Perineural Invasion and Perineural Tumor Spread in Head and Neck Cancer.

Perineural invasion (PNI), the neoplastic invasion of nerves, is a common pathologic finding in head and neck cancer that is associated with poor clinical outcomes. PNI is a histologic finding of tumor cell infiltration and is distinct from perineural tumor spread (PNTS), which is macroscopic tumor involvement along a nerve extending from the primary tumor that is by definition more advanced, being radiologically or clinically apparent. Despite widespread acknowledgment of the prognostic significance of PNI and PNTS, the mechanisms underlying its pathogenesis remain largely unknown, and specific therapies targeting nerve invasion are lacking. The use of radiation therapy for PNI and PNTS can improve local control and reduce devastating failures at the skull base. However, the optimal volumes to be delineated with respect to targeting cranial nerve pathways are not well defined, and radiation can carry risks of major toxicity secondary to the location of adjacent critical structures. Here we examine the pathogenesis of these phenomena, analyze the role of radiation in PNI and PNTS, and propose guidelines for radiation treatment design based on the best available evidence and the authors' collective experience to advance understanding and therapy of this ominous cancer phenotype.

Sensory Innervation of the Human Soft Palate.

The human soft palate plays an important role in respiration, swallowing, and speech. These motor activities depend on reflexes mediated by sensory nerve endings. To date, the details of human sensory innervation to the soft palate have not been demonstrated. In this study, eight adult human whole-mount (soft palate-tongue-pharynx-larynx-upper esophagus) specimens were obtained from autopsy. Each specimen was bisected in the midline, forming two equal and symmetrical halves. Eight hemi-specimens were processed with Sihler's stain, a whole-mount nerve staining technique. The remaining eight hemi-soft palates were used for immunohistochemical study. The soft palatal mucosa was dissected from the oral and nasal sides and prepared for neurofilament staining. Our results showed that the sensory nerve fibers formed a dense nerve plexus in the lamina propria of the soft palatal mucosa. There was a significant difference in the innervation density between both sides. Specifically, the oral side had higher density of sensory nerve fibers than the nasal side of the soft palate. The mean number and percent area of the sensory nerve fibers in the mucosa of the nasal side was 78% and 72% of those in the mucosa of the oral side, respectively (P < 0.0001). The data presented here could be helpful for further investigating the morphological and quantitative alterations in the sensory nerves in certain upper airway disorders involving the soft palate such as obstructive sleep apnea (OSA) and for designing effective therapeutic strategies to treat OSA. Anat Rec, 301:1861-1870, 2018. © 2018 Wiley Periodicals, Inc.

Somatosensory innervation of the oral mucosa of adult and aging mice.

Oral mechanoreception is implicated in fundamental functions including speech, food intake and swallowing; yet, the neuroanatomical substrates that encode mechanical stimuli are not well understood. Tactile perception is initiated by intricate mechanosensitive machinery involving dedicated cells and neurons. This signal transduction setup is coupled with the topology and mechanical properties of surrounding epithelium, thereby providing a sensitive and accurate system to detect stress fluctuations from the external environment. We mapped the distribution of anatomically distinct neuronal endings in mouse oral cavity using transgenic reporters, molecular markers and quantitative histomorphometry. We found that the tongue is equipped with an array of putative mechanoreceptors that express the principal mechanosensory channel Piezo2, including end bulbs of Krause innervating individual filiform papillae and a novel class of neuronal fibers innervating the epithelium surrounding taste buds. The hard palate and gums are densely populated with three classes of sensory afferents organized in discrete patterns including Merkel cell-neurite complexes, Meissner's corpuscles and glomerular corpuscles. In aged mice, we find that palatal Merkel cells reduce in number at key time-points that correlate with impaired oral abilities, such as swallowing and mastication. Collectively, this work identifies the mechanosensory architecture of oral tissues involved in feeding.

The course and distribution of the buccal nerve: clinical relevance in dentistry.

