Chronic orofacial pain disorders are common debilitating conditions, affecting the trigeminal system. Its underlying pathophysiological mechanisms are still unclear and the therapy is often unsatisfactory, therefore, preclinical models are crucial to identify the key mediators and novel treatment options. Complete Freund\'s adjuvant (CFA)-induced orofacial inflammatory allodynia/hyperalgesia is commonly used in rodents, but it has not been validated with currently used drugs. Here we tested the effects of the adjuvant analgesic/antiepileptic voltage-gated Na+ channel blocker complex mechanism of action topiramate in comparison with the gold standard antimigraine serotonin 5-HT1B/D receptor agonist sumatriptan in this model. CFA was injected subcutaneously into the right whisker pad of male Sprague-Dawley rats (250-300 g), then mechanonociceptive threshold values were investigated with von Frey filaments (3, 5, and 7 days after CFA injection). Effects of topiramate (30 mg/kg per os) and sumatriptan (1 mg/kg subcutaneous) on the adjuvant-induced chronic inflammatory orofacial allodynia were investigated 60, 120, and 180 min after the treatments each day. To determine the optimal concentration for drug effect analysis, we tested the effects of two different CFA-concentrations (1 and 0.5 mg/mL) on mechanonociceptive thresholds. Both concentrations of CFA induced a chronic orofacial allodynia in 60% of all rats. Although, higher CFA concentration induced greater allodynia, much more stable threshold reduction was observed with the lower CFA concentration: on day 3 the thresholds decreased from 18.30 g to approximately 11 g (low) and 5 g (high), respectively, however a slight increase was observed in the case of higher CFA concentration (on days 5, 7, and 11). In all investigation days, topiramate showed significant anti-allodynic effect comparing the pre and post drug dose and comparing the vehicle treated to the drug treated groups. Sumatriptan also caused a significant threshold increase compared to pre dose thresholds (day 3) and also showed a slight anti-allodynic effect compared to the vehicle-treated group (day 3 and 5). In the present study CFA-induced chronic orofacial allodynia was reversed by topiramate in rats validating the model with the adjuvant analgesic. Other than establishing a validated orofacial pain-related syndrome model in rats, new ways are opened for the repurposing of topiramate.

BACKGROUND: The reduction in joint load is a potential beneficial factor in managing osteoarthritis of the temporomandibular joint (TMJ). This paper aims to compare the effectiveness of the intramuscular injection of botulinum toxin (BTX-A) as an adjunct to TMJ arthrocentesis plus viscosupplementation with arthrocentesis plus viscosupplementation alone in the management of TMJ osteoarthritis.
METHODS: A pilot clinical retrospective study examined TMJ osteoarthritis treatments. Patients were divided into two groups: Group A received BTX-A injections and arthrocentesis with viscosupplementation, while Group B received only arthrocentesis with viscosupplementation. The study assessed outcomes based on mouth opening (MO), pain at rest (PR), pain at mastication (PF), and masticatory efficiency (ME) at various time points (baseline (T0), 1 week (T1), 2 weeks (T2), 3 weeks (T3), and 4 weeks (T4)) up to 2 months after treatment.
RESULTS: The study included two groups, each with five patients. Group A received five weekly sessions of arthrocentesis plus viscosupplementation and a single BTX-A injection during the first arthrocentesis appointment. Group B underwent the five-session protocol of arthrocentesis plus viscosupplementation alone. MO, PF, PR, and ME improved quickly in T2 in both groups, but the improvement was of greater importance over the following weeks and lasted longer in Group A.
CONCLUSIONS: Arthrocentesis with viscosupplementation associated with BTX-A was found to be more effective than arthrocentesis alone in improving clinical outcomes. This suggests that patients with TMJ osteoarthritis and myofascial pain may benefit from reduced muscle tone and joint load.

BACKGROUND: Temporomandibular disorders (TMDs) frequently cause orofacial pain and dysfunction, with treatment options spanning from conservative therapies to invasive surgical procedures. The aim of this systematic review was to analyze and compare the efficacy and safety profiles of conservative, minimally invasive interventions and surgical procedures in patients diagnosed with TMDs and disc displacement.
METHODS: Following PRISMA recommendations, PubMed, Scopus, and Web of Science databases were searched for randomized clinical trials (RCT). Data were synthesized in a table and evaluated through the Cochrane risk of bias 2 (RoB 2) tool.
RESULTS: Thirty-eight RCTs, most with moderate RoB, were selected. Conservative approaches, including physical therapy and occlusal devices, led to an improvement in symptoms and function. Pharmacological treatments demonstrated effectiveness in reducing pain and improving function; however, they can have undesirable side effects. Minimally invasive and invasive treatments also demonstrated efficacy, although most trials did not show their superiority to conservative treatments.
CONCLUSIONS: The primary approach to TMDs should be a conservative, multimodal treatment plan tailored to patient complaints and characteristics. Treatment goals should focus on symptom control and functional recovery. Surgical treatment should be reserved for cases with a precise diagnosis and a clear etiology.

