Search Results (39)

Myricetin (MYR), a naturally occurring flavonoid widely distributed in fruits and vegetables, was investigated for its potential to reduce inflammation-induced hyperexcitability in the spinal trigeminal nucleus caudalis (SpVc), which is associated with hyperalgesia. The study also compared MYR’s impact with that of celecoxib (CEL), a non-steroidal anti-inflammatory drug (NSAID). To induce inflammation, Complete Freund’s adjuvant was injected into the whisker pads of rats. Subsequently, we measured the mechanical escape threshold by applying mechanical stimuli to the orofacial region. We found that inflamed rats exhibited a significantly lower threshold compared to naive rats (each group, n = 4). This reduced threshold returned to the naive level two days after the administration of MYR (16 mg/kg, i.p.), CEL (10 mg/kg, i.p.), and a combination of MYR (8 mg/kg, i.p.) + CEL (5 mg/kg, i.p.). To investigate the nociceptive neural response to orofacial mechanical stimulation, we performed extracellular single-unit recordings to measure the activity of SpVc wide-dynamic range (WDR) neurons in anesthetized subjects. In inflamed rats, administration of MYR, CEL, or 1/2MYR + 1/2CEL (each group, n = 4) significantly reduced both the average spontaneous activity and the evoked firing rate of SpVc neurons in response to non-painful and painful mechanical stimuli. The increased average receptive field size in inflamed rats was normalized to the naive level following treatment with MYR, CEL, or 1/2MYR + 1/2CEL. These findings suggest that MYR administration can mitigate inflammatory hyperalgesia by reducing the heightened excitability of SpVc WDR neurons. This supports the notion that MYR could be a viable therapeutic option in complementary and alternative medicine for preventing trigeminal inflammatory mechanical hyperalgesia, potentially serving as an alternative to selective cyclooxygenase-2 blockers. Full article

This study investigated the potential of astaxanthin (AST), a natural carotenoid, to mitigate inflammation-induced hyperexcitability in the spinal trigeminal nucleus caudalis (SpVc) and the associated hyperalgesia. The efficacy of systemic AST application was compared to that of celecoxib (CEL). Inflammation was induced by injecting Complete Freund’s adjuvant into the whisker pads of rats. The mechanical escape threshold was then assessed by delivering mechanical stimuli to the orofacial region. Although inflamed rats exhibited a significantly lower mechanical threshold compared to naïve rats, this threshold was restored to normal levels two days after treatment with AST, CEL, and the 1/2 CEL + 1/2 AST combination. The activity of SpVc wide-dynamic range (WDR) neurons was measured using extracellular single-unit recordings in response to mechanical stimulation of the orofacial area under anesthesia. In inflamed rats, AST, CEL, and 1/2 CEL + 1/2 AST administration significantly reduced the average firing rate of these neurons elicited by both non-noxious and noxious mechanical stimuli. In addition, all three treatments significantly decreased the heightened average spontaneous activity of SpVc neurons and normalized the increased average receptive field size in inflamed rats. This study provides evidence that systemic AST administration attenuates inflammatory mechanical hyperalgesia. This action is associated with the suppression of hyperexcitability in nociceptive SpVc WDR neurons, likely through the inhibition of the cyclooxygenase-2 signaling pathway. These findings support the potential of AST as a therapeutic agent for complementary and alternative medicine. It may provide a valuable alternative to non-steroidal anti-inflammatory drugs for the prevention of trigeminal inflammatory mechanical hyperalgesia. Full article

