Extracellular ATP and cAMP signaling promote Piezo2-dependent mechanical allodynia after trigeminal nerve compression injury.

Trigeminal neuralgia (TN) is a type of severe paroxysmal neuropathic pain commonly triggered by mild mechanical stimulation in the orofacial area. Piezo2, a mechanically gated ion channel that mediates tactile allodynia in neuropathic pain, can be potentiated by a cyclic adenosine monophosphate (cAMP)-dependent signaling pathway that involves the exchange protein directly activated by cAMP 1 (Epac1). To study whether Piezo2-mediated mechanotransduction contributes to peripheral sensitization in a rat model of TN after trigeminal nerve compression injury, the expression of Piezo2 and activation of cAMP signal-related molecules in the trigeminal ganglion (TG) were detected. Changes in purinergic P2 receptors in the TG were also studied by RNA-seq. The expression of Piezo2, cAMP, and Epac1 in the TG of the TN animals increased after chronic compression of the trigeminal nerve root (CCT) for 21 days, but Piezo2 knockdown by shRNA in the TG attenuated orofacial mechanical allodynia. Purinergic P2 receptors P2X4, P2X7, P2Y1, and P2Y2 were significantly up-regulated after CCT injury. In vitro, Piezo2 expression in TG neurons was significantly increased by exogenous adenosine 5'-triphosphate (ATP) and Ca2+ ionophore ionomycin. ATP pre-treated TG neurons displayed elevated [Ca2+ ]i and faster increase in responding to blockage of Na+ /Ca2+ exchanger by KB-R7943. Furthermore, mechanical stimulation of cultured TG neurons led to sustained elevation in [Ca2+ ]i in ATP pre-treated TG neurons, which is much less in naïve TG neurons, or is significantly reduced by Piezo2 inhibitor GsMTx4. These results indicated a pivotal role of Piezo2 in peripheral mechanical allodynia in the rat CCT model. Extracellular ATP, Ca2+ influx, and the cAMP-to-Epac1 signaling pathway synergistically contribute to the pathogenesis and the persistence of mechanical allodynia.

Increase in IGF-1 Expression in the Injured Infraorbital Nerve and Possible Implications for Orofacial Neuropathic Pain.

Insulin-like growth factor-1 (IGF-1) is upregulated in the injured peripheral nerve bundle and controls nociceptive neuronal excitability associated with peripheral nerve injury. Here, we examined the involvement of IGF-1 signaling in orofacial neuropathic pain following infraorbital nerve injury (IONI) in rats. IONI promoted macrophage accumulation in the injured ION, as well as in the ipsilateral trigeminal ganglion (TG), and induced mechanical allodynia of the whisker pad skin together with the enhancement of neuronal activities in the subnucleus caudalis of the spinal trigeminal nucleus and in the upper cervical spinal cord. The levels of IGF-1 released by infiltrating macrophages into the injured ION and the TG were significantly increased. The IONI-induced the number of transient receptor potential vanilloid (TRPV) subfamily type 4 (TRPV4) upregulation in TRPV subfamily type 2 (TRPV2)-positive small-sized, and medium-sized TG neurons were inhibited by peripheral TRPV2 antagonism. Furthermore, the IONI-induced mechanical allodynia was suppressed by TRPV4 antagonism in the whisker pad skin. These results suggest that IGF-1 released by macrophages accumulating in the injured ION binds to TRPV2, which increases TRPV4 expression in TG neurons innervating the whisker pad skin, ultimately resulting in mechanical allodynia of the whisker pad skin.

Does Piezosurgery Influence the Severity of Neurosensory Disturbance Following Bilateral Sagittal Split Osteotomy?