[This corrects the article DOI: 10.3389/fpain.2024.1374929.].

UNASSIGNED: Herpes Zoster in humans is the result of varicella zoster virus (VZV) infection. Injecting rats with varicella zoster virus produces pain similar to herpes zoster \"shingles\" pain in humans. . In a previous study, orofacial pain was induced by injecting the whisker pad of male rats with VZV and the pain response increased after attenuating neurexin 3 (Nrxn3) expression in the central amygdala. Neurons descend from the central amygdala to the lateral parabrachial nucleus and orofacial pain signals ascend to the lateral parabrachial nucleus. GABAergic neurons within the central amygdala regulate pain by inhibiting activity within the lateral parabrachial nucleus. Attenuating Nrxn3 expression in the central amygdala increased GABA release in the lateral parabrachial nucleus suggesting Nrxn3 controls pain by regulating GABA release. Nrxn3 can also control synaptic connections between neurons, and we hypothesized that Nrxn3 knockdown in the central amygdala would reduce the number of GABAergic synaptic connections in the lateral parabrachial nucleus and increase VZV associated pain.
UNASSIGNED: To test this idea, the number of synaptic connections between GABAergic cells of the central amygdala and excitatory or dynorphin positive neurons within the lateral parabrachial nucleus were quantitated after infusion of a virus expressing synaptophysin. Synaptophysin is a synaptic vesicle protein that labels neuronal synaptic connections. These connections were measured in rats with and without whisker pad injection of VZV and knockdown of Nrxn3 within the central amygdala. Orofacial pain was measured using a place escape avoidance paradigm.
UNASSIGNED: GABAergic synaptic connections were reduced in the lateral parabrachial nucleus after Nrxn3 knockdown. Rats with a reduction in the number of connections had an increase in VZV associated orofacial pain. Immunostaining with the pain marker prodynorphin indicated that the reduction in GABAergic connections was primarily associated with prodynorphin positive neurons.
UNASSIGNED: The results suggest Nrxn3 reduces VZV associated orofacial pain, in part, by enhancing synaptic connections between GABA cells of the central amygdala and pain neurons within the lateral parabrachial nucleus.

OBJECTIVE: This study aimed to evaluate the prevalence of temporomandibular disorders (TMDs) in a sample of general dental patients seeking dental treatments in a northeastern Italian university clinic.
METHODS: Records of all patients presented for the first time to the dental division of Maggiore Hospital, Italy, between January 1, 2016, and December 31, 2017, were collected. Patients comprised those presenting to the dental clinics for non-TMD complaints, who, upon general examination, were found to have TMD signs and were referred for TMD evaluation. Data were extracted and analyzed, retrospectively. The prevalence of TMDs, age, gender, signs, and symptoms were evaluated.
RESULTS: Out of the 18,774 patients studied, 284 had signs of TMD. Women predominance was evident (73%), and patients aged 45-50 were the most frequent sub-population within the TMD population. Clicking was the most commonly present symptom (26.8%), and arthralgia was most commonly diagnosed among this sample (30.7%). A considerable number of patients suffered from muscular disease (myalgia and myofascial pain with 10.1% and 20.7% of the patients, respectively). Significant associations were found among those with myofascial pain on the one hand and degenerative disease and disc displacement with reduction, on the other hand. Furthermore, disc displacement with reduction on one side was associated with displacement without reduction on the other side.
CONCLUSIONS: A considerable number of patients presenting with dental complaints may have asymptomatic TMDs. This highlights the importance of systematic screening of dental patients for TMDs as part of general assessment.