BACKGROUND: The buccal branch of the mandibular division of the trigeminal nerve is commonly anaesthetized for dental procedures and may be damaged during surgery. Descriptions of the distribution of the buccal nerve (BN) in anatomical texts are generally lacking in detail and do not provide information about the extent of its variation between individuals. There are also commonly-held clinical beliefs about the BN that lack support from anatomical dissections. METHODS: Detailed dissections of the course and distribution of the BN were performed in a sample of 12 hemi-heads from 11 edentulous and partially dentate human adult cadavers. RESULTS: A broader distribution of the BN was found than described previously, with innervation extending to the lips in all cases. Approximately half of the lateral sides of the lips were innervated by the BN in two cases and approximately one-third of their lateral sides in the other 10 cases. Distribution of the BN to the lower lips was wider than to the upper lips. CONCLUSIONS: Our findings provide a stronger anatomical basis to underpin clinical procedures involving the BN and indicate that some commonly-held clinical views about this nerve are not supported by anatomical evidence.

The involvement of TRP channels in sensory irritation: a mechanistic approach toward a better understanding of the biological effects of local irritants.

Peripheral nerves innervating the mucosae of the nose, mouth, and throat protect the organism against chemical hazards. Upon their stimulation, characteristic perceptions (e.g., stinging and burning) and various reflexes are triggered (e.g., sneezing and cough). The potency of a chemical to cause sensory irritation can be estimated by a mouse bioassay assessing the concentration-dependent decrease in the respiratory rate (50 % decrease: RD50). The involvement of the N. trigeminus and its sensory neurons in the irritant-induced decrease in respiratory rates are not well understood to date. In calcium imaging experiments, we tested which of eight different irritants (RD50 5-730 ppm) could induce responses in primary mouse trigeminal ganglion neurons. The tested irritants acetophenone, 2-ethylhexanol, hexyl isocyanate, isophorone, and trimethylcyclohexanol stimulated responses in trigeminal neurons. Most of these responses depended on functional TRPA1 or TRPV1 channels. For crotyl alcohol, 3-methyl-1-butanol, and sodium metabisulfite, no activation could be observed. 2-ethylhexanol can activate both TRPA1 and TRPV1, and at low contractions (100 µM) G protein-coupled receptors (GPCRs) seem to be involved. GPCRs might also be involved in the mediation of the responses to trimethylcyclohexanol. By using neurobiological tools, we showed that sensory irritation in vivo could be based on the direct activation of TRP channels but also on yet unknown interactions with GPCRs present in trigeminal neurons. Our results showed that the potency suggested by the RD50 values was not reflected by direct nerve-compound interaction.

Peripheral nervous system involvement in primary burning mouth syndrome--results of a pilot study.

OBJECTIVE: The pathophysiology of primary burning mouth syndrome (BMS) has remained enigmatic, but recent studies suggest pathology within the nervous system at multiple levels. This study aimed to investigate in detail the contribution of either focal or generalized alterations within the peripheral nervous system (PNS) in the etiopathogenesis of BMS. SUBJECTS AND METHODS: Intraepithelial nerve fiber density (IENFD) of tongue mucosa was assessed in 10 carefully characterized BMS, and the results were compared to 19 age- and gender-matched cadaver controls, 6 with lifetime diabetes. Extensive neurophysiologic and psychophysical examinations of the trigeminal system and distal extremities were performed to profile PNS function in BMS. RESULTS: Patients with BMS had significantly fewer intraepithelial nerve fibers (0,27, s.e. 0,18 mm(-1); P = 0.0253) than non-diabetic controls (0,92, s.e. 0,15 mm(-1)). In the subepithelial space, the amount of nerve fibers did not differ between the groups. The majority (9/10) of patients with BMS showed neurophysiologic or psychophysical signs of a more generalized PNS dysfunction. CONCLUSIONS: Our results in neurophysiologically optimally characterized BMS patients confirm that pure focal small fiber neuropathy of the oral mucosa has a role in the pathophysiology of primary BMS. Furthermore, BMS may be related to a more generalized, yet subclinical peripheral neuropathy.

Ontogeny and innervation of taste buds in mouse palatal gustatory epithelium.

