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ObjectivesThis study was aimed to establish a neural-related gene risk score (NRGRS) for the prediction of head and neck squamous cell carcinoma (HNSCC) prognosis, and explore its prognostic value on the benefit of immune checkpoint inhibitor (ICI) therapy.Materials and MethodsBased on the transcriptome data of HNSCC patients (n = 546) from The Cancer Genome Atlas (TCGA), 37 neural-related hub genes were identified by weighted gene co-expression network analysis. Four genes (ITGA5, PYGM, GNG7 and ATP2A3) were identified to construct NRGRS using Lasso-Cox regression method based on the TCGA cohort and validated in the Gene Expression Omnibus (GEO) cohort (n = 109). The survival analysis and Cox regression were performed to validate the prognostic value of NRGRS. Afterward, the molecular and immune characteristics in NRGRS-defined subgroups were analyzed and the prediction value of NRGRS on the benefit of ICI therapy was compared with other biomarkers.ResultsNRGRS-high patients had a worse overall survival than NRGRS-low patients. A low NRGRS was correlated with DNA repair-related and immune response-related pathways, while a high NRGRS was associated with Wnt-beta-catenin signaling, neurotrophic signaling and metabolism-related pathways. Tumors with high NRGRS were more likely to have high TP53, CDKN2A, FAT1 and NOTCH1 mutation rates and have high infiltration of naive CD4 + T cells, resting NK cells, M0, M2 macrophages and resting mast cells, which illustrated suppressive immunity and less benefit from ICI therapy.ConclusionIn conclusion, NRGRS is a promising prognostic biomarker to predict the survival, the molecular and immune characteristics, and also immunotherapy benefit for HNSCC patients.Clinical RelevanceThis study provides evidence for the potential correlation between neural-related transcriptome alteration and immune activity in HNSCC.

Epigenetic regulation of gene expression has been implicated in the development of chronic pain. However, little is known about whether this regulation is involved in the development and treatment of chronic pain comorbidities such as fibromyalgia syndrome (FMS) and temporomandibular disorder (TMD), a comorbidity predominantly occurring among women. Here we explored the impact of the histone deacetylase (HDAC) inhibitor suberoylanilide hydroxamic acid (SAHA) on somatic hyperalgesia induced by stress or stress combined with orofacial inflammation, which mimicked the comorbidity of FMS and TMD in rats. Our data showed that somatic thermal hyperalgesia and mechanical allodynia induced by both conditions were completely prevented by intrathecal injection of SAHA, which upregulated 5-HT

Temporomandibular disorders (TMD) are a group of diseases in the oral and maxillofacial region that can manifest as acute or chronic persistent pain, affecting millions of people worldwide. Although hundreds of studies have explored mechanisms and treatments underlying TMD, multiple pathogenic factors and diverse clinical manifestations make it still poorly managed. Appropriate animal models are helpful to study the pathogenesis of TMD and explore effective treatment measures. At present, due to the high cost of obtaining large animals, rodents and rabbits are often used to prepare TMD animal models. Over the past decade, various animal models have been intensively developed to understand neurobiological and molecular mechanisms of TMD, and seek effective treatments. Although these models cannot carry out all clinical features, they are valuable in revealing the mechanisms of TMD and creating curative access. Currently, there are multitudinous animal models of TMD research. They can be constructed in different means and summarized into four ways according to the various causes and symptoms, including chemical induction (intra-articular injection of ovalbumin, collagenase, formalin, vascular endothelial growth factor, intramuscular injection of complete Freund’s adjuvant, etc.), mechanical stress stimulation (passive mouth opening, change of chewing load), surgical operation (partial disc resection, joint disc perforation) and psychological stress induction. Here, we summarize and discuss different approaches of animal models for determining neurophysiological and mechanical mechanisms of TMD and assess their advantages and limitations, respectively.

