Article

Effect of Systemic Monosodium Glutamate (MSG) on Headache and Pericranial Muscle Sensitivity

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Abstract

We conducted a double-blinded, placebo-controlled, crossover study to investigate the occurrence of adverse effects such as headache as well as pain and mechanical sensitivity in pericranial muscles after oral administration of monosodium glutamate (MSG). In three sessions, 14 healthy men drank sugar-free soda that contained either MSG (75 or 150 mg/kg) or NaCl (24 mg/kg, placebo). Plasma glutamate level, pain, pressure pain thresholds and tolerance levels, blood pressure (BP), heart rate and reported adverse effects were assessed for 2 h. No muscle pain or robust changes in mechanical sensitivity were detected, but there was a significant increase in reports of headache and subjectively reported pericranial muscle tenderness after MSG. Systolic BP was elevated in the high MSG session compared with low MSG and placebo. These findings add new information to the concept of MSG headache and craniofacial pain sensitivity.

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... When compared to the low MSG and placebo sessions, the high MSG session had higher systolic blood pressure. (36) MSG is thought to be connected with headaches and craniofacial problems such as temporomandibular disorders. This study examined about how the administration of MSG affects muscular pain sensitivity prior to and after experimentally induced muscle pain in 16 healthy persons. ...
... Neonate male Wistar rats (4 g/kg body weight) 55 3. The neurotoxic effects seen with sub-chronic intake of high quantities of MSG may have a biochemical explanation including increased oxidative and cholinergic activities and lower dopamine levels nymphs of lobster cockroaches (0.1 mg/g, 1 mg/g, 10 mg/g, and 100 mg/g) 67 4. the erythrocyte glucose level was significantly increased with more lipid peroxidation. 36 2. MSG consumption has no effect on pain intensity or pressure pain sensitivity in the masseter and temporalis muscles that were injected with glutamate 16 healthy adult subjects, randomized, doubleblinded, placebocontrolled study, MSG (150 mg/kg) 35 3. Excessive repeated MSG consumption has no effect on interstitial glutamate levels in the masseter muscle in healthy men 32 ...
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Monosodium glutamate (MSG), a commonly used flavour enhancer, in almost all savory foods. However, there are still unanswered health-related problems surrounding MSG use in humans. Research suggests that MSG is the root cause of a number of diseases, including obesity, the Chinese syndrome disorder, redox imbalance, and adverse effects on reproduction. Similarly, additional clinical research contradicts MSG's unfavorable health effects and demonstrates its positive effects on issues like appetite, salt intake, and bone development, etc. This article reviews the research on the beneficial and harmful effects of MSG on homo sapiens. MSG was regarded as safe by the WHO, US FDA, United Nations Food and Agriculture Organization, and many other regulatory bodies, although it shouldn't be consumed in amounts that exceed. INTRODUCTION The consequences of using the flavor enhancer monosodium glutamate (MSG) on human health are essential to be discussed. (1)Worldwide, the food industry frequently uses monosodium glutamate (MSG) to enhance the flavor of food. (2)Although food safety regulators usually consider this as safe but some studies have expressed concern about its long-term safety. MSG treatment has been linked in preclinical investigations to premalignant changes, cardiotoxicity, hepatotoxicity, and neurotoxicity. MSG use has been linked to genotoxic effects in lymphocytes, increased oxidative stress and apoptosis in thymocytes, and cancer. (3)Commercial foods are now the lifeline of the urban population by saving time and resources, but their nutritious content is sacrificed. One of the most often used food additives is monosodium glutamate. According to several research, MSG is hazardous to developing fetuses, children, adolescents, and adults. Hypertension, obesity, digestive tract issues, and impairment of brain, neurological system, reproductive, and endocrine system function are physiological complications occurred by MSG toxicity. MSG's impact is influenced by its dosage and manner of delivery. (11) MSG imparts to processed meals a distinct aroma known as umami in Japanese and is also termed China salt in many nations and it is one of the variants of glutamic acid, has been used to season food for more than a century and also referred to as "Chinese Restaurant Syndrome. Humans can normally metabolize significant amounts of glutamate, which is synthesized in the gut through the process of protein degradation by exopeptidase enzymes. For mice and rats, the median fatal dose (LD50) ranges from 15 to 18 g/kg body weight. It is categorized by the European Union as a food additive that is allowed in specific foods but has a quantitative limit. (13) In Europe, the daily
... When compared to the low MSG and placebo sessions, the high MSG session had higher systolic blood pressure. (36) MSG is thought to be connected with headaches and craniofacial problems such as temporomandibular disorders. This study examined about how the administration of MSG affects muscular pain sensitivity prior to and after experimentally induced muscle pain in 16 healthy persons. ...
... Neonate male Wistar rats (4 g/kg body weight) 55 3. The neurotoxic effects seen with sub-chronic intake of high quantities of MSG may have a biochemical explanation including increased oxidative and cholinergic activities and lower dopamine levels nymphs of lobster cockroaches (0.1 mg/g, 1 mg/g, 10 mg/g, and 100 mg/g) 67 4. the erythrocyte glucose level was significantly increased with more lipid peroxidation. 36 2. MSG consumption has no effect on pain intensity or pressure pain sensitivity in the masseter and temporalis muscles that were injected with glutamate 16 healthy adult subjects, randomized, doubleblinded, placebocontrolled study, MSG (150 mg/kg) 35 3. Excessive repeated MSG consumption has no effect on interstitial glutamate levels in the masseter muscle in healthy men 32 ...
... The results of this double-blinded, placebocontrolled crossover study, also showed an elevation of systolic blood pressure for the higher dose. No muscle pain or robust changes in mechanical sensitivity were reported (Baad-Hansen, Cairns, Ernberg, & Svensson, 2009). Other studies using MSG quantities ranging between 2.5 and 5 g also reported an increase in the incidence of headache (four out of five clinical studies; Geha et al., 2000b;Shimada et al., 2016;Tarasoff & Kelly, 1993;Yang et al., 1997). ...
... These studies are summarized in Table 11. Nevertheless, given the small sample size, it is difficult to extrapolate these results to the general population (Baad-Hansen et al., 2009;Shimada et al., 2016) and to determine a dose that exceeded the taste threshold, thus affecting the "blind" study design (Geha et al., 2000b). Taken together, there seems to be some evidence in support of the hypothesis that MSG might trigger headaches, but again, so may other food-derived molecules (Finocchi & Sivori, 2012;Taheri, 2017). ...
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Monosodium glutamate (MSG) is an umami substance widely used as flavor enhancer. Although it is generally recognized as being safe by food safety regulatory agencies, several studies have questioned its long‐term safety. The purpose of this review was to survey the available literature on preclinical studies and clinical trials regarding the alleged adverse effects of MSG. Here, we aim to provide a comprehensive overview of the reported possible risks that may potentially arise following chronic exposure. Preclinical studies have associated MSG administration with cardiotoxicity, hepatotoxicity, neurotoxicity, low‐grade inflammation, metabolic disarray, and premalignant alterations, along with behavioral changes. However, in reviewing the available literature, we detected several methodological flaws, which led us to conclude that these studies have limited relevance for extrapolation to dietary human intake of MSG risk exposure. Clinical trials have focused mainly on MSG effects on food intake and energy expenditure. Besides its well‐known impact on food palatability, MSG enhances salivary secretion and interferes with carbohydrate metabolism, while the impact on satiety and post‐meal recovery of hunger varied in relation to meal composition. Reports on MSG hypersensitivity or links of its use to increased pain sensitivity and atopic dermatitis were found to have little supporting evidence. Many of the reported negative health effects of MSG have little relevance for chronic human exposure and are poorly informative as they are based on excessive dosing that does not meet with levels normally consumed in food products. We conclude that further clinical and epidemiological studies are needed, with an appropriate design, accounting for both added and naturally occurring dietary MSG.
... Glutamate levels are significantly elevated in the plasma and cerebrospinal fluid of patients with migraine during attacks (Ferrari et al., 1990;Martinez et al., 1993). Monosodium glutamate consumption can trigger headache attacks (Baad-Hansen et al., 2010). Glutamate has been discussed as a critical neurotransmitter in the central sensitisation mechanism of migraine (Hoffmann and Charles, 2018). ...
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Background While memantine has been considered a promising drug for migraine prevention, no conclusive evidence exists comparing its efficacy with other migraine-preventive medications. This network meta-analysis (NMA) aimed to access the effectiveness and acceptability of memantine and other guideline-recommended prophylactic agents for migraine. Methods We searched the Cochrane Register of Controlled Trials, Embase, PubMed, and ClinicalTrials databases from their inception to 1 June 2024. Randomized placebo-controlled trials (RCTs) examining the pharmacological prevention of adult migraine patients were included. The primary efficacy outcome was the change in migraine days, and the primary safety outcome was withdrawal due to adverse events. Secondary outcomes included 50% response rates and frequency of any adverse events. The analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Results Thirty-eight RCTs, including a total of 13,223 participants, were analyzed. Our analysis showed that memantine demonstrated the second-largest reduction in migraine days [standardized mean difference (SMD): −0.83; 95% confidence interval (CI): −1.26, −0.41 compared with placebo] and the highest 50% response rates [odds ratio (OR): 5.58, 95% CI: 1.31 to 23.69] in all studied interventions. Moreover, among all interventions, memantine appeared to show the lowest dropout rate and moderate frequency of adverse events. However, its confidence intervals contained null values. Conclusion This study provides prioritisation evidence for memantine in migraine prevention, as memantine can significantly decrease the frequency of migraine attacks, improves response rates, and fair acceptability. These beneficial effects were not inferior to currently recommended pharmacological regimens. However, due to the lack of long-term efficacy and safety data, as well as few direct comparisons with active control agents, the estimates of memantine may be overly optimistic. Clinicians should interpret the findings of current NMA cautiously and apply them in a relatively conservative manner.
... Behavioral aspects revealed in the survey unveil a noteworthy connection between MSG and addictive behaviors, with over half of the participants (52.61%) admitting to an addiction to fast food and energy drinks. This linkage necessitates a deeper exploration of the relationship between MSG and dietary choices, emphasizing the importance of considering broader lifestyle patterns in public health discussions [30]. The overwhelming support for excluding MSG from foods (85.47%) serves as a resounding call for regulatory measures or alternative options, indicating that the surveyed population perceives MSG as a significant health concern. ...
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Introduction Monosodium glutamate (MSG), a common global food additive in processed foods, influences flavors and textures due to its chemical complexity and nutritional intricacy. Despite an annual production of 1.9 million tons and historical safety concerns, the multifaceted impact on health, ranging from metabolic disorders to neurological and cardiovascular implications, necessitates ongoing research for informed consumption and balanced dietary practices. Materials and methods This cross-sectional study investigates MSG-associated intricacies among Saudi Arabia's urban population. The research included questionnaire development, translation, and cultural adaptation, and was validated by nutrition experts. A sample size of 420 was calculated for a 95% confidence level. Data collection occurred from September 13 to October 31, 2023, and ethical considerations were ensured. Statistical analysis, including chi-square tests, regression analysis, and SPSS, explored intricacy relationships. Results The MSG intricacy study in Saudi Arabia's urban population, involving 420 respondents, showed statistically significant correlations (P < 0.05) in demographics. The key findings indicate an awareness of the impact of MSG on health, its associations with various conditions, and strong support for its exclusion from foods. Region, gender, age, and social status correlations highlighted diverse perspectives. The Western province showed the highest response rate at 42.61%, prompting regional awareness questions. Gender dynamics showed that 90.47% of the respondents were females, emphasizing potential gender-specific concerns. Concentration among ages 20-30 (61.9%) underscored generational factors. While commendable baseline awareness was noted, 73.09% of the participants believing MSG is harmful prompts further investigation. Emotional responses, including happiness (25.95%) and frustration (18.33%), highlight the complexity of the individuals' experiences, emphasizing the need for tailored communication strategies. Conclusion The MSG intricacy study in Saudi Arabia's urban population reveals insights into knowledge, attitudes, and behaviors, emphasizing the need for nuanced interventions considering regional and emotional differences. The findings underscore health concerns, supporting regulations, and knowledge impact on behavior. This survey serves as a valuable tool for informed public discourse and decision-making in the unique socio-cultural context of urban Saudi Arabia.
... After 30 minutes of MSG administration, glutamate levels in blood plasma increased 395% at a dose of 75 mg/kg bodyweight and increased to 556% at a dose of 150 mg/kg bodyweight (36). The presence of a clearance mechanism for increased glutamate levels in blood plasma (extracellular levels) does not cause an excitotoxicity reaction, in which extracellular glutamate levels are maintained at 5-10 µM levels (37). However, if high levels of glutamate occur continuously, there may be a failure of the clearance mechanism triggered by endogenous excitotoxic conditions. ...