We investigated the relationship between mouse taste bud development and innervation of the soft palate. We employed scanning electron microscopy and immunohistochemistry using antibodies against protein gene product 9.5 and peripherin to detect sensory nerves, and cytokeratin 8 and α-gustducin to stain palatal taste buds. At E14, nerve fibers were observed along the medial border of the palatal shelves that tracked toward the epithelium. At E15.5, primordial stages of taste buds in the basal lamina of the soft palate first appeared. At E16, the taste buds became large spherical masses of columnar cells scattered in the soft palate basal lamina. At E17, the morphology and also the location of taste buds changed. At E18-19, some taste buds acquired a more elongated shape with a short neck, extending a variable distance from the soft palate basal lamina toward the surface epithelium. At E18, mature taste buds with taste pores and perigemmal nerve fibers were observed on the surface epithelium of the soft palate. The expression of α-gustducin was demonstrated at postnatal day 1 and the number of pored taste buds increased with age and they became pear-shaped at 8 weeks. The percent of pored fungiform-like papillae at birth was 58.3% of the whole palate; this increased to 83.8% at postnatal day 8 and reached a maximum of 95.7% at 12 weeks. The innervation of the soft palate was classified into three types of plexuses in relation to taste buds: basal nerve plexus, intragemmal and perigemmal nerve fibers. This study reveals that the nerve fibers preceded the development of taste buds in the palate of mice, and therefore the nerve fibers have roles in the initial induction of taste buds in the soft palate.

[Changes of the innervation in the mucous membrane and glands of the tongue in early and late experimental diabetes mellitus]. / A nyelv nyálkahártya és mirigyek innervációjának változása korai és késoi kisérletes diabetes mellitusban.

The number of the different neuropeptides-containing nerve fibres and immunocompetent cells was changed in diabetes mellitus (DM) in different organs. In this work we investigated the effect of DM on quantitation of the nerve fibres using immunhistochemistry. After two weeks of the DM the quantitiy of the different nerve fibres increased significantly both in the mucous membrane and glands of the tongue. The number of the immunocompetent cells (lymphocytes, plasma cells, mast cells) increased as well significantly. Some of these cells showed also immunoreactivity for substance P and neuropeptide Y. A few substance P cells were in very close relation to the SP immunoreactive nerve fibres. After four weeks of DM the number of the nerve fibres was decreased compared to the 2 weeks treatment, however, the number of them was higher compared to the control. The close correlation between the nerve fibres and immune cells might play a crucial role in maintaining the homeostasis in the mucous membrane and glands of the tongue as well as in the increasing inflammation and elimination of it.

The application of neuropathic pain questionnaires in burning mouth syndrome patients.

AIMS: To evaluate and compare the validity of the PainDETECT, DN4, and abbreviated DN4 (DN4i) neuropathic pain questionnaires for primary burning mouth syndrome (BMS), which is a burning sensation in the oral mucosa in the absence of any identifiable organic etiology. METHODS: Eighty-one patients (42 with primary BMS and 39 with nociceptive pain) complaining of a burning sensation and pain in their oral mucosa were enrolled in this study. All of the patients completed the neuropathic pain questionnaires. The sensitivity, specificity, positive predictive value, negative predictive value, and the area under the receiver operating characteristic (ROC) curve were estimated. Then the relationship between pain intensity and total neuropathic pain score was investigated. Data were analyzed with the chi-square test and independent t test for subjects' baseline characteristic differences, and with Pearson correlation coefficients for the relationship of variables. RESULTS: The mean area under the ROC curves (AUCs) for PainDETECT, DN4, and DN4i were 0.81, 0.79, and 0.81, respectively. There was no statistically significant difference in the AUCs among the questionnaires. PainDETECT, DN4, and DN4i had a lower sensitivity and specificity for BMS compared to previous validation studies. The total scores for PainDETECT, DN4, and DN4i in the primary BMS group were significantly associated with pain intensity. CONCLUSION: Although the results of this study suggest that neuropathic pain questionnaires, such as PainDETECT and DN4, are not ideal principal screening tools for BMS patients, a substantial proportion of neuropathic symptoms in primary BMS patients were identified.

Involvement of TRPV1 and TRPA1 in incisional intraoral and extraoral pain.