Aim: Pacifiers play a critical role in the early stages of craniofacial and palate development during infancy. While they provide comfort and aid in soothing, their use can also have significant impacts on the growth and function of the oral cavity. This study aimed to simulate and predict the behavior of six different types of pacifiers and their functional interaction with the tongue and palate, with the goal of understanding their potential effects on orofacial growth and development. Materials and Methods: Biomechanical analysis using Finite Element Analysis (FEA) mathematical models was employed to evaluate the behavior of six different commercial pacifiers in contact with the palate and tongue. Three-dimensional solid models of the palate and tongue were based on the mathematical framework from a 2007 publication. This allowed for a detailed investigation into how various pacifier designs interact with soft and hard oral tissues, particularly the implications on dental and skeletal development. Results: The findings of this study demonstrate that pacifiers exhibit different interactions with the oral cavity depending on their geometry. Anatomical–functional pacifiers, for instance, tend to exert lateral compressions near the palatine vault, which can influence the hard palate and contribute to changes in craniofacial growth. In contrast, other pacifiers apply compressive forces primarily in the anterior region of the palate, particularly in the premaxilla area. Furthermore, the deformation of the tongue varied significantly across different pacifier types: while some pacifiers caused the tongue to flatten, others allowed it to adapt more favorably by assuming a concave shape. These variations highlight the importance of selecting a pacifier that aligns with the natural development of both soft and hard oral tissues. Conclusions: The results of this study underscore the crucial role of pacifier geometry in shaping both the palate and the tongue. These findings suggest that pacifiers have a significant influence not only on facial bone growth but also on the stimulation of oral functions such as suction and feeding. The geometry of the pacifier affects the soft tissues (tongue and muscles) and hard tissues (palate and jaw) differently, which emphasizes the need for careful selection of pacifiers during infancy. Choosing the right pacifier is essential to avoid potential negative effects on craniofacial development and to ensure that the benefits of proper oral function are maintained. Therefore, healthcare professionals and parents should consider these biomechanical factors when introducing pacifiers to newborns. Full article

Objective: Given the side effects and reduced efficacy of conventional local anesthetics in inflammatory conditions, there is a compelling need for complementary alternative medicine (CAM), particularly those based on phytochemicals. While a previous study showed that in vivo local injection of (-)-epigallocatechin-3-gallate (EGCG) into the peripheral receptive field suppresses the excitability of rat trigeminal ganglion (TG) neurons in the absence of inflammation, the acute effects of EGCG in vivo, especially on TG neurons under inflammatory conditions, are still unknown. We aimed to determine if acute local EGCG administration into inflamed tissue effectively attenuates the excitability of nociceptive TG neurons evoked by mechanical stimulation. Methods: The escape reflex threshold was measured to assess hyperalgesia caused by complete Freund’s adjuvant (CFA)-induced inflammation. To assess neuronal activity, extracellular single-unit recordings were performed on TG neurons in anesthetized CFA-inflamed rats in response to orofacial mechanical stimulation. Results: The mechanical escape threshold was significantly lower in CFA-inflamed rats compared to before CFA injection. EGCG (1–10 mM) reversibly and dose-dependently inhibited the mean firing frequency of TG neurons evoked by both non-noxious and noxious mechanical stimuli (p < 0.05). For comparison, 1% lidocaine (37 mM), a local anesthetic, also caused reversible inhibition of the mean firing frequency in inflamed TG neurons responding to mechanical stimuli. Importantly, 10 mM EGCG produced a significantly greater magnitude of inhibition on TG neuronal discharge frequency than 1% lidocaine (noxious, lidocaine vs. EGCG, 19.7 ± 3.3% vs. 42.3 ± 3.4%, p < 0.05). Conclusions: Local injection of EGCG into inflamed tissue effectively suppresses the excitability of nociceptive primary sensory TG neurons, as indicated by these findings. Significantly, locally administered EGCG exerted a more potent local analgesic action compared to conventional voltage-gated sodium channel blockers. This heightened efficacy originates from EGCG’s ability to inhibit both generator potentials and action potentials directly at nociceptive primary nerve terminals. As a result, EGCG stands out as a compelling candidate for novel analgesic development, holding particular relevance for CAM strategies. Full article

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is one of the side effects of bisphosphonate (BP) administration. Despite some preventive measures having been suggested, a definitive and effective treatment strategy for BRONJ remains to be established. Recent evidence has indicated that BPs dramatically impair the function of orofacial bone marrow stromal cells (BMSCs), which may contribute to the development of osteonecrosis. Thus, we hypothesized that recovery-impaired function of BMSCs at lesion sites could be beneficial in treating BRONJ. N6-methyladenosine (m6A) modification is the most common epigenetic modification and has been demonstrated to play a vital role in the modulation of BMSCs’ function. We detected the role of m6A modification in regulating the function of orofacial BMSCs under BP stimulation, and found that BPs led to a reduction in the global m6A methylation level, SAM level, and METTL3 expression in BMSCs during the osteogenic differentiation period. Meanwhile, betaine, a methyl group donor, effectively reversed the BP-decreased global m6A methylation level and SAM level in BMSCs, as well as rescuing the differentiation ability of impaired BMSCs. In the last part, we built a BRONJ rat model and supplemented rats with betaine via drinking water. The results showed that betaine successfully attenuated bone lesions and promoted wound healing in BP-injected rats, thereby providing new insight into future clinical treatment for BRONJ. Full article