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Introduction: The toxicity of high concentration monosodium glutamate (MSG) has become a controversial issue because of its inconsistent results in human and animal studies. This present study aims to evaluate the effect of subchronic high-doses oral administration of MSG on spatial memory performance and hippocampal pyramidal cells number. Methods: This study involved twenty-eight male Wistar rats, which were divided into a control group of NaCl 0.9% and three intervention groups of MSG 1.0 mg/g bodyweight (M1), 2.0 mg/g bodyweight (M2), and 4.0 mg/g bodyweight (M3) for 30 days. Statistical analysis used a One-way ANOVA test. Results: The result showed significant differences in spatial memory on the Morris Water Maze (MWM) test, including path length (p = 0.020) and escape latency (p = 0.011) according to general linear model repeated measurement analysis. The mean difference of estimated hippocampal pyramidal cells total number among the groups showed volume (p = 0.001), numerical density (p = 0.590), and cells number (p = 0.004). Furthermore, Post-Hoc analysis in both spatial memory and hippocampal pyramidal cells showed that the increasing MSG dose from 1.0 to 4.0 mg/g bodyweight led to a decrease in the results of spatial memory performance on the MWM test and a decrease in hippocampal cells. Conclusion: The present study has provided novel quantitative data that subchronic administration of high-dose MSG caused deleterious effects on the spatial memory function and the volume and number of hippocampal pyramidal cells.
... However, considering the probability of diminished BBB integrity in migraine patients [224][225][226][227][228], it is likely that the amount of dietary glutamate entering the brain is higher than in healthy individuals. This idea is supported by multiple studies that have shown that MSG administration can induce headaches [229][230][231]. Moreover, some dietary components could have a triggering effect on a migraine attack as reported by patients in epidemiological studies [232,233]. ...
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Glutamate, the main excitatory neurotransmitter in the central nervous system, is implicated in both the initiation of migraine as well as central sensitization, which increases the frequency of migraine attacks. Excessive levels of glutamate can lead to excitotoxicity in the nervous system which can disrupt normal neurotransmission and contribute to neuronal injury or death. Glutamate-mediated excitotoxicity also leads to neuroinflammation, oxidative stress, blood-brain barrier permeability, and cerebral vasodilation, all of which are associated with migraine pathophysiology. Experimental evidence has shown the protective effects of several nutrients against excitotoxicity. The current review focuses on the mechanisms behind glutamate’s involvement in migraines as well as a discussion on how specific nutrients are able to work towards restoring glutamate homeostasis. Understanding glutamate’s role in migraine is of vital importance for understanding why migraine is commonly comorbid with widespread pain conditions and for informing future research directions.
... After 30 minutes of MSG administration, glutamate levels in blood plasma increased 395% at a dose of 75 mg/kg bodyweight and increased to 556% at a dose of 150 mg/kg bodyweight (36). The presence of a clearance mechanism for increased glutamate levels in blood plasma (extracellular levels) does not cause an excitotoxicity reaction, in which extracellular glutamate levels are maintained at 5-10 µM levels (37). However, if high levels of glutamate occur continuously, there may be a failure of the clearance mechanism triggered by endogenous excitotoxic conditions. ...
Article
Full-text available
Introduction: The toxicity of high concentration monosodium glutamate (MSG) has become a controversial issue because of its inconsistent results in human and animal studies. This present study aims to evaluate the effect of sub-chronic high-doses oral administration of MSG on spatial memory performance and hippocampal pyramidal cells number. Methods: This study involved twenty-eight male Wistar rats, which were divided into a control group of NaCl 0.9% and three intervention groups of MSG 1.0 mg/g bodyweight (M1), 2.0 mg/g bodyweight (M2), and 4.0 mg/g bodyweight (M3) for 30 days. Statistical analysis used a One-way ANOVA test. Results: The result showed significant differences in spatial memory on the Morris Water Maze (MWM) test, including path length (p = 0.020) and escape latency (p = 0.011) according to general linear model repeated measurement analysis. The mean difference of estimated hippocampal pyramidal cells total number among the groups showed volume (p = 0.001), numerical density (p = 0.590), and cells number (p = 0.004). Furthermore, Post-Hoc analysis in both spatial memory and hippo-campal pyramidal cells showed that the increasing MSG dose from 1.0 to 4.0 mg/g bodyweight led to a decrease in the results of spatial memory performance on the MWM test and a decrease in hippocampal cells. Conclusion: The present study has provided novel quantitative data that subchronic administration of high-dose MSG caused delete-rious effects on the spatial memory function and the volume and number of hippocampal pyramidal cells.
... In addition, it was found that MSG can limit the adipogenicity potential of 3T3-L1 preadipocytes, and this may be related to the clonal expansion of mitosis [74] . In 1981, Allen & Baker reported for the first time that asthma occurred 12 h after eating in a Chinese restaurant [75] Subsequently, they reported that 14 of 32 patients had asthma attacks after ingesting MSG in 1987 [76] . A double-blind, placebo-controlled, crossover study revealed that after 14 healthy men drank sugar-free soda containing MSG for 2 h, human subjects had a significant increase in headache and pericrania muscle tenderness [77] . ...
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Monosodium glutamate is a non-essential amino acid in the human body that has been widely used as a food additive since 1909 due to its unique umami taste. Typical food containing monosodium glutamate include tomatoes, yeast extracts, fermented soy products, and cheese. After entering the human body, it is mainly absorbed in the small intestine by passive diffusion. Subsequent binding to TAS1R1-TAS1R3 promotes the release of intracellular calcium that ultimately activates the brain’s taste center, recognized as an umami taste of monosodium glutamate. However, more and more preclinical and clinical data indicates that monosodium glutamate exerts adverse effects on humans, including metabolic syndrome, neurotoxicity, renal toxicity, cardiovascular disease, infertility and fetal underdevelopment, cancer, immune malfunction and so on. In addition, it has been found that medicinal plants and nutraceuticals could mitigate or treat the adverse effects of monosodium glutamate adverse. Taken together, we hope to raise the correct awareness of monosodium glutamate and improve the understanding of monosodium glutamate quality approaches to maximize their use.
... An increase of the glutamate concentration in serum and cerebrospinal fluid has been observed in fibromyalgia patients (7)(8)(9). For that reason, the influence of glutamate acquired by the diet has been extensively studied, and monosodium glutamate (MSG)-related symptoms have been found to be dose related, as well as reports of a good correlation between plasma glutamate concentration and muscle pain and headache (10,11). However, oral administration of MSG results in highly variable serum glutamate concentrations (12), and decreased consumption does not consistently reduce associated pain (13). ...
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Several studies have described the contribution of glutamate-transforming microbiota to the development of chronic ailments. For instance, the blood concentration of glutamate is higher in some patients with fibromyalgia, chronic fatigue, and pain. Taking advantage of a naturally occurring strain of Bifidobacterium that is able to transform glutamate in γ-aminobutyric caid (GABA), B. adolescentis IPLA60004, we designed a placebo-controlled intervention to test if the presence of this GABA-producing bifidobacteria in mice was able to impact the concentration of glutamate in the blood in comparison with the administration of other strain of the same species lacking the genes of the glutamate decarboxylase (gad) cluster. Animals were fed every day with 8 log CFU of bacteria in a sterilized milk vehicle for 14 days. Samples from feces and blood were collected during this period, and afterwards animals were sacrificed, tissues were taken from different organs, and the levels of different metabolites were analyzed by ultrahigh-performance liquid chromatography coupled to mass spectrometry. The results showed that both bacterial strains orally administered survived in the fecal content, and animals fed B. adolescentis IPLA60004 showed a significant reduction of their glutamate serum concentration, while a nonsignificant decrease was observed for animals fed a reference strain, B. adolescentis LGM10502. The variations observed in GABA were influenced by the gender of the animals, and no significant changes were observed in different tissues of the brain. These results suggest that orally administered GABA-producing probiotics could reduce the glutamate concentration in blood, opening a case for a clinical trial study in chronic disease patients. IMPORTANCE This work presents the results of a trial using mice as a model that were fed with a bacterial strain of the species B. adolescentis, which possesses different active genes capable of degrading glutamate and converting it into GABA. Indeed, the bacterium is able to survive the passage through the gastric tract and, more importantly, the animals reduce over time the concentration of glutamate in their blood. The importance of this result lies in the fact that several chronic ailments, such as fibromyalgia, are characterized by an increase in glutamate. Our results indicate that an oral diet with this probiotic-type bacteria could reduce the concentration of glutamate and, therefore, reduce the symptoms associated with the excess of this neurotransmitter.
... Changes in the Glu concentration cause Huntington's disease [2,3]. Moreover, Glu is a crucial indicator for various other illnesses [4], such as musculoskeletal pain [5], tumors [6], and Alzheimer's disease [7]. Currently, Glu has been detected using multiple neurochemical probes, including carbon fiber microsensors based on enzymes or microdialysis [8]. ...
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Herein, dendrimer-modified montmorillonite (Mt)-decorated poly-Ɛ-caprolactone (PCL) and chitosan (CHIT)-based nanofibers were prepared. Mt was modified with a poly(amidoamine) generation 1 (PAMAMG1) dendrimer, and the obtained PAMAMG1–Mt was incorporated into the PCL–CHIT nanofiber’s structure. The PCL–CHIT/PAMAMG1–Mt nanofibers were conjugated with glutamate oxidase (GluOx) to design a bio-based detection system for monosodium glutamate (MSG). PAMAMG1–Mt was added to the PCL–CHIT backbone to provide a multipoint binding side to immobilize GluOx via covalent bonds. After the characterization of PCL–CHIT/PAMAMG1–Mt/GluOx, it was calibrated for MSG. The linear ranges were determined from 0.025 to 0.25 mM MSG using PCL–CHIT/Mt/GluOx and from 0.0025 to 0.175 mM MSG using PCL–CHIT/PAMAMG1–Mt/GluOx (with a detection limit of 7.019 µM for PCL–CHIT/Mt/GluOx and 1.045 µM for PCL–CHIT/PAMAMG1–Mt/GluOx). Finally, PCL–CHIT/PAMAMG1–Mt/GluOx was applied to analyze MSG content in tomato soup without interfering with the sample matrix, giving a recovery percentage of 103.125%. Hence, the nanofiber modification with dendrimer-intercalated Mt and GluOx conjugation onto the formed nanocomposite structures was performed, and the PCL–CHIT/PAMAMG1–Mt/GluOx system was successfully developed for MSG detection.
... Interestingly, migraine preventive therapies were found to reduce plasma glutamate levels [32]. The involvement of glutamate signaling in headache and migraine was further reinforced by the finding that (1) the consumption of a single dose (150 mg/kg) of monosodium glutamate (MSG) caused headache, craniofacial sensitivity, and nausea in healthy participants [33], and (2) repeated MSG intake (150 mg/kg) for five daily sessions for one-week reduced pressure pain thresholds and caused headache in healthy participants compared to placebo [34]. ...
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Backgrounds: Several acute and preventive medications were developed for the treatment of migraine. Yet, a significant proportion of patients reports an inadequate response and a lack of tolerability, emphasizing the need for new options. Glutamate is the most important excitatory neurotransmitter in the brain, and glutamate receptors including N-Methyl-D-Aspartate Receptor (NMDAR) are expressed at several levels of the trigeminovascular system, which is the anatomical and physiological substrate of migraine pain. Objective: To review preclinical and clinical studies investigating the role of the NMDAR in migraine pathophysiology. Methods: No protocol was registered for this study. References for the present review were identified from a narrative search of the PubMed database. Search terms such as glutamate, migraine, N-Methyl-D-Aspartate Receptor, and NMDAR were used. No restrictions were made in terms of the language and date of publication. Results: In animal models, administration of monosodium glutamate (MSG) activated and sensitized trigeminovascular neurons. In healthy human participants, consumption of MSG caused headaches, craniofacial sensitivity, and nausea. In in vivo models and through immunolabeling, NMDAR subunits NR1, NR2A, and NR2B were expressed in trigeminal ganglion neurons. In humans, NMDAR antagonists such as ketamine and memantine caused a significant reduction in pain intensity and monthly headache frequency. Conclusions: Accumulative evidence indicates that NMDAR is a promising new target for the treatment of migraine. Selective NMDAR antagonists without central effects are needed to investigate their therapeutic benefit in the treatment of migraine.
... Penelitian pada tahun 2003, menyatakan bahwa MSG yang diberikan pada hewan uji coba (tikus) dapat mengganggu metabolisme lipida dan aktivitas enzim anti-oksidan di jaringan pembuluh darah, serta dapat meningkatkan resiko hipertensi dan penyakit kardiovaskular (Singh & Ahluwalia, 2003). Penelitian lainnya pada responden yang memperoleh pemberian tinggi MSG menunjukkan adanya peningkatan tekanan darah sistolik (Baad-Hansen et al., 2010). Penelitian lain juga menyimpulkan bahwa asupan MSG berasosiasi dengan peningkatan tekanan darah sistolik dan diastolik secara signifikan (Shi et al., 2011). ...