Oxytocin (OT) is recognized as a critical neuropeptide in pain-related disorders. Chronic pain caused by the comorbidity of temporomandibular disorder (TMD) and fibromyalgia syndrome (FMS) is common, but whether OT plays an analgesic role in the comorbidity of TMD and FMS is unknown. Female rats with masseter muscle inflammation combined with 3-day forced swim (FS) stress developed somatic hypersensitivity, which modeled the comorbidity of TMD and FMS. Using this model, the effects of spinal OT administration on mechanical allodynia and thermal hyperalgesia in hindpaws were examined. Furthermore, the protein levels of OT receptors and 5-HT2A receptors in the L4–L5 spinal dorsal horn were analyzed by Western blot. The OT receptor antagonist atosiban and 5-HT2A receptor antagonist ritanserin were intrathecally injected prior to OT injection in the separate groups. Intrathecal injection of 0.125 μg and 0.5 μg OT attenuated the hindpaw hyperalgesia. The expression of OT receptors and 5-HT2A receptors in the L4–L5 spinal dorsal horn significantly increased following intrathecal injection of 0.5 μg OT. Intrathecal administration of either the OT receptor antagonist atosiban or 5-HT2A receptor antagonist ritanserin blocked the analgesic effect of OT. These results suggest that OT may inhibit hindpaw hyperalgesia evoked by orofacial inflammation combined with stress through OT receptors and/or 5-HT2A receptors, thus providing a therapeutic prospect for drugs targeting the OT system and for patients with comorbidity of TMD and FMS.

Background Social media has become increasingly important as a source of information for the public and is widely used for health-related information. The outbreak of the coronavirus disease (COVID-19) has exerted a negative impact on dental practices. Objective The aim of this study is to analyze the nature and diffusion of COVID-19–related oral health information on the Chinese social media site Weibo. Methods A total of 15,900 tweets related to oral health and dentistry information from Weibo during the COVID-19 outbreak in China (December 31, 2019, to March 16, 2020) were included in our study. Two researchers coded 1000 of the total tweets in advance, and two main thematic categories with eight subtypes were refined. The included tweets were analyzed over time and geographic region, and coded into eight thematic categories. Additionally, the time distributions of tweets containing information about dental services, needs of dental treatment, and home oral care during the COVID-19 epidemic were further analyzed. Results People reacted rapidly to the emerging severe acute respiratory syndrome coronavirus 2 threat to dental services, and a large amount of COVID-19–related oral health information was tweeted on Weibo. The time and geographic distribution of tweets shared similarities with epidemiological data of the COVID-19 outbreak in China. Tweets containing home oral care and dental services content were the most frequently exchanged information (n=4803/15,900, 30.20% and n=4478, 28.16%, respectively). Significant differences of public attention were found between various types of bloggers in dental services–related tweets (P Conclusions Our study overviewed and analyzed social media data on the dental services and oral health information during the COVID-19 epidemic, thus, providing insights for government organizations, media, and dental professionals to better facilitate oral health communication and efficiently shape public concern through social media when routine dental services are unavailable during an unprecedented event. The study of the nature and distribution of social media can serve as a useful adjunct tool to help make public health policies.

BACKGROUND Social media has become increasingly important as a source of information for the public and is widely used for health-related information. The outbreak of the coronavirus disease (COVID-19) has exerted a negative impact on dental practices. OBJECTIVE The aim of this study is to analyze the nature and diffusion of COVID-19–related oral health information on the Chinese social media site Weibo. METHODS A total of 15,900 tweets related to oral health and dentistry information from Weibo during the COVID-19 outbreak in China (December 31, 2019, to March 16, 2020) were included in our study. Two researchers coded 1000 of the total tweets in advance, and two main thematic categories with eight subtypes were refined. The included tweets were analyzed over time and geographic region, and coded into eight thematic categories. Additionally, the time distributions of tweets containing information about dental services, needs of dental treatment, and home oral care during the COVID-19 epidemic were further analyzed. RESULTS People reacted rapidly to the emerging severe acute respiratory syndrome coronavirus 2 threat to dental services, and a large amount of COVID-19–related oral health information was tweeted on Weibo. The time and geographic distribution of tweets shared similarities with epidemiological data of the COVID-19 outbreak in China. Tweets containing home oral care and dental services content were the most frequently exchanged information (n=4803/15,900, 30.20% and n=4478, 28.16%, respectively). Significant differences of public attention were found between various types of bloggers in dental services–related tweets (P CONCLUSIONS Our study overviewed and analyzed social media data on the dental services and oral health information during the COVID-19 epidemic, thus, providing insights for government organizations, media, and dental professionals to better facilitate oral health communication and efficiently shape public concern through social media when routine dental services are unavailable during an unprecedented event. The study of the nature and distribution of social media can serve as a useful adjunct tool to help make public health policies.

