Glossodynia-related pain refers to persistent, chronic pain occurring on the oral mucosal surface. Various medications are prescribed depending on symptom profiles and have demonstrated therapeutic benefits; however, these agents are often associated with adverse effects such as drowsiness or dizziness. Goreisan, a traditional Japanese Kampo medicine, has long been used empirically for glossodynia-related pain, particularly in patients reporting symptom fluctuation associated with weather changes. Nevertheless, high-quality clinical evidence supporting its efficacy remains limited. This multicenter, randomized, open-label preliminary exploratory study enrolled patients receiving treatment for glossodynia-related pain. Participants were assigned to receive either Goreisan (7.5 g/day for 12 weeks) in addition to standard therapy or standard therapy alone. Pain intensity was assessed using the visual analog scale (VAS) at baseline and at 4, 8, and 12 weeks. Salivary amylase activity was measured as an exploratory stress-related biomarker, and atmospheric pressure was recorded at each outpatient visit. Owing to insufficient enrollment, all analyses were descriptive and exploratory. Pain intensity improved from baseline in both groups. However, the proportion of patients achieving ≥ 20% improvement in VAS at week 12 was not higher in the Goreisan group than in the control group. Weak negative correlations between VAS scores and barometric pressure were observed in both groups (r ≈ - 0.2). No clinically relevant adverse events or hepatic dysfunction related to Goreisan were identified. This preliminary exploratory study did not confirm a clear analgesic efficacy of Goreisan for glossodynia. However, the findings provide descriptive data on pain trajectories, safety, and potential meteorological associations, supporting the need for future large-scale, double-blind, placebo-controlled trials.

Background Lowering barometric pressure (LP) can exacerbate neuropathic pain. However, animal studies in this field are limited to a few conditions. Furthermore, although sympathetic involvement has been reported as a possible mechanism, whether the sympathetic nervous system is involved in the hypothalamic-pituitary-adrenal (HPA) axis remains unknown. To address these issues, we investigated LP-induced hyperalgesia by focusing on the cumulative effect of LP and measuring plasma corticosterone levels as a marker of HPA axis activation in mice. Methods Mice with chronic constriction injury (CCI) were used in this study. For behavioral tests, two types of LP stimulation were adopted: a single LP at 20 hPa (Single LP) and three consecutive LPs at 20 hPa (3LPs). Twelve mice were used for each protocol. The no-pressure-change protocol was used as the control. The mechanical sensitivity was tested before and after LP stimulation using von Frey filaments (vF). For corticosterone measurements, six CCI and six intact mice were exposed to 3LPs (CCI-3LPs and INT-3LPs), and another six CCI and six intact mice were exposed to the no-pressure-change protocol (CCI-NP and INT-NP). Blood samples were collected immediately after exposure. Plasma corticosterone levels were measured by ELISA. Results The number of paw elevations by vF before and after LP stimulation did not differ significantly in either the Single LP or the no-pressure-change protocol. For the 3LPs, the number of paw elevations after LP stimulation was significantly greater than before stimulation. Plasma corticosterone levels in the CCI-3LPs were significantly higher than those in CCI-NPs. In intact mice, there was no significant difference in plasma corticosterone levels between the INT-3LPs and INT-NPs. Conclusions LP has a cumulative effect on neuropathic pain. Hypothalamic-pituitary-adrenal axis activation may have an important relationship with LP-induced pain in mice.

This immunohistochemical study evaluated the activity of primary sensory neurons in the vestibular ganglion in response to lowered barometric pressure (LBP) in mice to assess whether changes in barometric pressure were perceived by the vestibular system. Mice were anesthetized and exposed to three consecutive barometric pressure drops within the range of natural weather variations (-20 hPa from the atmospheric pressure). Following anesthetization and paraformaldehyde perfusion 1-hour post-LBP exposure, activity-regulated cytoskeleton-associated protein (Arc) immunoreactive cells in the superior vestibular ganglion (SVG) and inferior vestibular ganglion (IVG) were counted bilaterally and compared with those of controls. In the positive control study, anesthetized mice were placed in the prone position and subjected to rotary motion (RM). The total number of Arc-positive neurons in the IVG, but not in the SVG, was significantly higher in LBP-exposed mice than in controls, regardless of sex. The total number of Arc-positive neurons in the SVG, but not in the IVG, was significantly higher in RM-stimulated mice than in controls. These data showed that primary sensory neurons in the IVG responded to LBP, strongly suggesting that changes in barometric pressure might be perceived by the saccule or posterior semicircular canal innervated by IVG neurons in mice.