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Hipertensi masih menjadi masalah utama di dunia hingga saat ini. Banyak penelitian yang telah membuktikan bahwa hipertensi berhubungan dengan tingkat kesakitan dan kematian akibat penyakit kardiovaskular. Oleh sebab itu, penyakit hipertensi harus dicegah dan diobati, baik dengan obat-obatan maupun dengan modifikasi diet. Berdasarkan beberapa hasil penelitian, diketahui perlu adanya bahan makanan tertentu yang memiliki kemampuan antihipertensi dan dapat dimanfaatkan sebagai penyedap masakan yang aman bagi penderita hipertensi, salah satu yang dikaji yaitu bekasam. Bekasam merupakan produk hasil fermentasi spontan menggunakan kadar garam tinggi dengan bahan dasar ikan air tawar. Rasa dan aroma bekasam memiliki sangat khas dan dapat digunakan sebagai penyedap masakan. Bekasam diproduksi dengan mencampur ikan dengan nasi dan yang kemudian difermentasi selama 5-7 hari. Karakteristik daging bekasam sedikit kenyal dibandingkan dengan ikan segar, memiliki rasa asam asin khas bekasam dengan aroma tertentu. Berbagai penelitian menunjukkan bahwa bekasam ikan memiliki beberapa manfaat bagi kesehatan, antara lain aktivitas penghambatan Angiotensin-I-Converting Enzyme (ACE), yaitu enzim yang menyebabkan hipertensi dan juga sebagai penurun kolesterol karena mengandung lovastatin.
... Many reports have demonstrated the adverse effects of low dose MSG resulting from chronic consumption [1,2,71,72]. MSG doses between 1.25 and 12 gr were used in human experimental studies [73,74], dosages ranging from 0.04 to 100 g in animal studies [2,12,75,76], and dosages between 0.75 and 3 mg/g egg in chicken embryo studies [41,70]. In this study, both human daily MSG intake and previous chicken embryo studies were taken into account in the adjustment of MSG doses (0.12 mg/g, 0.6 mg/g, and 1.2 mg/g eggs). ...
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MSG is the most ubiquitous food additive in the food industry. The aim of this report was to investigate the effects of in ovo MSG administration on embryonic chicken eye development using histological and histometric methods. A total of 410 fertilized eggs obtained from Babcock Brown laying hens (Gallus gallus domesticus) were used and divided into 5 groups: I (untreated control), II (vehicle control), III (0.12 mg/g egg MSG), IV (0.6 mg/g egg MSG), and V (1.2 mg/g egg MSG), and injections were performed via the egg yolk. At incubation day 15, 18, and 21, 6 embryos from each group were sacrificed by decapitation and pieces of eye tissue were obtained. In all MSG groups, it was determined that both corneal epithelium thickness and total corneal thickness decreased at incubation time points 15, 18, and 21 days compared with the controls (p < 0.05). The total retinal thickness, thickness of the outer nuclear layer (ONL), inner nuclear layer (INL), ganglion cell layer (GL), and nerve fibre layers (NFL), as well as the number of ganglion cells decreased significantly at incubation days 15, 18, and 21 (p <0.05), and degenerative changes such as vacuolar degeneration and retinal pigment epithelial detachment were also observed. In conclusion, MSG in ovo administration can affect the cornea and distinct layers of retinal cells.
... Monosodium glutamate (MSG) is the sodium salt of glutamic acid; an amino acid that is naturally found in the plants and animals [1]. MSG is one of the commonly used food additives, with a code number of E621, according to European regulations [2,3]. MSG is also a flavor enhancer to give the unique Umami taste [4] in fast food products, such as instant noodles, soups, sauces, pizza, crisps and potato snacks [5,6]. ...
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A simple, fast, and ecofriendly spectrofluorometric method was developed and validated for determination of mono sodium glutamate (MSG). The method depended on the reaction between MSG and iron (III) salicylate based on ligand exchange mechanism. Addition of MSG turned-on the fluorescent response of iron (III) salicylate at λem 411 nm. Reaction conditions including reagent concentration, pH, and time were optimized. The method was validated regarding the ICH guidelines. The method determined MSG within the linearity range of 25—250 µM with a coefficient of determination of 0.9967 and a calculated limit of detection of 1.73 µM. Furthermore, the developed method was successfully applied for the determination of MSG in food preparation (instant noodles). The results were compared to those obtained by a published HPLC method using t-test and F-test at 95% confidence interval; no statistically significant difference was found. Based on the analytical Eco-scale and the green analytical procedure index (GAPI), the developed method was assessed to be greener than the published HPLC method. The developed method offered advantages over other spectrophotometric reported methods and was convenient for routine determination of MSG in foodstuffs.
... Several researchers have realized that the presence of glutamate in the cerebral cortex is one of the key points for intracellular signal pathways, and the concentration change of glutamate is possibly related to HD [1,4,5]. In addition, glutamate is also an important biomarker for other diseases, such as musculoskeletal pain [6], tumor cells [7], and Alzheimer's disease [8]. Hence, the detection of glutamate can be applied in clinical diagnoses as well as symptom monitoring during the treatments of these diseases [9,10]. ...
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A non-enzymatic electrochemical sensor, based on the electrode of a chitosan-derived carbon foam, has been successfully developed for the detection of glutamate. Attributed to the chelation of Cu ions and glutamate molecules, the glutamate could be detected in an amperometric way by means of the redox reactions of chelation compounds, which outperform the traditional enzymatic sensors. Moreover, due to the large electroactive surface area and effective electron transportation of the porous carbon foam, a remarkable electrochemical sensitivity up to 1.9 × 104 μA/mM∙cm2 and a broad-spectrum detection range from nM to mM scale have been achieved, which is two-orders of magnitude higher and one magnitude broader than the best reported values thus far. Furthermore, our reported glutamate detection system also demonstrates a desirable anti-interference ability as well as a durable stability. The experimental revelations show that the Cu ions chelation-assisted electrochemical sensor with carbon foam electrode has significant potential for an easy fabricating, enzyme-free, broad-spectrum, sensitive, anti-interfering, and stable glutamate-sensing platform.
... Bar, 500 μm that MSG is a safe substance, several studies in humans and animals have revealed the negative effects after chronic consumption of even low dose of MSG (Hajihasani et al. 2020;Kazmi et al. 2017;Nguyen et al. 2020;Zanfirescu et al. 2019). While in human studies, the dose of MSG was between 1.25 and 12 g (Baad-Hansen et al. 2010;Obayashi and Nagamura 2016); in experimental animal studies, MSG was administered by oral at between 0.04 mg/kg and 100 g/ kg day doses (Abu Elnaga et al. 2019;Eweka et al. 2011;Umukoro et al. 2015;Zanfirescu et al. 2019) and by intraperitoneal at between 0.5 mg/kg and 8 g/kg day doses (Beas-Zárate et al. 2002;Onaolapo and Onaolapo 2011;Singh and Pushpa 2005). In addition, Al-Gamdi and Al-Hamdi (2020) injected MSG at a dose of 0.75 mg/g and Roongruangchai The doses of MSG used in this study (0.12, 0.6, and 1.2 mg/g egg) were determined by considering previous studies. ...
Article
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Monosodium glutamate (MSG) is a flavor enhancer commonly used in modern nutrition. In this study, it was aimed to determine the effect of in ovo administered MSG on the embryonic development of thymus, bursa of Fabricius, and percentages of alpha-naphthyl acetate esterase (ANAE) positive lymphocyte by using histological, histometrical, and enzyme histochemical methods in chickens. For this purpose, 410 fertile eggs were used. The eggs were then divided into five groups: group 1 (control group, n = 40 eggs), group 2 (distilled water-injected group, n = 62 eggs), group 3 (0.12 mg/g egg MSG-injected group, n = 80 eggs), group 4 (0.6 mg/g egg MSG-injected group, n = 90 eggs), and group 5 (1.2 mg/g egg MSG-injected group, n = 138 eggs), and injections were performed via the egg yolk. On the 18th and 21st days of the incubation, the eggs were randomly opened from each group until six live embryos were obtained. The embryos of each group were sacrificed by decapitation, and blood, thymus, and bursa of Fabricius tissue samples were taken from the obtained embryos. The MSG-treated groups were found to be retarded embryonic development of thymus and bursa of Fabricius tissue compared to the control and distilled water groups. MSG treatment also resulted in reduced lymphoid follicles count and follicle diameters in bursa of Fabricius (P < 0.05). The percentage of peripheral blood ANAE positive lymphocytes was significantly lower in the MSG-treated groups than in the control and distilled water groups (P < 0.05). In conclusion, it has been found that in ovo administered MSG can adversely affect the embryonic development of thymus and bursa of Fabricius and decrease percentage of ANAE positive lymphocyte.
... Monosodium glutamate administration caused headache in individuals was observed in a study. [33] In another study, GABA and glutamate concentrations in the occipital lobe and thalamus of a control group and patients with migraine attacks with aura were measured by proton magnetic resonance spectroscopy, and it was observed that the glutamate concentration in the occipital lobe and thalamus of migraine patients increased, but not in the control group. However, no relationship was found between glutamate concentration and pain intensity. ...
Article
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Migraine is a highly prevalent disease, with 4% of the population suffering from it. Although it was previously defined to be a vascular disease, current findings has shown that it is really such a complex neurological disorder. While the physiopathology of this condition, which is more common in women, is still unknown, the trigeminovascular system has supplied valuable data. Thus, migraine phases' clinical effects were correlated to their physiopathology, and the function of elements other than the trigeminovascular system (e.g., the hypothalamus) in migraine was revealed. Glutamate receptors, which are abundantly positioned in the nuclei of the trigeminovascular pathway in the medulla, contribute to the physiopathology of migraine. As a result, glutamate receptor modulators may be useful in the treatment of migraine.
... Increased salivary levels of glutamate have also been found in patients with episodic and chronic migraine [88,89]. Monosodium glutamate, the sodium salt of glutamic acid has been suggested to trigger headaches [90,91]. In terms of migraine and the group I metabotropic glutamate receptors -mGluR5 has undergone more investigation than mGluR1. ...
Article
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Introduction Migraine is a common and disabling neurological disorder. A greater understanding of the pathophysiological mechanisms underlying migraine has led to the availability of specific new drugs targeting calcitonin gene-related peptide (CGRP). The success of the CGRP inhibitors validates research efforts into migraine-specific therapies. Areas covered There are additional promising therapeutic targets that will be covered in this paper, focusing on the pain phase. They include pituitary adenylate cyclase-activating polypeptide (PACAP), the orexinergic system, the nitric oxide signaling pathway specifically neuronal nitric oxide synthase inhibitors (nNOSi), and metabotropic glutamate receptor 5 (mGluR5). Expert opinion Based on currently available research; the targets discussed in this paper are all on equal footing with each other in terms of their potential as effective novel migraine therapies. There is a need for more clinical trials to pinpoint which of these potential drug targets will be effective for migraine prevention.
... MSG has been a subject of heated controversy since 1969. It's consumption has been associated with weight gain and metabolic syndrome in some observational studies, although other research has found no association (Geha et al., 2000b;Mouritsen, 2012).Some people do have sensitivity to MSG and may experience symptoms like headaches, sweating and numbness after eating a large amount (Baad⇑Hansen, Cairns, Ernberg, & Svensson, 2009). ...
Chapter
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... Thus, further studies need to be done, especially given that other groups have reported preliminary relationships between MSG consumption and pain (27,28), in patients diagnosed with myofascial temporomandibular disorders or fibromyalgia. Additionally, other groups have found that in healthy individuals, MSG consumption was also associated with 6-fold greater incidence of pain symptoms when compared to ingestion of an equivalent amount of sodium chloride (27)(28)(29). ...
Article
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Introduction: Schizophrenia is a lifelong condition associated with several comorbid conditions such as physical illnesses like obesity, as well as co-occurring psychiatric symptoms such as depression. Research regarding susceptibility to some of these comorbidities has primary focused on genetic risks or neurotransmitters and very little work has been done to understand environmental factors such as diet. In particular, understanding the role of dietary glutamic acid consumption on co-morbidities in patients with schizophrenia is important, as evidence suggests that glutamic acid consumption may directly influence glutamatergic neurotransmission; a key neurotransmitter related to schizophrenia, its associated co-morbidities, and depression. Therefore, the aim of this study was to examine the potential relationship between dietary glutamic acid and depressive symptomatology in patients with schizophrenia, stratified by obesity status, due to its relationship with inflammation, antipsychotic use, and depressive symptoms. Methods: Subjects included in this analysis, were part of a parent cross-sectional study in which included three dietary recalls analyzed using protocols outlined as part of the National Health and Nutrition Examination Surveys (NHANES) standardized criteria. Additionally, body mass index (BMI), and Beck Depression Inventory were obtained at this visit. Subjects with a BMI ≥ 30 kg/m² were included in the obesity group, and the relationship between glutamic acid consumption and BDI scores was analyzed after controlling for age, race, sex, antidepressant and antipsychotic use, and animal and vegetable protein intake which provide natural forms of dietary glutamic acid. Results: A total of 168 participants were included in this study, of which 42.5% were female and 52.9% were White. The mean BMI for the group as a whole was 33.5 ± 8.7 (kg/m²) and the mean BDI was 14.5 ± 10.2 (range 2–50). No differences were found between obesity groups, other than a greater hyperlipidemia, hypertension, and lower waist to hip ratio. Overall, no relationship was found between dietary glutamic acid and BDI scores, However, for non-obese participants, diets higher levels of glutamic acid were associated with greater depression symptomatology (p = 0.021). Conclusion: These preliminary results indicate a possible correlation between dietary glutamic acid a depressive symptoms in non-obese patients with schizophrenia, although further research is needed to specifically examine this relationship.