The temporomandibular joint (TMJ) consists of bone, cartilage, ligaments, and associated masticatory muscles and tendons that coordinate to enable mastication in mammals. The TMJ is innervated by the trigeminal nerve (CNV), containing axons of motor and somatosensory neurons. Somatosensation includes touch, temperature, proprioception, and pain that enables mammals to recognize and react to stimuli for survival. The somatosensory innervation of the TMJ remains poorly defined. Disorders of the TMJ (TMD) are of diverse etiology and presentation. Some known symptoms associated with TMD include facial, shoulder, or neck pain, jaw popping or clicking, headaches, toothaches, and tinnitus. Acute or chronic pain in TMD stems from the activation of somatosensory nociceptors. Treatment of TMD may involve over- the-counter and prescription medication, nonsurgical treatments, and surgical treatments. In many cases, treatment achieves only a temporary relief of symptoms including pain. We suggest that defining the sensory innervation of the temporomandibular joint and its associated tissues with a specific focus on the contribution of peripheral innervation to the development of chronic pain could provide insights into the origins of joint pain and facilitate the development of improved analgesics and treatments for TMD.

This current systematic review aimed to evaluate the current evidence on the effect of topical capsaicin application to alleviate symptoms related to burning mouth syndrome (BMS). PubMed, Ovid SP, and Cochrane were searched from 1980 to 2022 to identify relevant literature. A total of 942 titles (PubMed, 84; Ovid SP, 839; Cochrane, 19) was retrieved, of which 936 were excluded based on the title and abstract. A total of 11 studies were further evaluated for full text analysis, of which 7 were excluded. As a result, 4 articles were included for qualitative synthesis of data. Capsaicin as a mouthwash can have potential application in the treatment of symptoms related to burning mouth. The quality of available studies is moderate to low, and a well-designed randomized multicentric study comparing capsaicin with other active agents is planned to obtain more definitive conclusions.

OBJECTIVE: Orofacial pain with high prevalence is one of the substantial human health issues. The importance of this matter became more apparent when it was revealed that orofacial pain, directly and indirectly, affects cognition performances. Currently, researchers have focused on investigating pharmaceutics to alleviate pain and ameliorate its subsequent cognitive impairments.
METHODS: In this study, the rats were first treated with the central administration of methyl jasmonate (MeJA), which is an antioxidant and anti-inflammatory bio-compound. After 20 min, orofacial pain was induced in the rats by the injection of capsaicin in their dental pulp. Subsequently, the animals\' pain behaviors were analyzed, and the effects of pain and MeJA treatments on rats learning and memory were evaluated/compared using the Morris water maze (MWM) test. In addition, the expression of tumor necrosis factor-α (TNF-α), IL-1β, BDNF, and COX-2 genes in the rats\' hippocampus was evaluated using real-time polymerase chain reaction.
RESULTS: Experiencing orofacial pain resulted in a significant decline in the rats learning and memory. However, the central administration of 20 μg/rat of MeJA effectively mitigated these impairments. In the MWM, the performance of the MeJA-treated rats showed a two- to threefold improvement compared to the nontreated ones. Moreover, in the hippocampus of pain-induced rats, the expression of pro-inflammatory factors TNF-α, IL-1β, and COX-2 significantly increased, whereas the BDNF expression decreased. In contrast, MeJA downregulated the pro-inflammatory factors and upregulated the BDNF by more than 50%.
CONCLUSIONS: These findings highlight the notable antinociceptive potential of MeJA and its ability to inhibit pain-induced learning and memory dysfunction through its anti-inflammatory effect.

This study compared the self-assessed health-related quality of life (HRQoL) and degree of depression between patients with chronic neuropathic nonodontogenic orofacial pain (NOFP) and healthy controls using the Short Form Survey (SF-36) health status questionnaire and Beck Depression Inventory II (BDI-II). This controlled cross-sectional study included 100 patients and 119 healthy controls. The diagnostic protocol recorded the following: 1) pain intensity using a visual analog scale for the time of examination and during the one-month prior; 2) evidence for neuropathic pain using the Leeds questionnaire for neuropathic signs and symptoms (LANSS); 3) emotional status using the BDI-II; and 4) HRQoL using the SF-36 questionnaire. The mean LANSS score was 17.18 in the patient group and 0.0 in the control group. The mean BDI-II score was 18.31 in the patient group and 5.87 in the control group. The SF-36 scores were shown with Mann-Whitney U testing to have statistically significant differences between the patient and healthy control groups in all categories. Vitality was the only SF-36 category in which the patient group scored higher than the control group. In conclusion, NOFP significantly reduces the self-reported HRQoL. NOFP is also related to the development of depression, but does not affect its severity. There is a significant correlation between depression and low quality of life in patients with NOFP.