Adverse or fluctuating weather conditions can negatively affect health, causing symptoms known as weather-related pain. Although pharmacological treatments, including painkillers, are commonly used, they frequently provide only symptomatic relief and may cause side effects. Therefore, interest in non-pharmacological and dietary interventions is increasing. While inner ear sensitivity to barometric pressure fluctuations—activating the sympathetic nervous system—has traditionally been considered the main mechanism, we propose that reduced oxygen utilization due to peripheral hypoxia under low barometric pressure is also a key factor. Kaempferol, a dietary flavonoid, has been shown in prior studies to enhance oxygen utilization and promote parasympathetic nervous system dominance. We hypothesized that daily kaempferol intake would alleviate weather-related discomfort by improving oxygen use and autonomic balance. In this pilot study, 458 individuals with moderate weather-related symptoms took 10 mg of kaempferol daily for 4 weeks. Participants completed questionnaires before and after the intervention. Data from 387 individuals with over 80

The data demonstrate that 1) TRPV1 and IR co-localize on small DRG neurons and 2) intramuscular insulin administration significantly augments sympathetic and pressor responses to chemical stimulation of skeletal muscle afferents. These findings suggest that insulin potentiates TRPV1 responsiveness at the muscle tissue level, possibly contributing to insulin-induced sympathoexcitation.

Systemic insulin administration evokes sympathoexcitatory actions, but the mechanisms underlying these observations are unknown. We reported that insulin sensitizes the response of thin-fibre primary afferents, as well as the dorsal root ganglion (DRG) that subserves them, to mechanical stimuli. However, little is known about the effects of insulin on primary neuronal responses to chemical stimuli. TRPV1, whose agonist is capsaicin (CAP), is widely expressed on chemically sensitive metaboreceptors and/or nociceptors. The aim of this investigation was to determine the effects of insulin on CAP-activated currents in small DRG neurons and CAP-induced action potentials in thin-fibre muscle afferents of normal healthy rodents. Additionally, we investigated whether insulin potentiates sympathetic nerve activity (SNA) responses to CAP. In whole-cell patch-clamp recordings from cultured mice DRG neurons in vitro, the fold change in CAP-activated current from pre- to post-application of insulin (n = 13) was significantly (P < 0.05) higher than with a vehicle control (n = 14). Similar results were observed in single-fibre recording experiments ex vivo as insulin potentiated CAP-induced action potentials compared to vehicle controls (n = 9 per group, P < 0.05). Furthermore, insulin receptor blockade with GSK1838705 significantly suppressed the insulin-induced augmentation in CAP-activated currents (n = 13) as well as the response magnitude of CAP-induced action potentials (n = 9). Likewise, the renal SNA response to CAP after intramuscular injection of insulin (n = 8) was significantly (P < 0.05) greater compared to vehicle (n = 9). The findings suggest that insulin potentiates TRPV1 responsiveness to CAP at the DRG and muscle tissue levels, possibly contributing to the augmentation in sympathoexcitation during activities such as physical exercise. Key points Evidence suggests insulin centrally activates the sympathetic nervous system, and a chemical stimulus to tissues activates the sympathetic nervous system via thin fibre muscle afferents. Insulin is reported to modulate putative chemical-sensitive channels in the dorsal root ganglion neurons of these afferents. In the present study, it is demonstrated that insulin potentiates the responsiveness of thin fibre afferents to capsaicin at muscle tissue levels as well as at the level of dorsal root ganglion neurons. In addition, it is demonstrated that insulin augments the sympathetic nerve activity response to capsaicin in vivo. These data suggest that sympathoexcitation is peripherally mediated via insulin-induced chemical sensitization. The present study proposes a possible physiological role of insulin in the regulation of chemical sensitivity in somatosensory thin fibre muscle afferents.