... 33 Monosodium glutamate (MSG) has been shown to be a causal factor in pericranial muscle tenderness and headaches. 34 MSG is found in an increasing number of foods and glutamate may be found in many other ingredients in processed foods and thus listed as ingredients other than MSG. Common foods containing MSG include processed meats, fast foods and many commercially flavored and processed snack foods, soups, sauces and dressings. ...
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Objective: To describe the outcome of Chiropractic Biophysics (CBP) technique along with dietary changes performed on an 8-year old with chronic headaches as well as chronic sore throat, fatigue, dizziness, queasiness, and radiographic diagnosed cervical subluxation. Clinical Features: An 8-year old male presented with chronic headaches for two years. He also suffered from sore throat, fatigue, queasiness, aches, pains, and dizziness. He had been seen by a neurologist, psychologist and nutritionist with limited health improvements. Radiographs of the cervical spine revealed a cervical spine second harmonic S-shaped neck with upper spine kyphosis and lower spine hyperlordosis. Interventions and Outcomes: The boy was treated with CBP mirror-image isokinetic exercises, postural adjustments, and cervical spine extension traction. Spinal manipulation, cervical mobilization and hydrotherapy were provided. One month into care, a food diary analysis prompted dietary modifications along with nutritional supplementation. The child was originally seen on a three times per week schedule as per CBP protocol then progressed to a maintenance schedule of two times per month, a total of 86. A lateral cervical radiograph taken 6-months after initiating care revealed that his cervical lordosis was improved to near normal for his age. Conclusion: This case presents the successful outcome in an 8-year old with a variety of health issues as well as headaches. This case and others suggests CBP cervical extension traction as well as manipulation is a safe and effective intervention for the pediatric headache.
... Salt (NaCl) and sodium glutamate (NaC 5 H 8 NO 4 ) are widely used in food industry to enhance flavor and to provide umami sodium glutamate [443]. However, overdosing both can raise the systolic and the diastolic blood pressure [444][445][446][447][448]. In 1968, Kwok [449] firstly realized that sodium glutamate is the main cause of the 'Chinese restaurant' syndromepeople like eating food with heavily-dosed aginomoto. ...
Chapter
Phonon spectrometrics examination of the effect of pressure, temperature, molecular undercoordination, and charge injection by acid, base, and salt solvation establishes the regulations for the hydrogen bonding and electronic dynamics and the properties of the deionized water and aqueous solutions. Consistency between theory and measurements confirms the essentiality of the quasisolid phase of negative thermal expansion due to O:H–O segmental specific heat disparity, and the supersolid phase due to electrostatic polarization by ions injection or molecular undercoordination. Lewis acid and base solvation creates the H↔H anti–HB due to the excessive protons and the O:⇔:O super–HB because of the excessive lone pairs, respectively. The multifield mediation of the HB network results in anomalies of water ice and aqueous solutions such as ice friction, ice floating, regelation, superheating and supercooling, warm water speedy cooling, and critical conditions for phase transition. Extending the knowledge towards the deep engineering of liquid water would be promising.
... Salt (NaCl) and sodium glutamate (NaC 5 H 8 NO 4 ) are widely used in food industry to enhance flavor and to provide umami sodium glutamate [443]. However, overdosing both can raise the systolic and the diastolic blood pressure [444][445][446][447][448]. In 1968, Kwok [449] firstly realized that sodium glutamate is the main cause of the 'Chinese restaurant' syndromepeople like eating food with heavily-dosed aginomoto. ...
Article
Aqueous charge injection in forms of electrons, protons, lone pairs, ions, and molecular dipoles by solvation is ubiquitously important to our health and life. Pursuing fine-resolution detection and consistent insight into solvation dynamics and solute capabilities has become an increasingly active subject. This treatise shows that charge injection by solvation mediates the O:H–O bonding network and properties of a solution through O:H formation, H↔H fragilization,O:⇐⇒:Ocompression,electrostaticpolarization,H2Odipolar shielding, solute–solute interaction, and undercoordinated H–O bond contraction. A combination of the hydrogen bond (O:H–O or HB with ‘:’ being the electron lone pairs of oxygen) cooperativity notion and the differential phonon spectrometrics(DPS) has enabled quantitative information on the following: ....
... Salt (NaCl) and sodium glutamate (NaC 5 H 8 NO 4 ) are widely used in food industry to enhance flavor and to provide umami sodium glutamate [443]. However, overdosing both can raise the systolic and the diastolic blood pressure [444][445][446][447][448]. In 1968, Kwok [449] firstly realized that sodium glutamate is the main cause of the 'Chinese restaurant' syndromepeople like eating food with heavily-dosed aginomoto. ...
Chapter
An incorporation of the hydrogen bond cooperativity theory to the DPS strategy and surface stress (contact angle) detection could resolve the solvation bonding and nonbonding dynamics and solute capabilities. The enabled information includes bond length and stiffness transition, electron polarization, and the fraction of bonds transformed from the mode of ordinary water to the hydration shells. A combination of the DPS and the ultrafast IR spectroscopy would be more revealing towards solute-solvent and solute-solute molecular interactions, solute capabilities, and solution properties. The DPS is focused on the solvation O:H–O segmental cooperative bonding dynamics and the ultrafast IR on molecular motion dynamics by measuring phonon relaxation time.
... Salt (NaCl) and sodium glutamate (NaC 5 H 8 NO 4 ) are widely used in food industry to enhance flavor and to provide umami sodium glutamate [443]. However, overdosing both can raise the systolic and the diastolic blood pressure [444][445][446][447][448]. In 1968, Kwok [449] firstly realized that sodium glutamate is the main cause of the 'Chinese restaurant' syndromepeople like eating food with heavily-dosed aginomoto. ...
Preprint
Charge injection in terms of anions, cations, electrons, lone pairs, protons, and molecular dipoles by acid,base, salt and organic molecular solvation mediates the O:HO bonding network and properties of the solution through O:H formation, HH fragillization, O:=:O compression, electrostatic polarization, H2O dipolar shielding, and solute/solute interaction
... The excellent bleaching property of MSG attracts the attention towards its potential harmful effect on many tissues and organs of the body when ingested as a flavor enhancer in food [4]. Hence, studies on animals orally ingested MSG in doses similar to the average human intake revealed multiple complications targeting many organs including; neurotoxicity, nephrotoxicity, hepatic steatosis, inflammation, and dysplasia in addition to various disturbances and alterations in metabolism [5]. ...
Article
Monosodium glutamate (MSG) is commonly used as a flavor enhancer in nutritional industries. But unfortunately, it leads to various harmful conditions that affect multiple organs. This study was designed to investigate the impact of different doses of MSG on the DNA damage and gadd45b gene expression in liver of adult male Spargue dawley rats. Fourty rats, 6-8 weeks old, weighing 160-180 g were divided equally into four groups. Group I: animals served as normal control, Group II, III and IV: animals received different doses of MSG (8, 600, 1600 mg/kg b.wt./day, respectively; by gavage) for 14 days. The results of the present study revealed a gradual significant increase, in a dose-dependent manner for AST, ALT and ALP while a significant decrease in both albumin and total proteins. An exponential increase was observed among all the studied groups in both IL-8, and Bax accompanied with decrease in Bcl-2 compared to control group. The present findings revealed a significant concentration-dependent increase in the tail length, tail intensity, as well as, tail moments in the liver of rats ingested with different MSG doses. Moreover, the results showed that the expression of the DNA damage marker gadd45b was increased by 1.1, 1.3 and 2.5-fold in the livers of rats ingested with 8, 600 and 1600 mg/kg of MSG, respectively. In conclusion, the results of the present study revealed the potent genotoxic stress of MSG. Due to its harmful health implications, it was recommended to minimize the use of MSG even with its lowest dose, especially in patients with liver disorders.
... MSG, another flavor enhancer, is potentially toxic to certain hypersensitive individuals. Baad-Hansen et al. (2010) and Husarova and Ostatnikova (2013) also reported that the intake of excess MSG on certain days can be toxic to the nerve cells, hepatic tissue and reproductive organs of various animals. Therefore, flavor enhancers in daily life not only contribute to the special flavors of foods and to medical functions but can also cause toxicity at high concentrations (Maga and Tu 1994). ...
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The objective of this study was to evaluate the toxicity of flavor enhancers to the oriental fruit fly Bactrocera dorsalis (Hendel). The flavor enhancers glycine, disodium guanylate, succinic acid disodium salt, monosodium glutamate (MSG), disodium inosinate, and l-alanine significantly increased the mortality of B. dorsalis flies. The mortality of flies that fed on glycine, disodium guanylate, succinic acid disodium salt, and MSG was greater than 90%. Additionally, fruit fly mortality increased with increases in both time and concentration. Glycine not only reduced the climbing ability of B. dorsalis but also affected the duration and frequency of its behavioral patterns (flight, walking, grooming and inactivity). Compared with adult flies in the control group, adult B. dorsalis flies that fed on glycine exhibited a significantly increased duration and frequency of inactivity and a decreased duration and frequency of both flight and walking. However, the effect of glycine on grooming activity was not significant. These findings demonstrate the toxic effects of flavor enhancers on B. dorsalis. Glycine also affected the behavior of adult flies at a low dose. Therefore, glycine has potentially toxic to insects and also likely to have a negative impact at sublethal concentrations.
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Over the past century, human lifestyles and eating habits have changed dramatically as people in developed countries resort to fast food, they are indiscriminate and get used to frequent snacking. Production of dietary dishes and increase in the range of food products lead to the fact that the manufacturer has to use a large number of functional ingredients, such as those that improve the flavor. One widely used additive is monosodium glutamate. Monosodium L-glutamate (E621) is the sodium salt of glutamic acid present in all protein products which is used worldwide as a food flavor enhancer. The legislation of the Russian Federation sets the level of introduction of monosodium glutamate, or additive E621, into a food product. In connection with the above, there was a need to develop a method for quantitative determination of the mass fraction of introduced monosodium glutamate in the production of food products. A new method for identification of added monosodium glutamate in food products is proposed within the framework of the work under consideration. The authors have developed a technique for the determination of the mass fraction of sodium glutamate in food products by high-performance liquid chromatography (HPLC) with precolumn derivatization. The metrological evaluation of the developed methodology is presented, accuracy and reproducibility indices in two concentration ranges are established.
Article
Targeting CGRP-pathways has substantially expanded our options for treating individuals with migraine. Although the efficacy of these drugs on migraine aura is yet to be fully revealed, it seems from existing studies that CGRP antagonism reduces the number of migraine auras. The present perspective summarizes the evidence linking CGRP to the migraine aura and proposes a model by which targeting the CGRP-pathways and, thus, inhibition the interaction between C- and Aδ-trigeminal fibers might reverse a possible high cortical glutamate level leading to a reduced number of migraine auras.
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Purpose of Review To review the evidence and role of monosodium glutamate (MSG) as a headache and migraine trigger. Recent Findings MSG is a common food additive, has widely been linked as a trigger of headache, as well as other symptoms. However, the evidence for MSG as a causative agent for headache is debated. Various clinical trials over the past several decades have reported conflicting results, with studies suggesting that MSG does and does not increase the incidence of headache. However, the dosages of MSG exposure are often inconsistent across studies, with many studies administering a dose significantly higher than the average consumption.. Additionally, there are misconceptions about which foods and cuisines have MSG in them. Summary MSG could be a potential trigger for migraine and headaches. It is unclear exactly how MSG plays into the migraine pathophysiology. It’s crucial to accurately determine if MSG is present in one’s diet to evaluate its potential impact on headaches.
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Over the last century the people’s mode of life and eating habits has dramatically changed: the people of developed countries began to consume fast food, and also started disorderly and frequent snacking. The production of dietary meals and the increase of food assortment, including food produced from low-quality ingredients, led to the manufacturer’s necessity to use a large number of functional ingredients, i. e. those that improve taste of the food. Monosodium glutamate (MSG) is one of the widely used additives. Monosodium L-Glutamate (E621) is the sodium salt of glutamic acid found in all protein foods; it is used throughout the world as a food flavor enhancer. The legislation of the Russian Federation limits the content of monosodium glutamate, or additive E621, in a food product. Due to the fact that the glutamic acid takes the major weight in the monosodium glutamate molecule, which molecule is naturally present in almost all food products, the weight of the molecule of the E621 additive was determined by content of this amino acid expressed in terms of monosodium glutamate. In connection with the foregoing, it became necessary to develop a method for the quantitative determination of the mass fraction of monosodium glutamate introduced into food during the production of food products. Within the framework of this research a new method for determining the share of added monosodium glutamate is proposed, which is not associated with the natural content of glutamic acid. The authors have developed a method for determining the mass fraction of monosodium glutamate in food products with the help of high performance liquid chromatography with precolumn derivatization. This research presents metrological assessment of the developed methodology, determines accuracy rates and reproducibility factors in two concentrations ranges. For a range of 0.1 to 1%, the reproducibility is set at 17% and the accuracy rate is set at 30%. For the range of 1–10%, the reproducibility is 6%, the accuracy rate is 10% respectively. Also, during the development of the method, the lower limits for the quantitative determination (Limit of Detection — LOD) and qualitative determination (Limit of Quantification — LOQ) of the method were calculated. LOQ was equal to 0.01% and LOD accounted for 0.1%. The method has successfully passed the metrological certification and is included in the Register of Measurement Methods of the Russian Federation. It can be used by accredited laboratories for assessment and control of food quality.