The present paper aims to evaluate the long-term incidence and severity of the neurosensory disturbance (NSD) of the inferior alveolar nerve following bilateral sagittal split osteotomy (BSSO) of the mandibular ramus performed with piezosurgery. A retrospective study on patients referred to the Maxillofacial Surgery and Dentistry Clinic of the University of Verona for orthognathic surgery between March 2013 and October 2015 was performed. Inclusion criteria were having undergone BSSO with piezosurgery and follow-up lasting at least 24 months. Exclusion criteria were history of surgical infection, osteosynthesis failure or re-do surgery. The extent of mandibular repositioning movements was retrieved and patients underwent 4 clinical neurosensory tests. Descriptive statistical analysis was performed. 52 patients met the inclusion criteria. Average follow-up was 40 months (range 24-75). 83% of the nerves examined have no or slightly altered sensitivity. Seventy-one percent of patients perceive a moderate to none discomfort and none describes the discomfort as serious (Visual Analogue Scale [VAS] >7). The extent of mandibular repositioning did not have significant influence on the development and severity of the NSD. Resulting data led the Authors to infer that using piezosurgery in BSSO, the severity of the NSD of inferior alveolar nerve is reduced, but the incidence of permanent nerve lesions remains unchanged, compared to historical controls.

Pain threshold monitoring during chronic constriction injury of the infraorbital nerve in rats.

Background: The chronic constriction injury (CCI) of the infraorbital nerve (ION) has been used to establish an animal mode of trigeminal neuralgia (TN), but key parameters of the model have not been quantified until now. Objective: The aim of the study was to quantify a standard of pain threshold to evaluate a successful TN model in Sprague-Dawley (SD) rats. Methods: Forty-eight adult SD rats (200-220 g) underwent chronic constriction injury of the infraorbital nerve. The pain threshold was tested one day preoperatively (baseline) and day 1, 3, 7, 14, 28 postoperatively using the up-down method. At day 28, all the animals were killed by dislocation of the cervical spine and the trigeminal nerve specimens were removed for electron microscopy. Results: The baseline pain threshold was 14.40 ± 0.87 g. Postoperatively, all the rats presented an initial reduced sensitivity to mechanical stimulation from day 1 (15.63 ± 1.92 g) through 7 (17.39 ± 1.43 g) after the surgery. At day 14, 32 (66.7%) began to show significant mechanical allodynia (0.71 ± 0.43 g) which did not change significantly till day 28 (0.88 ± 0.54 g). These animals were regarded as successful TN models with a 95% confidence interval of the pain threshold of 0.58-1.27 at Day 14. The electron microscopy demonstrated homogeneously demyelinated changes in those successful TN model animals rather than severe or mild epineurial lesions in those unsuccessful model animals. Conclusion: Our study showed that an animal TN model could be established with a two-week chronic constriction injury of the infraorbital nerve. The mechanical allodynia index <1.27 at Day 14 was suggested as a criterion for a successful model.

Experimental Study on Involvement of the Central Nervous System in Inferior Alveolar Nerve Damage-Associated Hyperalgesia of the Mental Region.

PURPOSE: Involvement of the central nervous system in sensory disturbances of the mental region occurring after inferior alveolar nerve damage was investigated using a rat model of inferior alveolar nerve damage. PATIENTS AND METHODS: The rat inferior alveolar nerve was damaged by ligation with thread, and the course of behavioral changes after surgery was observed for 42 days. In addition, activation of microglia and astroglia in the trigeminal spinal subnucleus caudalis (Vc) was analyzed using immunohistochemistry. c-Fos-positive cells were quantitatively evaluated to analyze the state of neuron excitement. RESULTS: The withdrawal threshold was significantly decreased 5 days after surgery in the inferior alveolar nerve-ligated (IANL) group compared with that in the sham group and subsequently recovered over time. In addition, microglia and astroglia were activated in the Vc region 5 days after surgery in the model group, and c-fos-positive cells were also significantly more frequent in the IANL group. However, no significant difference in the withdrawal threshold was seen between the IANL and sham groups on day 42, nor were any significant differences seen in the amounts of microglia, astroglia, or c-fos-positive cells. CONCLUSIONS: Interactions among microglia, astroglia, and neurons in the central nervous system might be involved in the progression of inferior alveolar nerve damage-associated mental hyperalgesia to a chronic state.

Lipopolysaccharide-mediated inflammatory priming potentiates painful post-traumatic trigeminal neuropathy.