To elucidate the relationship between chronic pain conditions with cast immobilization and autonomic function, we investigated the functional changes of the autonomic nervous system in conscious rats with chronic post-cast pain (CPCP) induced by a two-week cast immobilization of one hind limb. We telemetrically examined the time courses of systolic arterial blood pressure (SBP), heart rate (HR), and the middle-frequency (MF) component obtained from the power spectral analysis of SBP variability as a vasomotor sympathetic index. We also investigated the baroreflex sensitivity to phentolamine, an α-adrenoceptor antagonist, and the SBP and HR responses to a low ambient temperature (LT; 9.0 ± 0.2°C) exposure, a sympathetic stimulant. Rats exposed to cast immobilization exhibited mechanical allodynia lasting for at least 10 weeks after cast removal in the calf area (skin and muscle) of the bilateral hind limbs. Under resting conditions, the SBP, HR, and MF components were significantly increased during cast immobilization (all p < 0.001). Following cast removal, these parameters gradually decreased and within 1 week reached lower than baseline levels, lasting for over 10 weeks. Phentolamine administration (10 mg/kg, intraperitoneally) significantly decreased the SBP before and during cast immobilization (before, p < 0.001; during, p = 0.001) but did not lower the SBP after cast removal. The baroreflex gain after phentolamine administration, calculated as the HR increase divided by the SBP reduction, was significantly increased after cast removal (p = 0.002). The SBP increase on LT exposure was significantly greater after cast removal than that before cast immobilization, suggesting hypersensitivity to sympathetic neurotransmitters. These results revealed that, in the CPCP model, sympathetic activation was augmented during cast immobilization, which then decreased after cast removal and remained below normal levels with persisting pain behaviors. Additionally, the responsiveness of the autonomic nervous system was impaired in the CPCP model.

Weather changes accompanied by decreases in barometric pressure are suggested to trigger meteoropathy, i.e., weather–related pain. In this paper, the epidemiological and clinical features of weather–related pain (TENKITSU) are shown and the mechanism is briefly described. From the weather pain survey 2020, it is estimated that there are at least 10 million people who have weather pain in Japan, but it seems that it is difficult to deal with it in general clinical practice. It is necessary to establish a highly accurate meteoro­pathy forecast in order to establish effective preventive treatments. We conducted a large–scale Internet survey and built a predictive model. The survey period was about one year, and 35 surveys were done. We analyzed the correlation between the symptom reports obtained from weather news (WN) users (157,698 in total) and the barometric pressure data. The barometric pressure change pattern that contributes to the onset of weather–related pain was indexed. We found that obvious changes in atmospheric pressure, minute changes in atmospheric pressure (micro–pressure fluctuations) which occur as a precursor to the collapse of the weather, and diurnal fluctuations in atmospheric pressure (atmospheric tide) correlate with worsening of symptoms. Therefore, we weighted the contributions of these three factors, built a model that predicts the risk of developing weather pain up to 6 days ahead every 3 hours, and started using it at WN.

Background: Changes in atmospheric pressure are suggested to trigger headaches. This pilot study was made to determine craniofacial sensations accompanying short phases of changing barometric pressure. Methods: In a crossover design, 15 adult healthy subjects were exposed in a climate chamber to 8 min phases of barometric pressure lowering by 0, 20 and 40 hPa. The subjects rated their sensations of ear pressure, head compression and the occurrence of headache every minute on a visual analogue scale (VAS, range 0–10). Pulse rate was recorded as a parameter for autonomic functions. Results: Nearly all subjects experienced ear pressure and half of them compression of their head at variable degrees. These sensations started in most subjects during the phase of lowering barometric pressure and increased to an average rating of about 3 VAS when returning to ambient atmospheric pressure. Heart rate slightly decreased during this phase. Three subjects reported mild to moderate headache for various durations within these phases. Conclusions: Changes in barometric pressure can be associated with sensations of ear pressure and head compression and may trigger headaches. The generation of these sensations is discussed with regard to convergent trigeminal innervation of the ear, the paranasal sinuses and the cranial meninges.