Thermal and mechanical hypersensitivity in the injured region is a common complication. Although it is well known clinically that thermal and mechanical sensitivity of the oral mucosa is different from that of the skin, the mechanisms underlying injured pain of the oral mucosa remain poorly understood. The transient receptor potential (TRP) vanilloid 1 (TRPV1) and TRP ankyrin 1 (TRPA1) in primary afferent neurons are known to contribute to pathological pain. Therefore, we investigated whether TRPV1 and/or TRPA1 contribute to thermal and mechanical hypersensitivity following oral mucosa or whisker pad skin incision. Strong heat and mechanical and cold hypersensitivity was caused in the buccal mucosa and whisker pad skin following incisions. On day 3 after the incisions, the number of TRPV1-immunoreactive (IR) and TRPA1-IR trigeminal ganglion (TG) neurons innervating the buccal mucosa and whisker pad skin was significantly increased, and the number of TRPV1/TRPA1-IR TG neurons innervating whisker pad skin, but not the buccal mucosa, was significantly increased. Administration of the TRPV1 antagonist, SB366791, to the incised site produced a significant suppression of heat hyperalgesia in both the buccal mucosa and whisker pad skin, as well as mechanical allodynia in the whisker pad skin. Administration of the TRPA1 antagonist, HC-030031, to the incised site suppressed mechanical allodynia and cold hyperalgesia in both the buccal mucosa and whisker pad skin, as well as heat hyperalgesia in the whisker pad skin. These findings indicate that altered expressions of TRPV1 and TRPA1 in TG neurons are involved in thermal and mechanical hypersensitivity following the buccal mucosa and whisker pad skin incision. Moreover, diverse changes in the number of TRPV1 and TRPA1 coexpressed TG neurons in whisker pad skin-incised rats may contribute to the intracellular interactions of TRPV1 and TRPA1 associated with whisker pad skin incision, whereas TRPV1 and TRPA1 expression in individual TG neurons is involved in buccal mucosa-incised pain.

Expanded terminal fields of gustatory nerves accompany embryonic BDNF overexpression in mouse oral epithelia.

Brain-derived neurotrophic factor (BDNF) is expressed in gustatory epithelia and is required for gustatory neurons to locate and innervate their correct target during development. When BDNF is overexpressed throughout the lingual epithelium, beginning embryonically, chorda tympani fibers are misdirected and innervate inappropriate targets, leading to a loss of taste buds. The remaining taste buds are hyperinnervated, demonstrating a disruption of nerve/target matching in the tongue. We tested the hypothesis here that overexpression of BDNF peripherally leads to a disrupted terminal field organization of nerves that carry taste information to the brainstem. The chorda tympani, greater superficial petrosal, and glossopharyngeal nerves were labeled in adult wild-type (WT) mice and in adult mice in which BDNF was overexpressed (OE) to examine the volume and density of their central projections in the nucleus of the solitary tract. We found that the terminal fields of the chorda tympani and greater superficial petrosal nerves and overlapping fields that included these nerves in OE mice were at least 80% greater than the respective field volumes in WT mice. The shapes of terminal fields were similar between the two groups; however, the density and spread of labels were greater in OE mice. Unexpectedly, there were also group-related differences in chorda tympani nerve function, with OE mice showing a greater relative taste response to a concentration series of sucrose. Overall, our results show that disruption in peripheral innervation patterns of sensory neurons have significant effects on peripheral nerve function and central organization of their terminal fields.

Novel methods of applying direct chemical and mechanical stimulation to the oral mucosa for traditional behavioral pain assays in conscious rats.

BACKGROUND: Stomatitis induces severe and painful hypersensitivity to pungency and physical contact during meals. Many studies have used anesthetized animals to examine evoked nociception in the oral mucosa, but no reports have used traditional behavioral assays to evaluate nociception in conscious animals. NEW METHODS: We developed two new methods of applying chemical or mechanical stimulation directly to the oral mucosa of the mandibular vestibule of conscious rats. Nociceptive evaluations were performed by measuring facial grooming time and the head withdrawal threshold to von Frey stimulations. (1) For the intraoral dropping method, rat mucosa was transiently exposed by hand, and a drop of a pungent solution was applied. (2) For the stable intraoral opening method, rat mucosa was long-term exposed following piercing surgery of the mental skin after habitual training for 2-3 weeks. RESULTS: In the intraoral dropping method, the application of 100 µM capsaicin or 100 mM allyl isothiocyanate prolonged mouth-rubbing time. Capsaicin-induced mouth-rubbing time was further enhanced following the development of an acetic acid-induced ulcer. The stable intraoral opening method enabled stable measurements of the mechanical withdrawal threshold in the oral mucosa of conscious rats. Ulcer development decreased the mechanical threshold, whereas topical lidocaine treatment increased the threshold. COMPARISON WITH EXISTING METHODS: These new methods enable the evaluations of motivational nocifensive behaviors in response to intraoral stimulations without any anesthetic effects. CONCLUSIONS: The intraoral dropping and stable intraoral opening methods can be used in combination with traditional behavioral assays to evaluate nociception in the oral mucosa of conscious rats.