We explored the molecular and behavioral effects of a perineural Lipopolysaccharide (LPS)-mediated inflammatory priming on the development and maintenance of painful post-traumatic trigeminal neuropathy (PPTTN) following infra-orbital nerve chronic constriction injury (CCI-IoN) in rats. Rats were pretreated with repetitive perineural injections in the vicinity of the IoN of either LPS or vehicle (Vhcl) before being submitted to CCI-IoN. Orofacial pain-like behaviors (response to Von Frey Filament testing and spontaneous isolated face grooming) were measured during the period of LPS injections (three weeks) and following CCI-IoN surgery (two weeks). Local LPS administration induced an early pain-like behavior (i.e. an increase in spontaneous pain [SP] or mechanical static allodynia [MSA]) in both conditions, and following CCI-IoN, MSA and SP developed earlier and more severely in LPS-pretreated rats than in the control group. Ipsilateral increases of key neuropathic pain mRNA markers in the IoN parenchyma, trigeminal ganglia (TG) and spinal trigeminal nucleus caudalis (Sp5C) were observed in CCI-IoN injured animals as compared to controls. Although no significant molecular differences could be observed within the IoN parenchyma between LPS and Vhcl-pretreated animals, a significant increase of key inflammatory cytokine Interleukin 1 beta (IL - 1ß) could be found in the TG of LPS-pretreated CCI-injured animals versus controls. Finally, a higher increase of inducible nitric oxide synthase (iNOS) in ipsilateral Sp5C of LPS-pretreated animals was observed as compared to Sp5C of Vhcl-pretreated animals. These results suggest a key role of inflammatory priming in the development and maintenance of PPTTN implicating IL-1ß/iNOS-dependent central sensitization mechanisms.

Identifying criteria for diagnosis of post-traumatic pain and altered sensation of the maxillary and mandibular branches of the trigeminal nerve: a systematic review.

OBJECTIVE: The aim of the study was to systematically identify criteria used to diagnose patients with trigeminal nerve injury. STUDY DESIGN: A systematic review of the literature registered in the PROSPERO database. Inclusion criteria were patients diagnosed with nerve injury of the sensory divisions of the maxillary or mandibular branches of the trigeminal nerve, with reported tests and criteria used for diagnosis and persistent pain or unpleasant sensation associated with nerve injury. RESULTS: In total, 28 articles were included. Diagnostic tests included clinical neurosensory tests (89%), thermal quantitative sensory testing (QST; 25%), electromyography (7%), and patient interview (14%). Neuropathic pain was assessed by using the visual analogue scale (39%); patient use of neuropathic medication (7%); questionnaires, including McGill and PainDETECT (21%). Functional impact was assessed in 14% and psychological impact in 7% of articles. Methodology in performing clinical neurosensory tests, application of diagnostic terms and diagnostic grading of nerve injury was found to be inconsistent among the included articles, making direct comparison of results difficult. CONCLUSIONS: Recommendations for assessment and diagnosis of trigeminal nerve injury have been made based on the best available evidence from the review. There is an urgent requirement for a consensus in diagnostic criteria, criteria for assessment, and outcome reporting among stakeholder organizations to improve knowledge in this field.

Effect of Pregabalin and Diclofenac on tactile allodynia, mechanical hyperalgesia and pro inflammatory cytokine levels (IL-6, IL-1ß) induced by chronic constriction injury of the infraorbital nerve in rats.