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Monosodium glutamate induces behaviors thought to reflect headache and nausea in rats. We explored the effects of the N-methyl-d-aspartate receptor antagonist (2R)-amino-5-phosphonovaleric acid, the inotropic glutamate receptor antagonist kynurenic acid, and the CGRP receptor antagonist olcegepant, on monosodium glutamate-induced increases in nocifensive, headache-like and nausea behaviours. Effects of these antagonists on motor function were examined with a rotarod. The effect of the dopamine receptor antagonist metoclopramide and the serotonin 3 receptor antagonist ondansetron on nausea behaviour was also assessed. (2R)-amino-5-phosphonovaleric acid, and to a lesser extent, kynurenic acid and olcegepant, reduced nocifensive and headache-like behaviours evoked by monosodium glutamate. No alteration in motor function by (2R)-amino-5-phosphonovaleric acid, kynurenic acid or olcegepant was observed. No sex-related differences in the effectiveness of these agents were identified. Nausea behaviour was significantly more pronounced in male than in female rats. Olcegepant, ondansetron and metoclopramide ameliorated this nausea behaviour in male rats. Ondansetron and metoclopramide also reduced headache-like behaviour in male rats. These findings suggest that peripheral N-methyl-d-aspartate receptor activation underlies monosodium glutamate-induced headache-like behaviour but does not mediate the nausea behaviour in rats.
Article
Our recent study showed that glutamate can inhibit dopamine oxidation via chelating copper. l-Theanine is an amino acid analogue of glutamate, whereas tea (-)-epigallocatechin-3-gallate (EGCG) is similar to dopamine in avidly undergoing oxidation. We thus hypothesized that l-theanine could also restrain EGCG oxidation via chelating copper. The current study scrutinized influences of l-theanine on EGCG oxidation in vitro and in vivo. The in vitro results showed that l-theanine and copper formed an l-theanine-copper complex with impaired redox activity of copper. Accordingly, l-theanine effectively suppressed copper-facilitated EGCG oxidation, hydroxyl radical production, and DNA damage; inhibited EGCG autoxidation which in essence involves catalysis of transition metals such as copper; and reduced EGCG oxidation-associated formation of a quinone adduct with proteins known as quinoproteins. Consistently, l-theanine significantly increased hepatic EGCG levels and reduced hepatic quinoprotein levels and liver injury in mice treated with EGCG. These lines of evidence together suggest that tea l-theanine can protect against tea catechin oxidation.
Chapter
Glutamatergic neurotransmission is strongly implicated in both normal pain neurotransmission and the transition to chronic pain and central sensitization. As such, there is great interest in identifying optimal treatment options which beneficially reduce pain with limited side effects. Potential options include antagonism of ionotropic and Group I metabotropic glutamate (mGlu) receptors, agonism of Group II and III mGlu receptors, modulation of transporter function, reduction in neuroimmune cytokines which affect glutamate, improvement in glutamatergic and GABA neurotransmission through dietary modulation, and other non-pharmacological approaches such as electroacupuncture and exercise. Current pharmacological treatment options are limited due to widespread distribution of glutamate action in the body, making side effects very common. Non-pharmacological treatment options such as dietary intervention may be good adjunct treatments due to the positive effects on glutamatergic neurotransmission and reduction of inflammation, with little to no side effects. Current pharmacological and non-pharmacological treatment options which affect glutamatergic neurotransmission for the treatment of chronic pain are reviewed.
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Glutamic acid is a neurotransmitter that acts as a mediator of excitatory signals in the mammalian nervous system and is also involved in the brain’s normal functioning including cognition and learning as well as activation of NMDA (N-Methyl D- Aspartate) receptors found in the membrane of neuron cells. However, in a number of pathological conditions, including various brain disorders, excessive activation of glutamate receptors maybe responsible for neuronal injury or death. In the modern days MSG (monosodium Glutamate) stands as the most commonly used flavor enhancer in the food industry. Although, concerns were raised after incidences of several abnormalities emerged as one of the major causing diseases through its use. To investigate the onset and progression of disease many short-term human trials and animal studies were conducted. The present chapter tries to describe the effect of MSG on development, behavior, anxiety which includes growth retardation and mortality when used with a higher concentration. Thus, suggest maximum restraint during the consumption of the salt, especially in children.
Chapter
Monosodium glutamate (MSG) is a food flavor enhancer used widely for its umami potency in different cultures. This chapter documents the biological importance of MSG and found that it constitutes sodium, glutamate, and water and occurs richly in protein foods and in the human body. As a major nonessential amino acid in the human body, it performs several functions including energy for gut cells, material for protein metabolism and key metabolites, and also a neurotransmitter in the central nervous system. It can be found free or bound to proteins and the free form has the unique taste quality (umami) that translates savory taste in foods. This umami taste is distinct to other basic tastes. Human beings have been shown to adequately metabolize food glutamate and flavor-enhancing glutamate. Double blind placebo-controlled studies reported that flavor-enhancing glutamate at normal dietary levels found in umami foods can considerably improve health of older population and poses no risk for other age groups. The European established acceptable daily intake of 30 mg/kg body weight is well above the no adverse effect level. Proper labeling is specified for MSG on product labels. More work on MSG as consumed in human diet is encouraged.
Article
Ingestion of monosodium glutamate (MSG) causes headache, nausea and craniofacial tenderness in healthy individuals. The present study explored whether MSG produces behavioural signs of headache, nausea and changes in craniofacial sensitivity in rats. The behavior of male and female Sprague Dawley rats was video recorded before and after intraperitoneal (i.p.) injections of either MSG (1-1000 mg/kg), nitroglycerin (GTN, 10 mg/kg) or normal saline. Behaviors (grimace score, head-flicks, rearing, head scratches, facial grooming, lying-on-belly and temporalis muscle region mechanical withdrawal threshold (MT)) were evaluated. Facial cutaneous temperature of the nose and forehead was measured before and after i.p. injections via infrared thermography. Plasma glutamate and calcitonin-gene related peptide (CGRP) concentrations after administration of 1000 mg/kg MSG were measured in anesthetized rats. MSG induced nocifensive, headache- and nausea-like behaviors in a dose-related manner but had no effect on MT. MSG (1000 mg/kg) induced a significantly greater frequency of headache-like behavior in females, but a longer duration of nausea-like behavior in males. MSG produced a prolonged increase in plasma glutamate and CGRP concentrations. Co-administration of the median effective dose of MSG (350 mg/kg) with GTN (10 mg/kg) amplified headache-like behaviors, induced significant craniofacial sensitivity and produced increased nausea-like behaviour. Co-administration of sumatriptan or naproxen with MSG (1000 mg/kg), significantly attenuated MSG-induced nocifensive and headache-like behaviors. Our data suggests that systemic administration of MSG to rats induces behavioral correlates of headache and nausea. This model may offer another avenue for research on the mechanism and treatment of primary headache disorders such as migraine.
Chapter
Although many medications are currently available in the prevention and treatment of migraines, lifestyle modifications are still recommended to modify symptoms. The role of dietary and nutritional factors in causing as well as treating headache disorders has been widely studied. In this chapter, we review research related to common food triggers and IgG food sensitivity testing to prescribe an elimination diet. Prospective studies on various types of comprehensive diets such as the ketogenic diet, the modified Atkins diet, low glycemic index diet, and low-fat diet will also be summarized. Comprehensive diets do not require the exclusion of food triggers but the quantitative adjustment of micronutrients, protein, carbohydrates, and fats. Comorbid conditions such as obesity, irritable bowel syndrome, and celiac disease will be also examined in the context of migraines and studies on condition-specific dietary modifications evaluated. Finally, brain energy metabolism in migraineurs and its relationship to nutrient deficiencies will also be discussed in conjunction with the use of nutraceuticals and phytomedicine to improve migraine symptoms.
Article
Gulf War illness (GWI) is a chronic and multi-symptomatic disorder affecting veterans who served in the Gulf War. The commonly reported symptoms in GWI veterans include mood problems, cognitive impairment, muscle and joint pain, migraine/headache, chronic fatigue, gastrointestinal complaints, skin rashes, and respiratory problems. Neuroimaging studies have revealed significant brain structure alterations in GWI veterans, including subcortical atrophy, decreased volume of the hippocampus, reduced total grey and white matter, and increased brain white matter axial diffusivity. These brain changes may contribute to or increase the severities of the GWI-related symptoms. Epidemiological studies have revealed that neurotoxic exposures and stress may be significant contributors to the development of GWI. However, the mechanism underlying how the exposure and stress could contribute to the multi-symptomatic disorder of GWI remains unclear. We and others have demonstrated that rodent models exposed to GW-related agents and stress exhibited higher extracellular glutamate levels, as well as impaired structure and function of glutamatergic synapses. Restoration of the glutamatergic synapses ameliorated the GWI-related pathological and behavioral deficits. Moreover, recent studies showed that a low-glutamate diet reduced multiple symptoms in GWI veterans, suggesting an important role of the glutamatergic system in GWI. Currently, growing evidence has indicated that abnormal glutamate neurotransmission may contribute to the GWI symptoms. This review summarizes the potential roles of glutamate dyshomeostasis and dysfunction of the glutamatergic system in linking the initial cause to the multi-symptomatic outcomes in GWI and suggests the glutamatergic system as a therapeutic target for GWI.
Article
Purpose of review: Despite the development of several medications for the acute and preventive treatment of migraine, there are still many patients in whom lack of efficacy, tolerability, interactions or contraindications make other options necessary. CGRP-based drugs have opened the door to a new era of migraine-targeted treatments. Beyond CGRP, there are other promising targets covered here. Recent findings: For the acute treatment of migraine, 5-HT1F receptor agonists, ditans, are now available. Unlike triptans, 5-HT1B/1D receptor agonists, cardiovascular disease is not a contraindication for the use of ditans. The first study on a monoclonal antibody targeting PAC1 receptor was negative, although this may not be the end for the pituitary adenylate cyclase-activating polypeptide (PACAP) pathway as a target. Summary: Following positive phase-III clinical trials, lasmiditan is the first ditan to be FDA-approved. PACAP has experimental evidence suggesting a role in migraine pathophysiology. As for CGRP, the presence of PACAP in key migraine structures along with positive provocative tests for both PACAP-38 and PACAP-27 indicate this pathway may still be a pharmacological target. Glutamate-based targets have long been considered in migraine. Two clinical trials with memantine, an NMDA-R antagonist, for the preventive treatment of migraine have now been published. The hypothalamus has also been implicated in migraine pathophysiology: the potential role of orexins in migraine is discussed. Acid-sensing ion channels, as well as amylin-blocking drugs, may also become migraine treatments in the future: more research is warranted.
Article
Background Adenosine triphosphate (ATP) and glutamate are associated with some headache conditions, and purinergic (P2X) and glutamatergic N ‐methyl‐D‐aspartate (NMDA) receptor‐related processes in the medulla can modulate the effects of trigeminal nociceptive afferent inputs into the brainstem on craniofacial sensorimotor circuits. This study aimed to test whether neck muscle activity can be induced in rats by noxious stimulation of the frontal dura or superior sagittal sinus that involves P2X or NMDA receptor‐dependent mechanisms. Methods While electromyographic activities of neck and craniofacial muscles were being recorded in anesthetized rats (n= 46), the inflammatory irritant mustard oil (0.2 µl, 20% MO) or vehicle (mineral oil) was topically applied to the dura or sinus, preceded by 10 µl of the ATP antagonist 2′,3′‐O‐(2,4,6‐ trinitrophenyl) adenosine 5′‐triphosphate (TNP‐ATP , 0.1 mM; n=8) or 2‐amino‐5‐phosphonopentanoic acid (APV, 0.05 mM; n=7) or phosphate‐buffered saline (PBS as vehicle control; n=10). Results Application of MO but not vehicle to the frontal dura significantly increased (P <0.05) neck electromyographic activity whereas MO application to the superior sagittal sinus did not significantly increase neck electromyographic activity unless MO had previously been applied to the dura. Pre‐treatment (i.t.) with TNP‐ATP or APV but not vehicle control significantly reduced neck electromyographic activity evoked by MO application to the dura. Conclusions These data suggest that noxious stimulation of the frontal dura (but not superior sagittal sinus) may enhance neck muscle activity that is P2X and NMDA receptor‐dependent. These effects may contribute to neck muscle stiffness that occurs in some headache conditions.