Retrospective study of changes in the sensitivity of the oral mucosa: sagittal split ramus osteotomy (SSRO) versus intraoral vertical ramus osteotomy (IVRO).

We investigated changes in the sensitivity of cutaneous points and the oral mucosa after sagittal split ramus osteotomy (SSRO) and assessed the differences between SSRO and intraoral vertical ramus osteotomy (IVRO). The subjects included in this study were 46 patients with mandibular prognathism who underwent IVRO (88 rami) and 30 patients who underwent SSRO (59 rami). An objective evaluation of the neurosensory status of each patient was completed preoperatively and at 1, 4, 8, 12, and 24 weeks postoperatively. Other variables studied for each patient included sex, age, magnitude of mandibular setback, and amount of blood loss during surgery. We found that a neurosensory recovery occurred earlier in the oral mucosa than at cutaneous points. The number of oral mucosa points showing reduced neurosensory function and neurosensory disturbance after SSRO was significantly higher than after IVRO at 1, 4, and 8 weeks (P<0.05). The nerve recovery observed after SSRO was delayed for a longer period than that noted in our previous study of IVRO. In conclusion, we found changes in sensitivity at cutaneous points and the oral mucosa after SSRO and assessed the differences between SSRO and IVRO.

A systematic review on the innervation of peri-implant tissues with special emphasis on the influence of implant placement and loading protocols.

OBJECTIVES: To systematically review the available literature on the influence of dental implant placement and loading protocols on peri-implant innervation. MATERIAL AND METHODS: The database MEDLINE, Cochrane, EMBASE, Web of Science, LILACS, OpenGrey and hand searching were used to identify the studies published up to July 2013, with a populations, exposures and outcomes (PEO) search strategy using MeSH keywords, focusing on the question: Is there, and if so, what is the effect of time between tooth extraction and implant placement or implant loading on neural fibre content in the peri-implant hard and soft tissues? RESULTS: Of 683 titles retrieved based on the standardized search strategy, only 10 articles fulfilled the inclusion criteria, five evaluating the innervation of peri-implant epithelium, five elucidating the sensory function in peri-implant bone. Three included studies were considered having a methodology of medium quality and the rest were at low quality. All those papers reported a sensory innervation around osseointegrated implants, either in the bone-implant interface or peri-implant epithelium, which expressed a particular innervation pattern. Compared to unloaded implants or extraction sites without implantation, a significant higher density of nerve fibres around loaded dental implants was confirmed. CONCLUSIONS: To date, the published literature describes peri-implant innervation with a distinct pattern in hard and soft tissues. Implant loading seems to increase the density of nerve fibres in peri-implant tissues, with insufficient evidence to distinguish between the innervation patterns following immediate and delayed implant placement and loading protocols. Variability in study design and loading protocols across the literature and a high risk of bias in the studies included may contribute to this inconsistency, revealing the need for more uniformity in reporting, randomized controlled trials, longer observation periods and standardization of protocols.

A new protocol to evaluate the effect of topical anesthesia.