The present study evaluated the effects of systemic pregabalin (PG) and diclofenac (Dic) on neuropathic orofacial pain induced by chronic constriction injury (CCI) of the infraorbital nerve (ION) and on the pro-inflammatory cytokines levels in the affected nerve. Fifty-four rats underwent left infra orbital nerve CCI, and 7 days after the procedure as the pain developed, the rats were randomly assigned to one of the treatment groups: PG 300, 30 or 10 mg/kg, Dic 10, 5 or 1 mg/kg or saline group (Sal) (n/group = 8). Addiitonal 8 rats served as naïve control group. Tactile-allodynia and Mechano-hyperalgesia were tested before the surgical procedure and at days 7, 8, and 9 postoperatively. On the 9th day, the rats were euthanized and the affected and contralateral sciatic nerves were harvested to assess IL-6 and IL-1ß nerve levels employing enzyme linked immunosorbent assay (ELISA). Daily injection of PG (all doses) significantly reduced tactile-allodynia and mechano-hyperalgesia (p < .05) while Dic did not. On the 9th day, the ipsilateral nerve IL-6 levels were significantly decreased (p < .05) in the PG and DIC groups compared to the Sal group. IL-1ß levels demonstrated a significant reduction (p < .05) in the PG group when compared to saline. These results suggest that PG but not Dic may be effective in reducing neuropathic orofacial pain. The mechanisms of action may be associated to some extent with reduction in IL-1ß levels in the affected nerve.

Neurosensory Disturbance of the Inferior Alveolar Nerve After 3025 Implant Placements.

PURPOSE: The aim of this retrospective study was to evaluate the incidence of inferior alveolar nerve (IAN) lesion and duration of sensitivity disturbances after the insertion of dental implants. METHODS: One thousand sixty-five patients (mean age: 58.9 years) enrolled between February 2004 and July 2015 with partial or full mandibular edentulism were selected to receive dental implants for oral rehabilitation. A total of 3025 implants were placed. After surgical procedures, controls were scheduled at suture removal, that is, 10 days after surgery, and repeated at intervals of 1, 3, and 6 months, and comprised patient interview, clinical examination, and sensitivity tests. RESULTS: Only 23 (2.2%) of the 1065 patients presented sensitivity disturbances 1 month after implant insertion, and only 2 (0.19%) after 6 months, though a complete recovery was observed in these patients within 13 months. CONCLUSIONS: Considering the debilitating effects resulting from IAN lesion and the complexity of the therapeutic diagnostic protocols, all patients undergoing oral rehabilitation through dental implants should be evaluated with CBCT imaging.

Piezosurgery for Sagittal Split Osteotomy: Procedure Duration and Postoperative Sensory Perturbation.

PURPOSE: To evaluate piezosurgery for bilateral sagittal split osteotomy (BSSO) for its duration and inferior alveolar nerve (IAN) perturbation. PATIENTS AND METHODS: In this prospective randomized study, the authors evaluated 100 BSSO procedures in 50 patients. Piezoelectric (group I) and conventional (group II) osteotomies were carried out on each side of the mandible of a patient by 2 specialists. The surgeons had at least 1 year of experience using piezosurgery. The period from incision to complete splitting of the mandibular bone was recorded (ie, procedure duration). The intraoperative status (visibility and relocation) of the IAN also was recorded. The neurosensory function of the IAN was measured by the 2-point discrimination threshold and static light touch methods before surgery and postoperatively (1, 3, and 6 weeks and 6 and 12 months). Parameters were compared between the test groups by the paired t, nonparametric Wilcoxon, or χ2 test. RESULTS: Intergroup comparison showed the mean duration of osteotomy was significantly shorter for group I (17 ± 6 vs 25 ± 9 minutes; P < .001). The rate of intraoperative exposures of the IAN was slightly lower for group I (68%) compared with group II (81%). However, the difference was not relevant. Neurosensory disturbance and recovery of the IAN did not differ between groups. CONCLUSION: Piezoelectric osteotomy requires considerably less time than conventional mechanical approaches, but shows no advantage in preventing neurosensory perturbation.

Effect of Low-Level Laser and Light-Emitting Diode on Inferior Alveolar Nerve Recovery After Sagittal Split Osteotomy of the Mandible: A Randomized Clinical Trial Study.