Introduction: Hypoglossal nerve stimulation (HNS) “Inspire_© therapy” has garnered popularity among obstructive sleep apnea (OSA) patients seeking an alternative to continuous positive airway pressure (CPAP) therapy. The growth in HNS has been particularly high in older adults living with OSA. Consistent and proper use of HNS in the geriatric population faces unique age-associated barriers: a high rate of multiple chronic conditions (MCC) and polypharmacy (being on five or more drugs). Early recognition and patient-centered management of these barriers will allow older patients to obtain maximum benefits from HNS. HNS has distinct advantages in the geriatric population because it overcomes many concerns related to CPAP therapy adherence, such as mechanical limitations due to manual dexterity, maxillofacial anatomy, dental issues such as usage of dentures, allergy/otolaryngology-related disorders, and pre-existing post-traumatic stress disorder-related claustrophobia. This paper describes how we worked with older patients with OSA and their care partners to overcome these barriers so patients can continue to derive cardiovascular, neurologic, and quality of life benefits resulting from optimal OSA management. These benefits are especially important in the older population because of higher rates of comorbidities (dementia, coronary artery disease, and atrial fibrillation) exacerbated by sub-optimally treated OSA. In this article, we describe our clinical experience with elderly patients on Inspire_© therapy, with a focus on the everyday difficulties faced by these patients and the measures implemented to address and mitigate these barriers. Methods: A retrospective chart review was conducted to identify patients aged 65 and above who underwent hypoglossal nerve stimulator insertion. Experiences of older patients during and after the insertion procedure were documented and compared to a younger population of patients on HNS therapy. We specifically collected information on difficulties encountered during activation or follow-up visits and compared them between the different age groups. Using this information, we identified areas to improve treatment adherence from the patients’ perspectives. Results: We identified 43 geriatric (65 to 86 years old) patients who received the Inspire implant at a tertiary academic medical center and compared them to a younger population of 23 patients. Most common challenges noted—with a potential to impact adherence—included orofacial and lingual neuropraxia (ischemic or demyelination-induced neuropathy) at activation, cognitive dysfunction (memory problems), preexisting anxiety, and insomnia. Other difficulties that are less commonly reported but equally important to consistent and proper use of HNS included headaches, concerns of device malfunction, change in comfort levels after cardiac procedures, and general intolerance of the device. The older patient population had a statistically significant higher incidence of cognitive difficulties (30.2% vs. 4.4%) and a smaller social support system (62.8% vs. 91.3%) affecting device usage compared to the younger population. There were no statistically significant differences in the rates of other more commonly reported adverse effects such as headaches, dry mouth, and anxiety between the two age groups. Conclusion: Despite several challenges faced by geriatric patients, Inspire_© hypoglossal nerve stimulation remains a viable, alternative treatment option for OSA with improved tolerance and adherence compared to CPAP. After identifying less commonly reported barriers such as cognitive decline, sensory deficits, and decreased social support systems, minor adjustments and appropriate education on use allows older patients to correctly use and benefit from Inspire_© device therapy, with subsequent improvement in sleep and overall quality of life. Full article

Dysphagia in children poses a significant health concern. Difficulties in swallowing can lead to an impairment in food intake and malnutrition, as well as a risk of aspiration and pneumonia. It is a life-threatening condition, especially for newborns and infants. Children with dysphagia and their parents are experiencing increased anxiety and stress. Traditional methods of dysphagia therapy involve manual exercises of the orofacial muscles and modifications of the diet to fit the child’s abilities. These methods often do not achieve the desired results, which prompts researchers to look for new solutions to increase the effectiveness of standard therapy. One promising approach is neuromuscular electrical stimulation (NMES) applied to muscles involved in the process of swallowing. The purpose of this paper is to highlight and discuss the feeding difficulties associated with pediatric dysphagia, as well as the possibility of NMES application in its treatment. It is anticipated that NMES, by enhancing muscles that regulate swallowing, may improve the nutritional status of children with dysphagia. More research is needed to show that NMES is effective in improving the feeding and nutritional status of children with dysphagia. Full article