Stress facilitates pain perception and sensitizes pain pathways, but the underlying mechanism is still unclear. The purpose of this study was to investigate whether the activation of 5-hydroxytryptamine (5-HT) subtype-3 receptor in the spinal cord contributes to somatic hyperalgesia induced by repeated three-day forced swim in the estradiol replacement rats after ovariectomy. Somatic sensitivity was assessed by thermal withdrawal latency to radiant heat and mechanical withdrawal threshold to von Frey filaments. The expression of 5-HT3A receptor in the L4–L5 dorsal spinal cord was examined by Western blot. Repeated forced swim stress reduced the thermal withdrawal latency and mechanical withdrawal threshold, and the presence of estradiol exaggerated this hyperalgesia. The expression of 5-HT3A receptor in the L4–L5 dorsal spinal cord increased significantly following repeated forced swim in estradiol replacement rats. Intrathecal injection of 5-HT3 receptor antagonist Y-25130 blocked the somatic hyperalgesia induced by forced swim stress. These data indicate that 5-HT3 receptor activation through the descending facilitation system contributes to the somatic hyperalgesia evoked by forced swim stress. The results may provide a new therapeutic avenue for alleviating pain induced by stress.

Stress-induced hyperalgesia is a problematic condition that lacks an effective therapeutic measure, and hence impairs health-related quality of life. The regulation of stress by oxytocin (OT) has overlapping effects on pain. OT can alleviate pain directly mainly at the spinal level and the peripheral tissues. Additionally, OT plays an analgesic role by dealing with stress and fear learning. When OT relieves stress by targeting the prefrontal brain regions and the hypothalamic-pituitary-adrenal axis, the body's sensitivity to pain is attenuated. Meanwhile, OT facilitates fear learning and may, in turn, enhance the anticipatory actions to painful stimulation. The unique therapeutic value of OT in patients suffering from stress and stress-related hyperalgesia conditions is worth considering. We reviewed recent advances in animal and human studies involving the effects of OT on stress and pain, and discussed the possible targets of OT within the descending and ascending pathways in the central nervous system. This review provides an overview of the evidence on the role of OT in alleviating stress-induced hyperalgesia.

Visceral pain arising from internal organs is a common clinical symptom of multiple diseases impacting millions of people, yet it is poorly managed. There is evidence that changes in chromatin structure drive stable alterations in gene expression during pain conditions, which underlie several symptoms, including visceral hypersensitivity and anxiety. Epigenetic modulation including DNA methylation, histone modifications, and noncoding RNA regulates visceral pain through enhancing or suppressing receptors of neurotransmitters in the nervous system. Recent findings of epigenetic changes in the peripheral and central nervous system during visceral pain may guide fundamental progress in new treatment targets. In this chapter, we provide a brief overview of still-limited literature that directly implicates epigenetic modifications on visceral pain.

Chronic primary pain (CPP) is a group of diseases with long-term pain and functional disorders but without structural or specific tissue pathologies. CPP is becoming a serious health problem in clinical practice due to the unknown cause of intractable pain and high cost of health care yet has not been satisfactorily addressed. During the past decades, a significant role for the descending pain modulation and alterations due to specific diseases of CPP has been emphasized. It has been widely established that central sensitization and alterations in neuroplasticity induced by the enhancement of descending pain facilitation and/or the impairment of descending pain inhibition can explain many chronic pain states including CPP. The descending serotonergic neurons in the raphe nuclei target receptors along the descending pain circuits and exert either pro- or antinociceptive effects in different pain conditions. In this review, we summarize the possible underlying descending pain regulation mechanisms in CPP and the role of serotonin, thus providing evidence for potential application of analgesic medications based on the serotonergic system in CPP patients.

Visceral pain, a common characteristic of multiple diseases relative to viscera, impacts millions of people worldwide. Although hundreds of studies have explored mechanisms underlying visceral pain, it is still poorly managed. Over the past decade, strong evidence emerged suggesting that microRNAs (miRNAs) play a significant role in visceral nociception through altering neurotransmitters, receptors and other genes at the posttranscriptional level. Under pathological conditions, one kind of miRNA may have several target mRNAs and several kinds of miRNAs may act on one target, suggesting complex interactions and mechanisms between miRNAs and target genes lead to pathological states. In this review we report on recent progress in examining miRNAs responsible for visceral sensitization and provide miRNA-based therapeutic targets for the management of visceral pain.

Stress facilitates pain perception and sensitizes pain pathways, but the underlying mechanism is still unclear. The purpose of this study was to investigate whether the activation of 5-hydroxytrypt...