PURPOSE: The major concern of sagittal split osteotomy (SSO) is the neurosensory disturbance. The authors investigated the effect of low-level laser therapy and light-emitting diode on the inferior alveolar nerve recovery after SSO. METHODS: In this double-blinded randomized clinical trial, 20 subjects with inferior alveolar nerve injury after SSO of the mandible were studied. Neurosensory recovery was assessed by 6 tests: visual analog scale (VAS), brush stroke, 2-point discrimination, contact detect detection, pinprick nociception, and thermal discrimination, and each one was performed before and after the surgery on days 1, 3, 7, 14, 60, and 180. RESULTS: After 1 week, the VAS score in the laser group significantly improved in comparison with the control group. Visual analog scale score improvement was 25% (P = 0.015) at 2 weeks, 21% (P = 0.001) at 2 months, and 24% (P = 0.001) at 6 months. After 2 weeks, the brush stroke score improvement was significant in the laser group. The improvement values were 21.5% (P = 0.002) at 2 months and 15.1% (P = 0.004) at 6 months. CONCLUSION: Low-level laser therapy and light-emitting diode may improve VAS scores, 2-point discrimination, and brush stroke test results without any effect on the pinprick or contact detection test results.

Post-Traumatic Trigeminal Neuropathy Caused by an Orbital Stab Wound.

Sensory and motor neuropathy of the trigeminal nerve due to trauma is quite rare. Furthermore, there have been no detailed reports on occlusal abnormalities and trismus associated with post-traumatic trigeminal motor neuropathy. Here, the authors report a case of trigeminal motor neuropathy and trigeminal sensory neuropathy in all 3 divisions caused by an orbital stab wound. During kendo practice, a 61-year-old man was injured in his right medial canthus with the splinter of a broken bamboo sword. Imaging examinations did not show a brain injury or orbital bone fracture. Intraoral and extraoral examination and needle electromyography revealed trismus, posterior open bite, and denervation of the right masseter. After the injury, the patient strived to use the right molars during mastication and began chewing exercises in the right molar region. A follow-up examination 7 months after the injury revealed an improvement of the functional problems in the masticatory system. Although slight facial numbness in the right ophthalmic division remained, the patient was satisfied with the present status. Further knowledge concerning the natural history of trigeminal neuropathy as well as the treatment of choice should be explored in the future.

Effects of Superpulsed, Low-Level Laser Therapy on Neurosensory Recovery of the Inferior Alveolar Nerve.

OBJECTIVE: The purpose of this investigation was to evaluate the therapeutic efficacy of superpulsed, low-level laser therapy (SLLLT) on neurosensory recovery of the inferior alveolar nerve (IAN) after oral surgical injury. BACKGROUND DATA: A survey of the literature reveals the uncertainty of outcomes for the surgical management of IAN injury and the efficacy of low-level laser therapy in the treatment of IAN injury. METHODS: In this study, the authors report the results for SLLLT in 57 patients affected by paresthesia of the lip, chin, gingival, and buccal regions. Each patient was subjected to 10 laser treatments, once a week, with a GaAs diode laser. Clinical neurosensory tests (soft touch, 2-point discrimination, pin prick, thermal test) and the visual analogue scale were used before every treatment to evaluate the extent of neurosensory recovery. RESULTS: The authors' results demonstrate that 83.3% of the patients had a significant neurosensory recovery, as evident in the objective and subjective tests. CONCLUSION: The results reported in this study indicate that SLLLT has the potential to improve neurosensory recovery in patients with IAN paresthesia.

Inferior alveolar nerve function after open reduction and internal fixation of mandibular fractures.