This double-blind, placebo-controlled, randomized cross-over clinical experimental study tested the reliability, validity, and sensitivity to change of punctuate pain thresholds and self-reported pain on needle penetration. Female subjects without orofacial pain were tested in 2 sessions at 1- to 2-week intervals. The test site was the mucobuccal fold adjacent to the first upper right premolar. Active lidocaine hydrochloride 2% (Dynexan) or placebo gel was applied for 5 minutes, and sensory testing was performed before and after application. The standardized quantitative sensory test protocol included mechanical pain threshold (MPT), pressure pain threshold (PPT), mechanical pain sensitivity (MPS), and needle penetration sensitivity (NPS) assessments. Twenty-nine subjects, mean (SD) age 29.0 (10.2) years, completed the study. Test-retest reliability intraclass correlation coefficient at 10-minute intervals between examinations was MPT 0.69, PPT 0.79, MPS 0.72, and NPS 0.86. A high correlation was found between NPS and MPS (r = 0.84; P < .001), whereas NPS and PPT were not significantly correlated. The study found good to excellent test-retest reliability for all measures. None of the sensory measures detected changes in sensitivity following lidocaine 2% or placebo gel. Electronic von Frey assessments of MPT/MPS on oral mucosa have good validity.

Topographical relationship of the greater palatine artery and the palatal spine. Significance for periodontal surgery.

AIM: The aims of this study were to (1) identify the branching pattern and course of the greater palatine artery (GPA), (2) carry out a morphological analysis of the palatal bony prominence that divides the medial and lateral grooves and (3) characterize the topographical relationships between these two structures. METHODS: Thirty-six hemimaxillae were studied with the aid of a surgical microscope to elucidate the GPA. A further 25 dry skulls were examined to establish the morphology of the palatal spine. RESULTS: The most common GPA branching pattern was type I (41.7%, 15 sides), which gave off the medial and canine branches after the bony prominence. The distances from the CEJ to the lateral branch of the GPA were 9.04 ± 2.93 mm (canine), 11.12 ± 1.89 mm (first premolar), 13.51 ± 2.08 mm (second premolar), 13.76 ± 2.86 mm (first molar) and 13.91 ± 2.20 mm (second molar). The palatal spine was frequently observed as the bony prominence (66.3%, 57 sides), and was located at 6.49 ± 1.76 mm from the greater palatine foramen, with a length of 10.42 ± 2.45 mm. There was no a correlation between the bony prominence shape and the GPA branching pattern. CONCLUSIONS: These results could provide the reference data regarding the topography of the GPA for periodontal surgery.

Differential roles of nonsynaptic and synaptic plasticity in operant reward learning-induced compulsive behavior.

BACKGROUND: Rewarding stimuli in associative learning can transform the irregularly and infrequently generated motor patterns underlying motivated behaviors into output for accelerated and stereotyped repetitive action. This transition to compulsive behavioral expression is associated with modified synaptic and membrane properties of central neurons, but establishing the causal relationships between cellular plasticity and motor adaptation has remained a challenge. RESULTS: We found previously that changes in the intrinsic excitability and electrical synapses of identified neurons in Aplysia's central pattern-generating network for feeding are correlated with a switch to compulsive-like motor output expression induced by in vivo operant conditioning. Here, we used specific computer-simulated ionic currents in vitro to selectively replicate or suppress the membrane and synaptic plasticity resulting from this learning. In naive in vitro preparations, such experimental manipulation of neuronal membrane properties alone increased the frequency but not the regularity of feeding motor output found in preparations from operantly trained animals. On the other hand, changes in synaptic strength alone switched the regularity but not the frequency of feeding output from naive to trained states. However, simultaneously imposed changes in both membrane and synaptic properties reproduced both major aspects of the motor plasticity. Conversely, in preparations from trained animals, experimental suppression of the membrane and synaptic plasticity abolished the increase in frequency and regularity of the learned motor output expression. CONCLUSIONS: These data establish direct causality for the contributions of distinct synaptic and nonsynaptic adaptive processes to complementary facets of a compulsive behavior resulting from operant reward learning.

Immediate analgesic effect of 8% lidocaine applied to the oral mucosa in patients with trigeminal neuralgia.

