathophysiology of VM. Although cortical spreading depression can affect cortical areas involved in processing vestibular information, functional neuroimaging techniques suggest a dysmodulation in the multimodal sensory integration and processing of vestibular and nociceptive information, resulting from a vestibulo-thalamo-cortical dysfunction, as the pathogenic mechanism underlying VM. The elevated prevalence of VM suggests that multiple functional variants may confer a genetic susceptibility leading to a dysregulation of excitatory–inhibitory balance in brain structures involved in the processing of sensory information, vestibular inputs, and pain. The interactions among several functional and structural neural networks could explain the pathogenic mechanisms of VM.