Background: Pain in glossodynia may be severe; it may prevent patients from working, interfere with daily life activities, and necessitate a patient's visit to a medical institution for consultation and treatment. The pain may be described as persistent and burning (tingling, tingling) or stinging. Patients may complain of dry mouth (dryness), which is thought to cause inflammation of the tongue and gingival mucous membranes and increased pain. Medications are prescribed based on the symptoms of glossodynia, and the therapeutic effect is confirmed. However, each drug has side effects, for example, pain may reduce, but drowsiness and dizziness may occur; further, there is always a tendency of drowsiness. On the other hand, Goreisan, a Chinese herbal medicine, has already been used by physicians to treat pain in the oral and maxillofacial regions resulting from rapid changes in air pressure. However, the lack of high-quality clinical research has been of concern, and a randomized clinical trial to investigate the efficacy and safety of Goreisan for treatment of pain in glossodynia is warranted. Methods/design: This multicenter, randomized, controlled study will involve patients treated for glossodynia-related pain. In the experimental group, Goreisan will be taken for 12 weeks in combination with conventional treatment. Participants in the control group will not take any Kampo medicine; only the standard treatment will be taken. Subsequently, the degree of pain will be assessed, and saliva tests of all the patients on their first visit will be performed. Goreisan will be taken at a dose of 7.5 g/d (minute 3) for 12 consecutive weeks. Twelve weeks later, the degree of pain of each patient will be assessed. Discussion The purpose of this study is to investigate the efficacy of Goreisan for pain reduction in patients undergoing treatment for glossodynia-related pain. If pain in glossodynia patients can be reduced by the administration of Goreisan, its candidacy as an alternative treatment for pain in glossodynia can be further supported by more reliable research.

Patients who complain of chronic pain have various symptoms and complicated pathologies, and there are often cases in which the symptoms worsen due to weather changes. However, few studies have examined the nature of pain affected by weather changes. In this time, we investigated the characteristics of patients with weather-related pain. As results, their pain intensity is moderate and they can maintain moderate daily activity. But in psychosocial factors, they have low self-efficacy and high catastrophic thinking. As treatment for chronic pain, exercise therapy managed by a therapist is highly recommended in non-drug therapy. Patients with weather-related pain often complain at head and neck shoulders. Evidences on the effects of exercise therapy for these body parts have also been reported. We hope that capturing the characteristics of patients with weather-related pain will lead to more appropriate treatments tailored to the pathological condition of the patients.

Weather changes accompanied by decreases in barometric pressure are suggested to trigger meteoropathy, i.e., weather-related pain. We previously reported that neuropathic pain-related behavior in rats is aggravated by lowering barometric pressure, and that this effect is abolished by inner ear lesions. These results suggest that mechanisms that increase vestibular neuronal activity may parallel those that contribute to meteoropathy generation. However, it remains unknown whether changes in barometric pressure activate vestibular neuronal activity. To address this issue, we used expression of c-Fos protein as a marker for neural activation. Male and female mice were placed in a climatic chamber, and the barometric pressure was lowered by 40 hPa, from 1013 hPa, for 50 min (LP stimulation). The total number of c-Fos-positive cells in the vestibular nuclei was counted bilaterally after LP stimulation. We also video-recorded mouse behaviors and calculated the total activity score during the LP stimulation. LP stimulation resulted in significant c-Fos expression in the superior vestibular nucleus (SuVe) of male and female mice. There was no effect of LP stimulation on the total activity score. These data show that distinct neurons in the SuVe respond to LP stimulation. Similar mechanisms may contribute to the generation of meteoropathy in humans.

Objective To retrospectively analyze the effects of our original combination therapy treatment on patients with nonodontogenic persistent dentoalveolar pain. Methods Twenty-one patients suffering from persistent dentoalveolar pain (nineteen females and two males; mean age ± standard deviation: 55.7 ± 19.6 years) participated in this study. They were treated with a therapy combination of jaw exercise and psychoeducation to reduce oral parafunctional activities every month. The intensity of pain in these subjects was evaluated using a numerical rating scale (NRS) before and after treatment. Results The NRSs at the baseline ranged from 5 to 10 (median, 8), from 0 to 10 (median, 2) at one month after treatment, from 0 to 10 (median, 1) at three months after treatment, and from 0 to 10 (median, 0) at the end of treatment. Pain intensity after treatment improved significantly. Conclusion There was a significant reduction in pain after our combination of therapies as nonpharmacological treatments, and therefore this treatment could be useful in the management of NPDP patients.