BACKGROUND: Trigeminal nerve block is widely used for trigeminal neuralgia (TN), though with much painful procedure and potential serious complications. The pain of TN occurs most frequently in the second and the third divisions of the trigeminal nerve, which are distributed in intraoral mucous membrane as well as face skin. Here, we examined the response to intraoral application of 8% lidocaine (LDC) in patients with oral TN pain in a double-blind, placebo (PBO)-controlled crossover study. METHODS: Twenty-four outpatients with oral TN pain were randomized to receive intraoral application of either 8% LDC or saline PBO to the painful area. Following 7-days period, patients were crossed over to receive the alternative treatment. The pain was assessed with a numerical rating scale (NRS) before and 15 minutes after treatment. Patients used a descriptive scale to grade pain outcome and were asked to note any recurrence and the latency for recurrence after therapy. RESULTS: Intraoral LDC, but not PBO, significantly decreased the NRS from 5 (4, 8) (median [25, 75 percentiles]) to 1 (0, 4) (P = 0.001). Of the 24 patients, 19 described marked or moderate relief of pain after LDC but only three described the same after PBO application. The effect of LDC and PBO persisted for 2.8 (0.3, 3.0) and 0 (0, 0) hours, respectively. CONCLUSIONS: Intraoral application of 8% LDC produced prompt analgesia without serious side effects in patients with TN who presented with severe intraoral pain.

Roles of innervation in developing and regenerating orofacial tissues.

The head is innervated by 12 cranial nerves (I-XII) that regulate its sensory and motor functions. Cranial nerves are composed of sensory, motor, or mixed neuronal populations. Sensory neurons perceive generally somatic sensations such as pressure, pain, and temperature. These neurons are also involved in smell, vision, taste, and hearing. Motor neurons ensure the motility of all muscles and glands. Innervation plays an essential role in the development of the various orofacial structures during embryogenesis. Hypoplastic cranial nerves often lead to abnormal development of their target organs and tissues. For example, Möbius syndrome is a congenital disease characterized by defective innervation (i.e., abducens (VI) and facial (VII) nerves), deafness, tooth anomalies, and cleft palate. Hence, it is obvious that the peripheral nervous system is needed for both development and function of orofacial structures. Nerves have a limited capacity to regenerate. However, neural stem cells, which could be used as sources for neural tissue maintenance and repair, have been found in adult neuronal tissues. Similarly, various adult stem cell populations have been isolated from almost all organs of the human body. Stem cells are tightly regulated by their microenvironment, the stem cell niche. Deregulation of adult stem cell behavior results in the development of pathologies such as tumor formation or early tissue senescence. It is thus essential to understand the factors that regulate the functions and maintenance of stem cells. Yet, the potential importance of innervation in the regulation of stem cells and/or their niches in most organs and tissues is largely unexplored. This review focuses on the potential role of innervation in the development and homeostasis of orofacial structures and discusses its possible association with stem cell populations during tissue repair.

Toll-like receptor 4 expression in trigeminal neurons is increased during ligature-induced periodontitis in rats.

BACKGROUND: Periodontitis, activated by oral bacteria and orchestrated by innate immune response, is regulated by primary nociceptive neurons, which are generally considered to have small- to medium-sized perikaryons. Bacterial byproducts (e.g., lipopolysaccharides) activate primary nociceptive neurons directly through Toll-like receptors (TLRs). Therefore, this study aims to morphometrically characterize rat trigeminal neurons, which express TLR4, and to investigate the changes in the TLR4 expression in neurons during periodontal inflammation. METHODS: Trigeminal neurons innervating gingivomucosa were identified by application of the retrograde tracer hydroxystilbamidine into the gingival sulcus of the maxillary molar in 14 rats. Periodontitis was induced by ligature around the same molar in seven rats. TLR4 expression was investigated by immunohistochemistry on paraffin sections of the trigeminal ganglia (TG). Semiquantitative method was used to identify the intensity of TLR4 expression. RESULTS: In the control group without the ligatures, TLR4 was detected in 19% of the neurons in the maxillary region of TG and in 29% of neurons innervating gingivomucosa. Expression of TLR4 was more frequent and intensive in small- to medium-sized neurons than in large-sized neurons. One week after ligature-induced periodontitis, the percentage of TLR4-positive neurons in the maxillary region and among the neurons innervating inflamed gingivomucosa significantly increased statistically to 32% and 41%, respectively. CONCLUSIONS: TLR4 is predominantly, but not exclusively, expressed in smaller trigeminal nociceptive neurons in the rat. Experimental periodontitis upregulates TLR4 expression in the trigeminal neurons. The hypothesis that bacterial byproducts regulate the pathogenesis of periodontitis by activation of trigeminal nociceptors through TLR4 should be explored.