Chapter
The excessive number of H⁺ or “:” and their asymmetrical distribution determines the performance of their surrounding water molecules in a way different from that of ordinary water. The naked lone pairs and protons are equally capable of interacting with the solvent H2O molecules to form O:H vdW bond, O:⇔:O super–HB or H↔H anti-HB without charge sharing or new bond forming. Solvation examination of alcohols, aldehydes, formic acids, and sugars reveals that O:H–O formation enables the solubility and hydrophilicity of alcohol; the H↔H anti-HB formation and interface structure distortion disrupt the hydration network and surface stress. The O:H phonon redshift depresses the freezing point of sugar solution of anti-icing.
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A single intake of monosodium glutamate (MSG) may cause headache and increased muscle sensitivity. We conducted a double-blinded, placebo-controlled, crossover study to examine the effect of repeated MSG intake on spontaneous pain, mechanical sensitivity of masticatory muscles, side effects, and blood pressure. Fourteen healthy subjects participated in 5 daily sessions for one week of MSG intake (150 mg/kg) or placebo (24 mg/kg NaCl) (randomized, double-blinded). Spontaneous pain, pressure pain thresholds and tolerance levels for the masseter and temporalis muscles, side effects, and blood pressure were evaluated before and 15, 30, and 50 min after MSG intake. Whole saliva samples were taken before and 30 min after MSG intake to assess glutamate concentrations. Headache occurred in 8/14 subjects during MSG and 2/14 during placebo (P = 0.041). Salivary glutamate concentrations on Day 5 were elevated significantly (P < 0.05). Pressure pain thresholds in masseter muscle were reduced by MSG on Day 2 and 5 (P < 0.05). Blood pressure was significantly elevated after MSG (P < 0.040). In conclusion, MSG induced mechanical sensitization in masseter muscle and adverse effects such as headache and short-lasting blood pressure elevation for which tolerance did not develop over 5 days of MSG intake.
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Human saliva mirrors the body's health and can be collected non-invasively, does not require specialized skills and is suitable for large population based screening programs. The aims were twofold: to evaluate the suitability of commercially available saliva collection devices for quantifying proteins present in saliva and to provide levels for C-reactive protein (CRP), myoglobin, and immunoglobin E (IgE) in saliva of healthy individuals as a baseline for future studies. Saliva was collected from healthy volunteers (n=17, ages 18-33years). The following collection methods were evaluated: drool; Salimetrics® Oral Swab (SOS); Salivette® Cotton and Synthetic (Sarstedt) and Greiner Bio-One Saliva Collection System (GBO SCS®). We used AlphaLISA® assays to measure CRP, IgE and myoglobin levels in human saliva. Significant (p<0.05) differences in the salivary flow rates were observed based on the method of collection, i.e. salivary flow rates were significantly lower (p<0.05) in unstimulated saliva (i.e. drool and SOS), when compared with mechanically stimulated methods (p<0.05) (Salivette® Cotton and Synthetic) and acid stimulated method (p<0.05) (SCS®). Saliva collected using SOS yielded significantly (p<0.05) lower concentrations of myoglobin and CRP, whilst, saliva collected using the Salivette® Cotton and Synthetic swab yielded significantly (p<0.05) lower myoglobin and IgE concentrations respectively. The results demonstrated significantly relevant differences in analyte levels based on the collection method. Significant differences in the salivary flow rates were also observed depending on the saliva collection method. The data provide preliminary baseline values for salivary CRP, myoglobin, and IgE levels in healthy participants and based on the collection method.
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In chronic musculoskeletal pain conditions, the balance between supraspinal facilitation and inhibition of pain shifts towards an overall decrease in inhibition. Application of a tonic painful stimulus results in activation of diffuse noxious inhibitory controls (DNIC). The aims of the present experimental human study were (1) to compare DNIC, evoked separately, by hypertonic saline (6%)-induced muscle pain (tibialis anterior) or cold pressor pain; (2) to investigate DNIC evoked by concomitant experimental muscle pain and cold pressor pain, and (3) to analyze for gender differences. Ten males and 10 age matched females participated in two sessions. In the first session unilateral muscle pain or unilateral cold pressor pain were induced separately; in the second session unilateral muscle pain and unilateral cold pressor pain were induced concomitantly. Pressure pain thresholds (PPT) were measured around the knee joint before, during, and after DNIC induction. Cold pressor pain increased PPT in both males and females with greater increases in males. Hypertonic saline-evoked muscle pain significantly increased PPT in males but not in females. When cold pressor and muscle pain were applied concomitantly the PPT increases were smaller when compared to the individual sessions. This study showed for the first time that two concurrent conditioning tonic pain stimuli (muscle pain and cold pressor pain) cause less DNIC compared with either of the conditioning stimuli given alone; and males showed greater DNIC than females. This may explain why patients with chronic musculoskeletal pain have impaired DNIC.
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To develop a methodology for translating the McGill Pain Questionnaire (MPQ) into a Danish version, and to make comparisons to studies of patients speaking other languages. Finding suitable Danish adjectives using the same methodology as that in the original MPQ. Comparison of Danish descriptors to the words in the English version of MPQ. Survey in healthy subjects and patients with rheumatoid arthritis (RA) and fibromyalgia (F). The general public and hospital outpatients. A random sample of 186 healthy volunteers, 20 patients with rheumatoid arthritis and 41 patients with fibromyalgia. Danish words translated as closely as possible to the descriptors in the original McGill Pain Questionnaire. A pain-assessment instrument making international pain description possible. A Danish version of the McGill Pain Questionnaire was developed with scale values of Danish descriptors not differing more than 5 x SEM from the 'patient' words in the English version. The subdivision into classes and subclasses was respected. In the reliability experiment, the same rank values were found in 85% of subclasses. In a study using two experimental pain stimulus intensities, seven of 10 subjects obtained higher MPQ scores following the high-intensity stimulus. In the clinical study, the pain profiles of patients with RA and F in English, Italian, and Danish patients were almost the same. The present methodology of translating the McGill Pain Questionnaire permits comparison of studies from English-speaking and non-English-speaking populations, thus facilitating international research exchange.
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We have previously shown that injection of the inflammatory irritant and small-fiber excitant mustard oil (MO) into the temporomandibular joint (TMJ) region can reflexively induce a prolonged increase in the activity of both digastric and masseter muscles in rats. It is possible that peripheral excitatory amino acid (EAA) receptors play a role in this effect, because MO-evoked increases in jaw muscle activity are attenuated by preapplication of the noncompetitive NMDA receptor antagonist MK-801 into the TMJ region. In the present study the EAA receptor agonists glutamate, NMDA, kainate, and AMPA were applied locally to the TMJ region. Jaw muscle responses similar to those evoked by MO application to the TMJ region were achieved with glutamate, NMDA, AMPA, and kainate. Repeated application of glutamate, NMDA, or AMPA at intervals of 30 min evoked responses in the ipsilateral jaw muscles that were of comparable magnitude. Co-application of the NMDA receptor antagonist DL-2-amino-5-phosphonovalerate (0.5 micromol) significantly reduced the magnitude of the glutamate- and NMDA-evoked ipsilateral jaw muscle responses without affecting responses evoked by AMPA. In contrast, co-application of the non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (1 nmol) significantly reduced the magnitude of the glutamate- and AMPA-evoked ipsilateral jaw muscle responses without affecting responses evoked by NMDA. This evidence suggests that both NMDA and non-NMDA EAA receptor types are located within the TMJ region and may contribute to jaw muscle activity that can be reflexively evoked from the TMJ region.
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Monosodium glutamate (MSG) ingestion is known to increase plasma glutamate concentration, and MSG infusion stimulates insulin secretion. We investigated the impact of MSG ingestion on both the plasma and intramuscular amino acid pools. Nine postprandial adults ingested MSG (150 mg/kg) and rested for 105 min. Venous blood was sampled preingestion and then every 15 min; vastus lateralis muscle biopsies were taken preingestion and at 45, 75, and 105 min postingestion. Venous plasma glutamate and aspartate concentrations increased (P </= 0.05) approximately 700-800 and 300-400%, respectively, after 30-45 min. Although several other plasma amino acids increased modestly, the rise in glutamate accounted for approximately 80% of the increase in total plasma amino acids. In addition, plasma insulin increased threefold after 15 min; this occurred before a significant increase in plasma glutamate, indicating a feed-forward stimulation from the gastrointestinal tract. The intramuscular amino acid pool was remarkably constant, with only glutamate increasing (P </= 0.05) by 3.56 mmol/kg dry wt. By 105 min, the plasma and muscle amino acids had returned to resting concentrations. This increase in muscle glutamate concentration could account for approximately 40% of the MSG ingested; we propose that resting skeletal muscle is a major sink for the glutamate and metabolizes it to aspartate.
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Glutamate is central to several transamination reactions that affect the production of ammonia, alanine, glutamine, as well as TCA cycle intermediates during exercise. To further study glutamate metabolism, we administered 150 mg/kg body wt of monosodium glutamate (MSG) and placebo to seven male subjects who then either rested or exercised (15-min cycling at approximately 85% maximal oxygen consumption). MSG ingestion resulted in elevated plasma glutamate, aspartate, and taurine, both at rest and during exercise (P < 0.05), whereas most other amino acids were unchanged. Neither plasma alanine nor ammonia was altered at rest. During exercise and after glutamate ingestion, alanine was increased (P < 0.05) and ammonia was attenuated (P < 0.05). Glutamine was also elevated after glutamate ingestion during rest and exercise trials. MSG administration also resulted in elevated insulin levels (P < 0.05), which were parallel to the trend in C-peptide levels. Thus MSG can successfully elevate plasma glutamate, both at rest and during exercise. The plasma amino acid responses suggest that increased glutamate availability during exercise alters its distribution in transamination reactions within active muscle, which results in elevated alanine and decreased ammonia levels.
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Increased muscle tenderness is the most prominent finding in patients with tension-type headache, and it has recently been shown that muscle blood flow is diminished in response to static exercise in tender points in these patients. Although tenderness has been ascribed to local inflammation and release of inflammatory mediators, the interstitial concentration of inflammatory mediators has not previously been studied in tender muscles of patients with tension-type headache. The aim of the present study was to investigate in vivo concentrations of prostaglandin E2 (PGE2), adenosine 5'-triphosphate (ATP), glutamate, bradykinin and other metabolites in a tender point of patients with chronic tension-type headache, in the resting state as well as in response to static exercise, and to compare findings with measurements in a matched non-tender point of healthy controls. We recruited 16 patients with chronic tension-type headache and 17 healthy control subjects. Two microdialysis catheters were inserted into the trapezius muscle and dialysates were collected at rest, 15 and 30 min after start of static exercise (10% of maximal force) and 15 and 30 min after end of exercise. All samples were coded and analysed blindly. There was no difference in resting concentration of any inflammatory mediators or metabolites between tender patients and non-tender controls (P > 0.05). We also found no difference in change in interstitial concentration of ATP, PGE2, glutamate, glucose, pyruvate and urea from baseline to exercise and post-exercise periods between patients and controls (P > 0.05). The present study provides in vivo evidence of normal interstitial levels of inflammatory mediators and metabolites in tender trapezius muscle in patients with chronic tension-type headache during both rest and static exercise. Thus, our data suggest that tender points in these patients are not sites of ongoing inflammation.
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Peripheral N-methyl-d-aspartate (NMDA) receptors are found in deep tissues and may play a role in deep tissue pain. Injection of the endogenous NMDA receptor agonist glutamate into the masseter muscle excites deep craniofacial afferent fibers in rats and evokes pain in human subjects. It is not clear whether peripheral NMDA receptors play a role in these effects of glutamate. Accordingly, the effect of NMDA on afferent activity as well as the effect of locally administered NMDA receptor antagonists on glutamate-evoked afferent discharges in acutely anesthetized rats and muscle pain in human subjects was examined. Injection of NMDA into the masseter muscle evoked afferent discharges in a concentration-related manner. It was found that the NMDA receptor antagonists 2-amino-5-phosphonvalerate (APV, 10 mM), ketamine (10 mM), and dextromethorphan (40 mM) significantly decreased glutamate-evoked afferent discharges. The effects of APV and ketamine, but not dextromethorphan, were selective for glutamate-evoked afferent discharges and did not affect hypertonic saline-evoked afferent discharges. In human experiments, it was found that 10 mM ketamine decreased glutamate-evoked muscle pain but had no effect on hypertonic saline-evoked muscle pain. These results indicate that injection of glutamate into the masseter muscle evokes afferent discharges in rats and muscle pain in humans in part through activation of peripheral NMDA receptors. It is conceivable that activation of peripheral NMDA receptors may contribute to masticatory muscle pain and that peripherally acting NMDA receptor antagonists could prove to be effective analgesics for this type of pain.