The aim of this study was to clarify the mechanism of disuse-induced muscle hyperalgesia through the evaluation of the pharmacological behaviour of muscle hyperalgesia profiles in chronic post-cast pain (CPCP) rats with acute and chronic-phase mirror-image muscle hyperalgesia treated with diclofenac (NSAID), pregabalin (an inhibitor of Ca2+ channel α2δ), and duloxetine (SNRI). After 2 weeks of cast immobilization, the peak cross-sectional area and muscle wet weight of the ipsilateral soleus and gastrocnemius muscles decreased more significantly in CPCP rats than in untreated rats. Histological findings revealed disuse-induced muscle atrophy in CPCP rats. The blood biochemical parameters of CPCP rats in acute and chronic phases did not differ significantly from those of untreated rats. The diclofenac and pregabalin-treated groups exhibited no improvement in acute or chronic muscle hyperalgesia. In contrast, the duloxetine-treated group exhibited an improvement in acute muscle hyperalgesia, but showed no apparent effect on chronic muscle hyperalgesia on ipsilateral or contralateral sides. However, the chronic muscle hyperalgesia was reversed by intrathecal administration of DAMGO (a μ-opioid receptor agonist). The results suggest that chronic muscle hyperalgesia in CPCP rats did not result from an inflammatory mechanism, and there is only a low probability that it's caused by a neuropathic mechanism.

Psychological stresses such as social loss and separation during childhood induce hardship, referred to as emotional pain. These experiences are well-documented risk factors for the development of physical pain in adulthood. However, the underlying neuronal mechanisms of this exacerbation of pain are largely unknown, and consequently there is no effective pharmacotherapy. In this study, we sought to determine whether infant maternal separation (MS) contributes to aggravation of neuropathic pain in adult mice. MS increased anxiety- and depression-like behavioral responses to adult stress. In MS animals, chronic constriction injury (CCI) heightened the sensory dimension of chronic pain relative to that of control mice. However, MS mice treated with fluoxetine for 4 weeks after MS did not exhibit augmentation of allodynia, and their emotional response was attenuated. Microglia were more abundant in the spinal cord in MS/CCI mice than in control/CCI mice. These results suggest that emotional impairment is related to augmentation of neuropathic pain, and that dysfunction of microglial activation contributes to heightened pain sensitivity.

慢性痛が天気の崩れで悪化することは以前より知られており, 疼痛治療の臨床において重要な問題である. 筆者は, 気象要素 (気圧, 気温) による慢性痛悪化のメカニズム研究により, 日常体験する程度の軽微な気圧変化あるいは低温への曝露が慢性痛モデル動物の痛み行動を増強し, 慢性痛有訴者の症状を再現することを実証してきた. また, 気圧変化による痛みの増強には内耳の気圧感受メカニズムが関与することを明らかにし, 温度変化による痛みの増強には皮膚の温度受容線維の反応性の変化が原因である可能性を示した. また, 慢性痛有訴者の一部では気圧や気温の変化に対して自律神経系が過剰に反応することがあり, それが症状悪化のもう1つの原因であることを示唆した.

Patients suffering from neuropsychiatric disorders such as substance-related and addictive disorders exhibit altered decision-making patterns, which may be associated with their behavioral abnormalities. However, the neuronal mechanisms underlying such impairments are largely unknown. Using a gambling test, we demonstrated that methamphetamine (METH)-treated rats chose a high-risk/high-reward option more frequently and assigned higher value to high returns than control rats, suggestive of changes in decision-making choice strategy. Immunohistochemical analysis following the gambling test revealed aberrant activation of the insular cortex (INS) and nucleus accumbens in METH-treated animals. Pharmacological studies, together with in vivo microdialysis, showed that the insular neural system played a crucial role in decision-making. Moreover, manipulation of INS activation using designer receptor exclusively activated by designer drug technology resulted in alterations to decision-making. Our findings suggest that the INS is a critical region involved in decision-making and that insular neural dysfunction results in risk-taking behaviors associated with altered decision-making.