Yuya Iwamoto

Background/Objectives: Regular physical exercise conditioning attenuates nociceptive responses. However, it remains unclear whether physical exercise performed before local inflammation exerts prolonged preventive effects. This study determined whether treadmill run (TR) preconditioning produces sustained preventive effects on craniofacial nociception and associated brain responses following persistent craniofacial inflammation. Methods: Male C57BL/6J mice were assigned to sedentary or TR groups. Daily TR conditioning was performed for 10 days before masseter muscle injection of complete Freund’s adjuvant (CFA) on Day 0. Craniofacial-pain- and related anxiety-like behaviors were determined by the orofacial formalin, elevated plus maze, and open-field tests before and 3 (CFA3) or 7 (CFA7) days after CFA injection. Brain responses in the amygdala, insular cortex, hippocampal CA1, and primary motor cortex were assessed using multiple epigenetic- and neural-activity-related markers. Results: Under sedentary conditions, both CFA3 and CFA7 groups showed increased pain- and anxiety-like behaviors and elevated expression of epigenetic- and neural-activity-related markers in most brain regions. TR preconditioning attenuated these behavioral responses even three and seven days after TR cessation and altered the expression of epigenetic markers in several brain regions, although the direction of change varied by region and time point. TR preconditioning consistently reduced the expression of neural activity markers in most brain areas in both the CFA3 and CFA7 groups, with a few exceptions. Conclusions: TR preconditioning exerted prolonged preventive effects on craniofacial-pain-like behaviors and associated brain responses following craniofacial inflammation.

Background/Objectives: Chronic craniofacial inflammation is recognized as a factor in anxiety-like behaviors, yet effective therapeutic options remain limited. Agmatine, a dietary bioactive compound found in fermented foods such as sake lees, exhibits modulatory effects on neural functions, alleviating psychological distress like anxiety associated with local inflammation. Methods: We investigated both the therapeutic and preventive effects of agmatine on anxiety-like behaviors and the related neural basis in a mouse model of persistent craniofacial inflammation induced by complete Freund’s adjuvant (CFA). Results: Comprehensive behavioral assessments, including the elevated plus maze, open field, dark–light box, social interaction, and novel object recognition tests, revealed that therapeutic agmatine administration (1.0 and 30 mg/kg) significantly reduced CFA-induced anxiety-like behaviors, with the higher dose showing more robust and sustained effects across multiple time points. These behavioral improvements were paralleled by reductions in acetylated histone H3, FosB, and c-Fos expression in key anxiety-related brain regions, suggesting a reversal of craniofacial inflammation-associated neural changes. In contrast, preventive agmatine treatment exerted modest and time-dependent behavioral benefits with minimal molecular normalization. Notably, preventive agmatine did not affect general locomotor activity (indicated by total movement distance), indicating that its anxiolytic effects were not confounded by altered locomotor activity. Metabolomic analysis confirmed the presence of agmatine in sake lees (~0.37 mM), supporting the hypothesis that fermented food products might offer dietary routes to emotional resilience. Conclusions: These findings underscore agmatine’s promise as a context-specific epigenetic modulator capable of mitigating anxiety-like behaviors by normalizing inflammation-driven molecular dysregulation in the brain.

This narrative review provides an overview of current knowledge on the impact of nutritional strategies on chronic craniofacial pain associated with temporomandibular disorders (TMDs). Individuals experiencing painful TMDs alter their dietary habits, avoiding certain foods, possibly due to chewing difficulties, which might lead to nutrient deficiencies. Our literature investigation revealed that the causal links between nutritional changes and craniofacial pain remain unclear. However, clinical and preclinical studies suggest that nutraceuticals, including vitamins, minerals, polyphenols, omega-3 fatty acids, isoprenoids, carotenoids, lectins, polysaccharides, glucosamines, and palmitoylethanolamides, could have beneficial effects on managing TMDs. This is described in 12 clinical and 38 preclinical articles since 2000. Clinical articles discussed the roles of vitamins, minerals, glucosamine, and palmitoylethanolamides. The other nutraceuticals were assessed solely in preclinical studies, using TMD models, mostly craniofacial inflammatory rodents, with 36 of the 38 articles published since 2013. Our investigation indicates that current evidence is insufficient to assess the efficacy of these nutraceuticals. However, the existing data suggest potential for therapeutic intervention in TMDs. Further support from longitudinal and randomized controlled studies and well-designed preclinical investigations is necessary to evaluate the efficacy of each nutraceutical intervention and understand their underlying mechanisms in TMDs.

The conditions of stress contagion are induced in bystanders without direct experiences of stressful events. This study determined the effects of stress contagion on masseter muscle nociception in mice. Stress contagion was developed in the bystanders after cohabitating with a conspecific mouse subjected to social defeat stress for 10 days. On Day 11, stress contagion increased anxiety‐ and orofacial inflammatory pain‐like behaviors. The c‐Fos and FosB immunoreactivities evoked by masseter muscle stimulation were increased in the upper cervical spinal cord, while c‐Fos expressions were increased in the rostral ventromedial medulla, including the lateral paragigantocellular reticular nucleus and nucleus raphe magnus in stress contagion mice. The level of serotonin in the rostral ventromedial medulla was increased under stress contagion, while the number of serotonin positive cells was increased in the lateral paragigantocellular reticular nucleus. Stress contagion increased c‐Fos and FosB expressions in the anterior cingulate cortex and insular cortex, both of which were positively correlated with orofacial inflammatory pain‐like behaviors. The level of brain‐derived neurotrophic factor was increased in the insular cortex under stress contagion. These results indicate that stress contagion can cause neural changes in the brain, resulting in increased masseter muscle nociception, as seen in social defeat stress mice.