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Increased excitability of the central nervous system generated by repetitive and sustained pericranial myofascial nociception may be responsible for transformation of episodic tension-type headache into chronic form. We aimed to compare mechanical and electrical (intramuscular and cutaneous) pain thresholds in trapezius and anterior tibial regions between 20 patients with chronic tension type headache and 20 healthy controls. Pain thresholds to three types of electrical stimulation (single pulse, 2 and 100 Hz) were significantly lower in patients than in controls in trapezius muscle (P < 0.02) and in skin overlying the trapezius muscle (P < 0.05), whilst electrical pain thresholds did not differ between groups in anterior tibial muscle and skin. Quantitative sensory testing revealed increased pain sensitivity in patients as assessed by pressure-controlled manual palpation (local tenderness score, LTS; P < 0.01) and by pressure algometry (mechanical pain thresholds; P < 0.05) in test areas over the trapezius muscle, but not the anterior tibial muscle. In summary, this study demonstrates lower pain thresholds in muscle and skin of the cephalic region but not in lower limb muscle and skin in patients with chronic tension-type headache than in healthy controls. Increased sensitivity in nociceptive pathways from cephalic region may be of importance in the pathophysiology of chronic tension type headache.
Article
Background. Referred pain is prevalent in the craniofacial region,and it would be helpful for dental practitioners to have drawings delineating regions with a high probability for a patient's referred pain source. Methods. The author applied firm pressure for approximately five seconds to trigger points, nodules of spot tenderness, and selected masticatory structures within the head and neck region on 230 patients with temporomandibular disorder, or TMD. As firm pressure was being applied, subjects were asked whether pain was developing or intensifying in a location different than that being palpated. Results. One hundred ninety-six subjects (85 percent) reported that referred pain was being generated. The cheek area, ear and forehead were the most frequently reported sites of referred pain generation; palpation over the trapezius muscle, lateral pterygoid area and masseter muscle were the most common sources of referred pain to the craniofacial region. The author provides figures displaying common referred pain sites and their sources. Conclusions, Patients with TMD often report referred craniofacial pain arising from palpation of the head and neck region. The author found that the pattern between referred pain source and site was consistent and predictable. Practice Implications. Practitioners should consider craniofacial pain's propensity for referral when treating patients with TMD. Practitioners can use the figures presented to determine regions of high probability for a patient's referred pain source.
Article
Objective: The aim of this study was to determine the relationship of high daily monosodium glutamate (MSG) consumption with glutamate concentrations in jaw muscle, saliva, and serum, and muscle pain sensitivity in healthy participants. Methods: A randomized, double-blinded, placebo-controlled study was conducted to investigate the effect of repetitive consumption of high-dose MSG on glutamate concentration in the masseter muscles measured by microdialysis and muscle pain sensitivity. In five contiguous experimental daily sessions, 32 healthy participants drank MSG (150 mg/kg) or NaCl (24 mg/kg) diluted with a 400 mL soda. The concentrations of glutamate before and after the ingestion were assessed in dialysate and plasma samples on the first and last days. Saliva glutamate concentration was assessed every day. Pressure pain threshold, pressure pain tolerance, autonomic parameters (heart rate, systolic and diastolic blood pressures) and reported side effects also were assessed. Results: No significant change was noted in the baseline concentration of glutamate in the masseter muscle, blood, or saliva, but the peak concentration in the masseter muscle increased significantly between day 1 and 5. A statistically significant increase in systolic and diastolic blood pressures after MSG administration was observed, as well as a significantly higher frequency of reports of nausea and headache in the MSG group. No robust effect of MSG on muscle sensitivity was found. Conclusion: Interstitial glutamate concentration in the masseter muscle is not highly disturbed by excessive repetitive intake of MSG in healthy man.
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Interest in human saliva proteomics for disease-specific biomarker screening increased in the last decade. We used whole saliva samples from periodontally healthy and diseased subjects with chronic periodontitis to screen for disease-associated differences in the protein pattern. We selected 20 periodontally healthy and 20 periodontally diseased subjects from the population-based cross-sectional Study of Health in Pomerania (SHIP-2 and SHIP-Trend). Saliva collection was performed with commercially available Salivette(®) (Sarstedt, Nümbrecht, Germany). Whole saliva proteins were analysed after trichloroacetic acid (TCA) precipitation and proteolytic digestion with trypsin by LC-MS/MS. MS-data were analysed and quantified using the Rosetta Elucidator software package. In whole saliva we identified 344 human protein groups across all samples. For label free quantitation we only considered 152 proteins identified with more than one unique peptide. In total, 20 proteins showed 1.5-fold difference in abundance between controls and patients (p < 0.05); the majority of these proteins showed higher abundance in the periodontally diseased subjects. Functional annotation of proteins linked the periodontally diseased status with acute phase response and inflammatory processes. Label free proteomic analysis of whole saliva is a powerful tool to characterize the periodontal disease status and differentiate between healthy and periodontally diseased subjects.
Article
The ability of muscle pain to generate somatosensory sensibility changes is controversial. Thus, in the present study, tonic infusion of hypertonic saline (5%, 7.1 ml administered over 15 min) into the tibialis anterior (TA) muscle was used as an experimental model to induce local and referred pain. The sensibility to high-intensity pressure stimuli applied to the local pain area, referred pain area and an arm was assessed in 14 healthy volunteers. Infusion of isotonic (0.9%) saline into the other leg served as control. The subject continuously scored the pain intensity on an electronic visual analogue scale (VAS). Pressure pain threshold (PPT) was determined on the TA muscle (2 cm and 10 cm from the infusion site), at the frontal aspect of the ankle (area of referred pain) and on the arm. To minimise the skin component of the PPT, the skin covering the assessment sites was anaesthetised with an anaesthetic creme. The PPTs were obtained before and after cutaneous analgesia, 1 min and 10 min after infusion start and 10 min after the pain had disappeared. Infusion of hypertonic saline caused significantly (P<0.05) higher VAS scores than infusion of isotonic saline. A significant (P<0.04) increase of the PPT (i.e., decreased sensibility) was found at the ankle and on the arm during muscle pain compared to the control condition. No significant differences in PPTs on the TA muscle were found during saline-induced muscle pain compared to the infusion of isotonic saline. The decrease in deep sensibility at the heterotopic sites (referred pain area and arm), but not at homotopic sites (TA muscle), probably reflected the phenomenon of diffuse noxious inhibitory control (DNIC). The inhibitory mechanism during muscle pain was shown to be effective for the deep tissue sensibility in healthy subjects. Thus, a pathologically disturbed inhibitory mechanism may result in widespread deep hyperalgesia in muscle pain patients.
Article
The function of the somatosensory system in patients with painful temporomandibular disorders is still a matter of discussion. We wished to determine cutaneous sensitivity to innocuous mechanical stimuli in the orofacial region before, during (3 and 12 min) and after standardized experimental jaw-muscle pain. Twelve healthy subjects were exposed to tonic infusion of hypertonic (5%) and isotonic (0.9%) saline into the masseter muscle. All subjects experienced moderate pain with hypertonic saline, and the area of self-reported pain increased significantly from 3 min after infusion start to 12 min after infusion start (mean±SEM: 115±49%; P<0.05). The psychophysical ratings of punctate von Frey hair stimulation were significantly increased 12 min after start of hypertonic saline infusion as compared to baseline and post-baseline ratings at the site of infusion (50±10%; P<0.05) and at two adjacent facial sites (18±7%, 37±9%; P<0.05). In contrast, isotonic saline infusion was associated with a significant decrease in ratings at post-baseline as compared to baseline ratings. The psychophysical ratings of a stroking cotton swab stimulation were not significantly affected by infusion of saline. These results in a human model of jaw-muscle pain are comparable to animal studies demonstrating increased size of cutaneous receptive fields and increased responsiveness of brain stem neurons to cutaneous mechanical stimuli. Similar hyperexcitability changes may be part of the pathophysiological mechanisms involved in painful temporomandibular disorders.
Article
Pain in myofascial temporomandibular disorder (TMD) can affect both the masseter and temporalis muscles. Glutamate injection into the masseter muscle evokes pain that is greater in men than in women and this pain is attenuated by co-injection of the N-methyl-d-aspartate (NMDA) receptor antagonist ketamine (10 mmol/L) in men. Animal studies suggested that pain induced by peripheral NMDA receptor activation could differ between the temporalis and masseter muscles and between men and women. The study aims were to investigate differences in glutamate-evoked pain between these muscles and the effectiveness of ketamine to attenuate glutamate-evoked pain in both genders. Pain and mechanical sensitivity were induced in 2 sessions of an experiment in 14 women and 16 men by repeated injections of glutamate (0.5 mol/L) with and without ketamine (20 mmol/L) into the masseter and temporalis muscles. Two injections were applied into the same masseter muscle and 2 injections into the same anterior temporalis muscle at each session. Visual analogue scale (VAS) pain intensities and pain drawing areas were assessed. Glutamate-evoked pain and pain drawing area were significantly greater from the temporalis muscle than from the masseter muscle (P<.02) in both genders. Women reported significantly greater glutamate-evoked masseter muscle pain than men (P<.03). Co-injection of ketamine, at higher dose than previously used, was equally effective in attenuating glutamate-evoked pain from both muscles in both genders (P<.01). The current findings indicate that the characteristics of pain generated by intramuscular injection of glutamate vary for different masticatory muscles and may be partially generated through activation of peripheral NMDA receptors.
Article
To determine if myofascial temporomandibular disorder (TMD) pain patients have elevated interstitial concentrations of glutamate in the masseter muscle. Thirteen patients (3 men, 10 women) diagnosed with myofascial TMD pain and 10 (2 men, 8 women) age-matched healthy controls participated in a single microdialysis session. Microdialysis was performed in the patients in the most painful point of the masseter muscle, while in the healthy subjects a standardized point in the muscle was chosen. Two microdialysis samples were collected over 40-minute epochs. A blood sample was also taken for analysis of plasma glutamate concentration. Numeric rating scale (NRS) scores of pain intensity and unpleasantness, McGill Pain Questionnaire data, pain drawing areas, pressure pain thresholds, pressure pain tolerances, maximum voluntary bite force, and maximum voluntary mouth opening were collected as secondary measurements. The median concentration of glutamate in the masseter muscle of the myofascial TMD pain patients (7.5 ± 2.6 ΜM) was significantly higher (P < .023, Mann-Whitney test) than the concentration in healthy controls (0.5 ± 0.4 ΜM). There were, however, no significant correlations between glutamate concentrations in the masseter muscle and NRS pain scores. Plasma concentrations of glutamate were similar in patients and healthy controls. The present study demonstrates a marked increase in interstitial glutamate concentration in the masseter muscle of myofascial TMD pain patients. These novel findings suggest that peripheral glutamate could be involved in the pathophysiology of myofascial TMD pain.
Article
Dorsal roots (L3‐L7) isolated from immature (1–9 day old) rats were depolarized selectively by kainate (1–100 μM). L‐Glutamate (25–1000 μM), but not L‐aspartate, mimicked the action of kainate. N‐methylaspartate had no activity on these preparations and quisqualate was thirty times less active than kainate. Depolarizations evoked by L‐glutamate (100–1000 μM) faded rapidly in the presence of L‐glutamate. Depolarizations evoked by kainate were depressed during the fade induced by L‐glutamate. Certain electrically evoked C‐fibre volleys in dorsal roots or leg nerves of rats at any age were selectively depressed or abolished in the presence of kainate. The effect of kainate was more selective than that of γ‐aminobutyric acid or capsaicin. Prolonged treatment of dorsal roots with kainate did not appear to be deleterious to C‐fibres. It is suggested that certain primary afferent C‐fibres possess kainate receptors which may be activated physiologically by L‐glutamate released at their central terminations.
Article
A hand-held pressure algometer with a pressure sensitive strain gauge at the tip was used to measure the pressure-pain threshold (PPT) in the temporal region of healthy volunteers. Various sizes of circular tips and various application rates were tested before selecting an area of 0.5 cm2 and a constant application rate of 0.68 N X sec-1 for future use. A highly significant correlation was found between PPT values obtained from the two sides (of the head) (P less than 0.001) and between PPT values obtained with a 3-week interval (P less than 0.001). In a series of 50 immediate consecutive measurements in the same individual, the mean PPT was 171 kPa (N = 6, 2 S.D. 24%). The mean relative change in PPT after a 3-week interval was 0 +/- 51% (N = 11, 2 S.D.). In the course of 5 repeated determinations at weekly intervals there was a significant increase in PPT (ANOVA, P less than 0.05). Subcutaneous lignocaine significantly elevated PPT compared to placebo. Due to the high inter-individual variation, determinations of PPT for group comparisons should include rather large population samples, whereas in paired studies, the intra-individual variation allows the investigation of much smaller groups (10-20 subjects). It is our experience that the pressure algometer is easy to operate in the hands of a skilled laboratory assistant.