PURPOSE: Mandibular fractures are amongst the most common facial fractures and are usually treated by open reduction and internal fixation (ORIF). Inferior alveolar nerve (IAN) injuries are seen frequently in mandibular fractures as well as after ORIF of these fractures due to the exposition and the close proximity of the nerve during fracture reduction. Therefore the continuity of the IAN can be disrupted. Permanent injury to the IAN can result in diminished quality of life. This retrospective study was designed to objectively analyse the incidence and the outcome of pre- and postoperative mental nerve hypoesthesia after ORIF of mandibular fractures. MATERIAL AND METHODS: Patients who were consecutively treated at the Department of Cranio-Maxillofacial and Oral Surgery of the University Hospital Zurich between 2004 and 2010 with mandibular fractures who underwent ORIF were included. Follow-up period was 12 months. Demographic, pre-, peri- and postsurgical data were tabulated and statistically evaluated using the χ(2) test and the Kruskall-Wallis-Test. RESULTS: 340 patients met the inclusion criteria. 27% of the study population presented with postinjury (preoperative) mental nerve hypoesthesia, 46% suffered from purely postoperative hypoesthesia and 27% showed no nerve damage. Complete recovery was seen in 70% of all cases, partial recovery in 20% of the cases and less than 10% suffered from a permanent (>12 months) IAN damage. Mandibular angle fractures were accompanied with significantly higher rates of hypoesthesia (79% vs. 68%). Recovery rate was significantly worse in older patients, when preoperative hypoesthesia was present (66% vs. 73%) and in patients with multiple fractures in proximity to the IAN (36% vs. 52%). Mandibular body fractures showed worse recovery rates than fractures that did not affect the body (44% vs. 52%). CONCLUSION: The present study shows that IAN injury is seen frequently in mandibular fractures. Mental nerve hypoesthesia may influence quality of life. Nerve continuity may not be preserved due to the initial trauma or may result as a postoperative complication. Nevertheless the results of this study show a high potential for full recovery.

The relationship between changes in the expression of growth associated protein-43 and functional recovery of the injured inferior alveolar nerve following transection without repair in adult rats.

OBJECTIVE: The objective of this study was to analyze the changes in the expression of growth associated protein-43 (GAP-43) in trigeminal ganglions (TGs) and in the distal stumps of transected inferior alveolar nerves (IANs), and to clarify the relationship between these changes and functional recovery of the transected IAN without repair using a rat IAN axotomy model. MATERIAL AND METHODS: Following transection, GAP-43 expression was measured at multiple time points. The functional recovery of the transected IAN was evaluated based on the compound muscle action potentials recorded from the digastric muscle. RESULTS: GAP-43 expression in TGs was significantly higher at 2, 7, 14, 28, and 56 days following IAN transection compared to that in samples from sham-operated rats (p < 0.0005, p < 0.0005, p < 0.0005, p = 0.007, and p = 0.023, respectively). GAP-43 expression in the distal stumps of transected IANs was significantly higher at 2, 7, 14, and 28 days following IAN transection compared to that in samples taken from sham rats (p < 0.0005, p < 0.0005, p < 0.0005, and p = 0.009, respectively). GAP-43 expression in the distal stumps of transected IANs returned nearly to sham levels by day 56 following IAN transection. On days 7, 14, 28, and 56 following transection, the amplitude of the compound muscle action potential gradually increased, the latency gradually decreased, and the duration gradually increased. The amplitude, latency, and duration of the compound muscle action potentials nearly returned to sham levels on post-transection day 56. CONCLUSIONS: Time-dependent changes in the expression of GAP-43 in both TGs and distal stumps of transected IANs without repair are synchronously consistent with the regeneration and functional recovery of the transected IAN. The recovery of the amplitude, latency, and duration of the compound muscle action potentials indicates increased myelination and increased axon density of the regenerated nerve fibers.

Electrophysiological evaluation of nerve function in inferior alveolar nerve injury: relationship between nerve action potentials and histomorphometric observations.

The objective of this study was to improve the accuracy of diagnosis of inferior alveolar nerve (IAN) injury by determining degrees of nerve disturbance using the sensory nerve action potential (SNAP) and sensory nerve conduction velocity (SCV). Crush and partial and complete nerve amputation injuries were applied to the IAN of rabbits, then SNAPs and histomorphometric observations were recorded at 1, 5, and 10 weeks. For crush injury, most nerves were smaller in diameter at 5 weeks than at 1 week, however after 10 weeks, extensive nerve regeneration was observed. The SNAP showed a decrease in SCV at weeks 1 and 5, followed by an increase at week 10. For partial nerve amputation, small to medium-sized nerve fibres were observed at weeks 1 and 5, then larger nerves were seen at week 10. Minimal changes in SCV were observed at weeks 1 and 5, however SCV increased at week 10. For complete nerve amputation, nerve fibres were sparse at week 1, but gradual nerve regeneration was observed at weeks 5 and 10. SNAPs were detectable from week 10, however the SCV was extremely low. This study showed SCV to be an effective factor in the evaluation of nerve injury and regeneration.