While the modulation of the excitatory and inhibitory neuronal transmission by the phytochemical flavonoid, myricetin (MYR), has been noted in the nervous system, the way in which MYR affects the excitability of nociceptive sensory neurons in vivo remains to be established. This study aimed to explore whether administering MYR intravenously, in acute doses, to rats, diminishes the excitability of SpVc wide-dynamic range (WDR) spinal trigeminal nucleus caudalis (SpVc) neurons in response to nociceptive and non-nociceptive mechanical stimulation in vivo. Recordings of extracellular single units were obtained from SpVc neurons when orofacial mechanical stimulation was applied to anesthetized rats. The average firing rate of SpVc WDR neurons, to both non-noxious and noxious mechanical stimuli, was significantly and dose-dependently inhibited by MYR (1–5 mM, intravenously), and the maximum reversible inhibition of the discharge frequency, for both non-noxious and noxious mechanical stimuli, occurred within 5–10 min. The suppressive effects of MYR continued for about 20 min. These findings indicate that an acute, intravenous administration of MYR reduces the SpVc nociceptive transmission, likely through the inhibition of the CaV channels and by activating the Kv channels. Therefore, MYR might be utilized as a treatment for trigeminal nociceptive pain, without causing side effects. Full article

Post-traumatic trigeminal neuropathy (PTTN) is a sensory abnormality caused by injury to the trigeminal nerve during orofacial surgery. However, existing analgesics are ineffective against PTTN. Abnormal microglial activation in the caudal part of the spinal trigeminal nucleus caudal part (Sp5C), where the central trigeminal nerve terminals reside, plays an important role in PTTN pathogenesis. Therefore, regulating microglial activity in Sp5C appears to be an important approach to controlling pain in PTTN. Cannabinoid receptor 2 (CB₂) is expressed in immune cells including microglia, and its activation has anti-inflammatory effects. The current study demonstrates that the repeated intranasal administration of CB₂ agonist HU-308 ameliorates the infraorbital nerve cut (IONC)-induced hyperresponsiveness to acetone (cutaneous cooling). The therapeutic efficacy of oral HU-308 was found to be less pronounced in alleviating cold hypersensitivity in IONC mice compared to intranasal administration, indicating the potential advantages of the intranasal route. Furthermore, repeated intranasal administration of HU-308 suppressed the activation of Sp5C microglia in IONC mice. Additionally, pretreatment with the CB₂ antagonist, SR 144528, significantly blocked the anti-nociceptive effect of repeated intranasal administration of HU-308 on cold hypersensitization in IONC mice. These data suggest that the continuous stimulation of CB₂ ameliorates PTTN-induced pain via the inhibition of microglial activation. Thus, CB₂ agonists are potential candidates for novel therapeutic agents against PTTN. Full article

The present study examines whether the systemic application of naringenin (NRG) reduces inflammation-induced hyperexcitability in the spinal trigeminal nucleus caudalis (SpVc) related to hyperalgesia, and compares its impact with that of diclofenac (DIC). To provoke inflammation, the whisker pads of rats were injected with complete Freund’s adjuvant, and subsequently, mechanical stimuli were administered to the orofacial region to determine the escape threshold. Compared to naïve rats, the inflamed rats showed a significantly lower mechanical threshold, and this reduced threshold returned to normal levels two days post-administration of NRG, DIC, and half-dose DIC plus half-dose NRG (1/2 DIC + 1/2 NRG). Using extracellular single-unit recordings, the activity of SpVc wide-dynamic range neurons was measured in response to mechanical stimulation of the orofacial area under anesthesia. The average firing rate of SpVc neurons when exposed to both non-painful and painful mechanical stimuli was significantly reduced in inflamed rats following NRG, DIC, and 1/2 DIC + 1/2 NRG administration. The heightened average spontaneous activity of SpVc neurons in rats with inflammation was significantly reduced following NRG, DIC, and 1/2 DIC + 1/2 NRG administration. The increased average receptive field size observed in inflamed rats reverted to normal levels after either NRG, DIC, or 1/2 DIC + 1/2 NRG treatment. These findings indicate that NRG administration can reduce inflammatory hyperalgesia linked to the heightened excitability of SpVc wide-dynamic range neurons. Full article

Obstructive sleep apnea (OSA) is a heterogenous disease process that cannot be adequately categorized by AHI alone. There is a significant prevalence of OSA in the general population with ongoing efforts to evaluate the risk factors contributing to OSA and its associated clinical implications. Only by improving our understanding of OSA can we advance our methods in the diagnosis and treatment of OSA. For this article, the authors reviewed keywords of obstructive sleep apnea diagnosis and therapy in the databases of Embase, Medline, and Medline ePub over the past 3 years, excluding any articles that only addressed sleep apnea in children under age 17 years. This review article is divided into three main sections. First, we will investigate the use of novel screening tools, biomarkers, anthropometric measurements, and novel wearable technologies that show promise in improving the diagnosis of OSA. There is mention of comorbid conditions seen in OSA patients since certain disease combinations can significantly worsen health and should raise our awareness to diagnose and manage those concomitant disorders. The second section will look at the current and developing treatment options for OSA. These include positive airway therapy (PAP), mandibular advancement device (MAD), exciting new findings in certain medications, orofacial myofunctional therapy (OMT), hypoglossal nerve stimulation therapy (HGNS), and other surgical options. We will conclude with a section reviewing the current Clinical Practice Guidelines for Diagnostic Testing in Adults with Obstructive Sleep Apnea from 2017, which strongly advises polysomnography (PSG) or home sleep apnea testing (HSAT), along with comprehensive sleep evaluation for uncomplicated patients with a clinical presentation of OSA. Full article

Although astaxanthin (AST) has demonstrated a modulatory effect on voltage-gated Ca²⁺ (Cav) channels and excitatory glutamate neuronal transmission in vitro, particularly on the excitability of nociceptive sensory neurons, its action in vivo remains to be determined. This research sought to determine if an acute intravenous administration of AST in rats reduces the excitability of wide-dynamic range (WDR) spinal trigeminal nucleus caudalis (SpVc) neurons in response to nociceptive and non-nociceptive mechanical stimulation in vivo. In anesthetized rats, extracellular single-unit recordings were carried out on SpVc neurons following mechanical stimulation of the orofacial area. The average firing rate of SpVc WDR neurons in response to both gentle and painful mechanical stimuli significantly and dose-dependently decreased after the application of AST (1–5 mM, i.v.), and maximum suppression of discharge frequency for both non-noxious and nociceptive mechanical stimuli occurred within 10 min. These suppressive effects persisted for about 20 min. These results suggest that acute intravenous AST administration suppresses the SpVc nociceptive transmission, possibly by inhibiting Cav channels and excitatory glutamate neuronal transmission, implicating AST as a potential therapeutic agent for the treatment of trigeminal nociceptive pain without side effects. Full article

Oral squamous cell carcinoma (OSCC) presents significant treatment challenges due to its poor survival and intense pain at the primary cancer site. Cancer pain is debilitating, contributes to diminished quality of life, and causes opioid tolerance. The stimulator of interferon genes (STING) agonism has been investigated as an anti-cancer strategy. We have developed STINGel, an extended-release formulation that prolongs the availability of STING agonists, which has demonstrated an enhanced anti-tumor effect in OSCC compared to STING agonist injection. This study investigates the impact of intra-tumoral STINGel on OSCC-induced pain using two separate OSCC models and nociceptive behavioral assays. Intra-tumoral STINGel significantly reduced mechanical allodynia in the orofacial cancer model and alleviated thermal and mechanical hyperalgesia in the hind paw model. To determine the cellular signaling cascade contributing to the antinociceptive effect, we performed an in-depth analysis of immune cell populations via single-cell RNA-seq. We demonstrated an increase in M1-like macrophages and N1-like neutrophils after STINGel treatment. The identified regulatory pathways controlled immune response activation, myeloid cell differentiation, and cytoplasmic translation. Functional pathway analysis demonstrated the suppression of translation at neuron synapses and the negative regulation of neuron projection development in M2-like macrophages after STINGel treatment. Importantly, STINGel treatment upregulated TGF-β pathway signaling between various cell populations and peripheral nervous system (PNS) macrophages and enhanced TGF-β signaling within the PNS itself. Overall, this study sheds light on the mechanisms underlying STINGel-mediated antinociception and anti-tumorigenic impact. Full article