Dysregulated TNFα promotes cytokine proteome profile increases and bilateral orofacial hypersensitivity.

BACKGROUND: Tumor necrosis factor alpha (TNFα) is increased in patients with headache, neuropathic pain, periodontal and temporomandibular disease. This study and others have utilized TNF receptor 1/2 (TNFR1/2) knockout (KO) animals to investigate the effect of TNFα dysregulation in generation and maintenance of chronic neuropathic pain. The present study determined the impact of TNFα dysregulation in a trigeminal inflammatory compression (TIC) nerve injury model comparing wild-type (WT) and TNFR1/2 KO mice. METHODS: Chromic gut suture was inserted adjacent to the infraorbital nerve to induce the TIC model mechanical hypersensitivity. Cytokine proteome profiles demonstrated serology, and morphology explored microglial activation in trigeminal nucleus 10weeks post. RESULTS: TIC injury induced ipsilateral whisker pad mechanical allodynia persisting throughout the 10-week study in both TNFR1/2 KO and WT mice. Delayed mechanical allodynia developed on the contralateral whisker pad in TNFR1/2 KO mice but not in WT mice. Proteomic profiling 10weeks after chronic TIC injury revealed TNFα, interleukin-1alpha (IL-1α), interleukin-5 (IL-5), interleukin-23 (IL-23), macrophage inflammatory protein-1ß (MIP-1ß), and granulocyte-macrophage colony-stimulating factor (GM-CSF) were increased more than 2-fold in TNFR1/2 KO mice compared to WT mice with TIC. Bilateral microglial activation in spinal trigeminal nucleus was detected only in TNFR1/2 KO mice. p38 mitogen-activated protein kinase (MAPK) inhibitor and microglial inhibitor minocycline reduced hypersensitivity. CONCLUSIONS: The results suggest the dysregulated serum cytokine proteome profile and bilateral spinal trigeminal nucleus microglial activation are contributory to the bilateral mechanical hypersensitization in this chronic trigeminal neuropathic pain model in the mice with TNFα dysregulation. Data support involvement of both neurogenic and humoral influences in chronic neuropathic pain.

Persistent pain and neurosensory disturbance after dental implant surgery: pathophysiology, etiology, and diagnosis.

Many studies have documented the successful outcomes of dental implants, but have also reported the association of sensory disturbances with the surgical implant procedure. Postsurgical pain is a normal response to tissue injury, and usually resolves after the tissue heals. However, some patients who receive dental implants experience persistent pain even after normal healing. This article describes the basic anatomy and pathophysiology associated with nerve injury. The incidence and diagnosis of these problems, in addition to factors that result in the development of chronic persistent neuropathic pain and sensory disturbances associated with surgical implant placement, are discussed.

Effect of local application of an antibody against brain-derived neurotrophic factor on neuroma formation after transection of the inferior alveolar nerve in the rat.

This study aimed to examine the contributions of brain-derived neurotrophic factor (BDNF) at the injury site toward neuroma formation and nerve regeneration after inferior alveolar nerve transection. Histological analysis confirmed neuroma formation at 2 weeks after complete transection of the inferior alveolar nerve. A local administration of an antibody to BDNF inhibited connective tissue proliferation at the injury site and promoted nerve fiber integrity. Fluorogold labeling showed a significantly higher number of labeled cells in the trigeminal ganglion in the anti-BDNF-treated group compared with the vehicle control group. In-situ hybridization histochemistry showed intense signals for tropomyosin receptor kinase B mRNA in the area of the injury site containing fibrous or granular tissue in the anti-BDNF-treated group. In contrast, these signals were close to the detection limit in the area of the perineurium in intact nerve trunks, indicating that the signals were expressed by fibroblasts within the connective tissue. These findings suggest that antagonization of endogenous BDNF induced by nerve injury reduces neuroma formation, without inhibiting damaged axon regeneration.