(1) Background: Transcranial direct current stimulation (tDCS) appears to alleviate chronic pain via a brain-down mechanism. Although several review studies have examined the effects of tDCS on patients with chronic pain, no systematic review or meta-analysis has comprehensively analyzed the effects of tDCS on chronic orthopedic joint pain in one study. We aim to evaluate the effectiveness of tDCS for pain reduction in chronic orthopedic patients; (2) Methods: A comprehensive search of five electronic databases (Medline, Embase, Web of Science, CINAHL, and Cochrane) was performed. Only randomized controlled trials that compared tDCS with a control intervention were included. Eighteen studies met our inclusion criteria. We identified four categories of chronic orthopedic pain: knee (k = 8), lower back (k = 7), shoulder (k = 2), and orofacial pain (k = 1). Random effect models were utilized, and a sensitivity analysis was conducted in the presence of significant heterogeneity. Studies within each pain condition were further classified according to the number of treatment sessions: 1–5 sessions, 6–10 sessions, and >10 sessions.; (3) Results: Significant reductions in chronic orthopedic joint pain were observed following tDCS compared to controls for knee (g = 0.59, p = 0.005), lower back (g = 1.14, p = 0.005), and shoulder (g = 1.17, p = 0.020). Subgroup analyses showed pain reductions after 6–10 tDCS sessions for knee pain and after 1–5 and >10 sessions for lower back pain; (4) Conclusions: tDCS could be considered a potential stand-alone or supplemental therapy for chronic knee and lower back pain. The effectiveness of tDCS treatment varies depending on the number of treatment sessions. Our findings suggest the importance of implementing individualized treatment plans when considering tDCS for chronic pain conditions. Full article

Myofascial pain syndrome is the most common cause of TMD, characterised by trigger points of skeletal muscles in the masticatory region. Patients with myofascial pain suffer from orofacial pain and headaches. Parafunctional activity such as unconscious teeth clenching predisposes a higher possibility of developing myofascial pain. We report the results of a prospective study of 10 patients with a myofascial pain diagnosis related to TMD who underwent treatment with passive aligners and biofeedback exercise. All patients underwent pain assessment (visual analogic scale and muscular palpation test), measurement of masseters thickness with Dolphin Imaging Software, nuclear magnetic resonance of the temporomandibular joint, and functional nuclear magnetic resonance of the brain before and after gnathological treatment. The same patients underwent pain assessment (VAS and palpation test) for the entire duration of their treatment. This study aimed to assess if the results obtained with the therapy were repeatable using functional magnetic resonance imaging. This enabled us to correlate a subjective datum (pain) to an objective one (variation in the functional connectivity of the networks correlated to pain perception). According to the pain assessment, the treatment considerably reduced the pain in 9 out of 10 patients. Furthermore, the functional nuclear magnetic resonance of the brain showed similar modifications in the cerebral pain and default mode networks in these nine patients. The change in the masseter muscle dimensions was not correlated with the modification of pain. Statistical analysis was performed to evaluate the effects of treatment on VAS and trigger point stimulation and on the length and width of the masseter muscle. Linear regression analysis was used to assess a correlation between the modification of the masseter muscle dimension and the amendment of VAS. A paired t-test was used to evaluate statistically significant differences in the connectivity of brain areas of the DMN and the pain network. Our results suggest that the proper treatment of myofascial pain can reduce pain and consistently modify the functional activation of the cerebral pain and default mode networks. Overall, the treatment was repeatable because brain network changes were homogeneous in all patients and did not relate to the intracapsular TMJ condition but only to pain symptoms. Full article