Article
IT has been suggested1-4 that monosodium glutamate (MSG) is responsible for the ``Chinese restaurant syndrome''-a burning sensation in the back of the neck spreading to the forearms and to the anterior thorax, accompanied by a feeling of infraorbital pressure, tightness and substernal discomfort. But no study of this phenomenon involved a double blind technique, or any other experimental condition which can be used to assess the significance of subjective reactions.
Article
Monosodium L-glutamate is the cause of the Chinese restaurant syndrome and can precipitate headaches. In appropriate doses it causes burning sensations, facial pressure, and chest pain. These are pharmacological effects obeying a dose-effect relationship. There is considerable variation in oral threshold does among individuals.
Article
It has been postulated that individuals reporting an idiosyncratic symptom response after glutamate ingestion might also experience such symptoms after aspartame ingestion. Such sensitive subjects might have been missed in earlier studies of aspartame. In the present study, six subjects reporting various symptoms after glutamate ingestion, but not after placebo, were administered aspartame (34 mg/kg body weight) or sucrose (1 g/kg body weight) dissolved in orange juice in a randomized, cross-over, double-blind study. No subject reported symptoms typical of a glutamate response after either sucrose or aspartame loading. One subject reported slight nausea approximately 1.5 h after aspartame ingestion, but indicated that the symptoms were not those of a glutamate response. Plasma phenylalanine and aspartate levels were similar to those noted in normal subjects administered identical doses of aspartame. The data indicate no effect of aspartame loading in glutamate-susceptible subjects.
Article
We evaluated plasma and platelet glutamate and glutamine levels in migraine with and without aura during headache-free periods and compared the results with those of normal controls. The plasma and platelet levels of glutamine in migraine with and without aura were normal. Migraine without aura patients had higher glutamate levels in plasma, and normal platelet levels. In migraine with aura patients, glutamate levels were high in platelets, but not in plasma. This suggests different profiles of excitatory amino acid metabolism in migraine with and without aura.
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This report of the proceedings of a workshop on monosodium glutamate (MSG) represents the output of an exchange of scientific information, discussed and debated, by a group of experts representing a variety of disciplines. Experts in the areas of food science, potential adverse reactions to foods, pharmacology, neuroscience, biochemistry, nutrition, pediatrics, and anatomy reviewed the current scientific literature relative to the safe use of MSG in foods. These proceedings supplement the extensive literature compiled by various prestigious international expert committees since the flavor-enhancing properties of MSG were identified around the turn of the century,
Article
71 healthy subjects were treated with placebos and monosodium L-glutamate (MSG) doses of 1.5, 3.0 and 3.15 g/person, which represented a body mass-adjusted dose range of 0.015-0.07 g/kg body weight before a standardized breakfast over 5 days. The study used a rigorous randomized double-blind crossover design that controlled for subjects who had MSG after-tastes. Capsules and specially formulated drinks were used as vehicles for placebo and MSG treatments. Subjects mostly had no responses to placebo (86%) and MSG (85%) treatments. Sensations, previously attributed to MSG, did not occur at a significantly higher rate than did those elicited by placebo treatment. A significant (P < 0.05) negative correlation between MSG dose and after-effects was found. The profound effect of food in negating the effects of large MSG doses was demonstrated. The common practice of extrapolating food-free experimental results to 'in use' situations was called into question. An exhaustive review of previous methodologies identified the strong taste of MSG as the factor invalidating most 'blind' and 'double-blind' claims by previous researchers. The present study led to the conclusion that 'Chinese Restaurant Syndrome' is an anecdote applied to a variety of postprandial illnesses; rigorous and realistic scientific evidence linking the syndrome to MSG could not be found.
Article
Pain-pressure thresholds (PPTs) and stimulus-response (S-R) curves in masseter muscles and index fingers of 11 female patients with chronic jaw-muscle pain were compared with that of 11 matched control subjects. Experimental hyperalgesic and hypoalgesic conditions in the masseter muscles of control subjects were induced by intramuscular injection of 5% saline and of local anesthetic, respectively. The PPTs were found to be significantly lower in the masseter muscles of pain patients than in those of control subjects. The mean slopes of the S-R curves were significantly steeper for the masseter muscles of pain patients (0.481 +/- 0.213) than of control subjects (0.274 +/- 0.201, P < .0256). There were no statistically significant differences in PPTs or S-R curves for the index finger. The PPTs in masseter muscles of control subjects were not significantly affected by injection of 5% saline; however, the slopes of the S-R curves for the masseter muscles were significantly steeper for saline-injection values compared to baseline values (21.7% +/- 29.6%, P < .037). Injection of local anesthetic into masseter muscles of control subjects increased the PPTs significantly and reduced the slopes of the S-R curves significantly as compared to baseline values (-22.9% +/- 34.6%, P < .0155). The present results suggest that PPTs and S-R curves are valuable tools for quantitative description of chronic and experimental jaw muscle pain.
Article
This study examined the role of glutamate receptor activation in the regulation of microvascular tone in the hippocampus and neocortex of the rat. Microvascular and neuronal responses were simultaneously recorded in brain slices using videomicroscopic analysis in conjunction with electrophysiological recording. Glutamate and other glutamate receptor agonists, including NMDA, kainic acid, and ACPD elicited dose-dependent dilation in preconstricted hippocampal microvessels. The lower concentrations of NMDA elicited dilation with an increase in neuronal excitability while dilatory responses to other agonists were associated with substantial depolarization. NMDA-mediated dilation was inhibited completely with a sodium channel blocker (TTX), an NOS inhibitor (L-NNA), or a specific inhibitor of neuronal NOS (7-NI). Inhibition of the GABA(A) or the A2 adenosine receptor did not attenuate the NMDA-induced dilation. The role of spontaneous glutamate receptor activation by endogenous glutamate in the regulation of resting dilatory tone was also examined. Blocking AMPA or metabotropic glutamate receptors did not induce significant responses in resting hippocampal vessels. However, the NMDA receptor antagonist, APV, elicited a dose-dependent constriction. In surface vessels of the neocortex, NMDA elicited a comparable dose-dependent dilation, and APV elicited a significantly smaller dose-dependent constriction. A 60 min period of hypoxia elicited a significant dilation of preconstricted hippocampal microvessels. APV did not significantly influence this dilatory response indicating that hypoxia-induced dilation is not mediated by NMDA receptor activation. Taken together, these results indicate that glutamate contributes to the dilatory tone of cerebral microvessels under physiologic conditions and that this effect is mediated by NMDA receptors. Glutamatergic vasodilation is dependent on neuronal discharge activity and the neuronal production of NO. The tonic influence is more pronounced in hippocampal microvessels than in neocortical vessels suggesting that the contribution of NMDA receptor activation to resting dilatory tone is dependent on the location of vessels within the brain.
Article
Considerable debate swirls about the validity of symptoms described by many people after ingestion of monosodium glutamate (MSG), and the question has remained unresolved largely because of a paucity of well-designed challenge studies. We conducted oral challenge studies in self-identified MSG-sensitive subjects to determine whether they had a statistically significant difference in the incidence of their specific symptoms after ingestion of MSG compared with placebo. First, 5 gm MSG or placebo was administered in random sequence in a double-blind fashion. Subjects who reacted only to a single test agent then underwent rechallenge in random sequence in a double-blind fashion with placebo and 1.25, 2.5, and 5 gm MSG. A positive response to challenge was defined as the reproduction of > of 2 of the specific symptoms in a subject ascertained on prechallenge interview. Sixty-one subjects entered the study. On initial challenge, 18 (29.5%) responded to neither MSG nor placebo, 6 (9.8%) to both, 15 (24.6%) to placebo, and 22 (36.1%) to MSG (p = 0.324). Total and average severity of symptoms after ingestion of MSG (374 and 80) were greater than respective values after placebo ingestion (232 and 56; p = 0.026 and 0.018, respectively). Rechallenge revealed an apparent threshold dose for reactivity of 2.5 gm MSG. Headache (p < 0.023), muscle tightness (p < 0.004), numbness/tingling (p < 0.007), general weakness (p < 0.040), and flushing (p < 0.016) occurred more frequently after MSG than placebo ingestion. Oral challenge with MSG reproduced symptoms in alleged sensitive persons. The mechanism of the reaction remains unknown, but symptom characteristics do not support an IgE-mediated mechanism. According to Food and Drug Administration recommendations, the symptoms, originally called the Chinese restaurant syndrome, are better referred to as the MSG symptom complex.
Article
Monosodium glutamate (MSG) has been allocated an "ADI not specified" by the JECFA, which indicates that no toxicological concerns arise associated with its use as a food additive in accordance with good manufacturing practice (GMP) and for that reason it is not necessary to allocate a numerical ADI. The question in this case, then, is not whether excursions above a numerical ADI might occur but whether high peak intakes might arise which could invalidate the assumption of absence of hazard. Two major issues have arisen in relation to high intakes of MSG: (1) What is the significance of neural damage (focal necrosis in the hypothalamus) seen following high parenteral or intragastric doses of MSG to neonatal animals and is this a particular risk for children? (2) What is the role of MSG in "Chinese Restaurant Syndrome" (flushing, tightness of the chest, difficulty in breathing, etc.) following consumption of Chinese foods? In relation to the first issue, human studies have been crucial in resolving the question. The threshold blood levels associated with neuronal damage in the mouse (most sensitive species) are 100-130 mumol/dl in neonates rising to > 630 mumol/dl in adult animals. In humans, plasma levels of this magnitude have not been recorded even after bolus doses of 150 mg/kg body wt (ca. 10 g for an adult). Additionally, studies in infants have confirmed that the human baby can metabolize glutamate as effectively as adults. It is concluded that blood levels of glutamate + aspartate do not rise significantly even after abuse doses and babies are no more at risk than adults. Intake levels associated with the use of MSG as a food additive and natural levels of glutamic acid in foods therefore do not raise toxicological concerns even at high peak levels of intake. It is not envisaged that use of MSG according to GMP requires the allocation of a numerical ADI. With regard to the second issue, controlled double-blind crossover studies have failed to establish a relationship between Chinese Restaurant Syndrome and ingestion of MSG, even in individuals reportedly sensitive to Chinese meals, and MSG did not provoke bronchoconstriction in asthmatics. Thus, high usage of MSG in ethnic cuisines does not represent a situation in which intakes might achieve unsafe levels, even among individuals claiming idiosyncratic intolerance of such foods. In the light of the toxicological studies, the human metabolic studies in neonates and adults, and the physiological and nutritional role of glutamic acid and the fact that food additive use does not markedly increase the total dietary burden, no foreseeable circumstances arise in which intakes would be such as to invalidate the appropriateness of allocating an ADI not specified to MSG.
Article
Referred pain is prevalent in the craniofacial region, and it would be helpful for dental practitioners to have drawings delineating regions with a high probability for a patient's referred pain source. The author applied firm pressure for approximately five seconds to trigger points, nodules of spot tenderness, and selected masticatory structures within the head and neck region on 230 patients with temporomandibular disorder, or TMD. As firm pressure was being applied, subjects were asked whether pain was developing or intensifying in a location different than that being palpated. One hundred ninety-six subjects (85 percent) reported that referred pain was being generated. The cheek area, ear and forehead were the most frequently reported sites of referred pain generation; palpation over the trapezius muscle, lateral pterygoid area and masseter muscle were the most common sources of referred pain to the craniofacial region. The author provides figures displaying common referred pain sites and their sources. Patients with TMD often report referred craniofacial pain arising from palpation of the head and neck region. The author found that the pattern between referred pain source and site was consistent and predictable. Practitioners should consider craniofacial pain's propensity for referral when treating patients with TMD. Practitioners can use the figures presented to determine regions of high probability for a patient's referred pain source.
Article
The frequency of reactions reported to occur after the consumption of monosodium glutamate (MSG) is the subject of controversy. We conducted a multicenter, multiphase, double-blind, placebo-controlled study with a crossover design to evaluate reactions reportedly caused by MSG. In 3 of 4 protocols (A, B, and C), MSG was administered without food. A positive response was scored if the subject reported 2 or more symptoms from a list of 10 symptoms reported to occur after ingestion of MSG-containing foods within 2 hours. In protocol A 130 self-selected reportedly MSG-reactive volunteers were challenged with 5 g of MSG and with placebo on separate days (days 1 and 2). Of the 86 subjects who reacted to MSG, placebo, or both in protocol A, 69 completed protocol B to determine whether the response was consistent and dose dependent. To further examine the consistency and reproducibility of reactions to MSG, 12 of the 19 subjects who responded to 5 g of MSG but not to placebo in both protocols A and B were given, in protocol C, 2 challenges, each consisting of 5 g of MSG versus placebo. Of 130 subjects in protocol A, 50 (38. 5%) responded to MSG only, 17 (13.1%) responded to placebo only (P <. 05), and 19 (14.6%) responded to both. Challenge with increasing doses of MSG in protocol B was associated with increased response rates. Only half (n = 19) of 37 subjects who reacted to 5 g of MSG but not placebo in protocol A reacted similarly in protocol B, suggesting inconsistency in the response. Two of the 19 subjects responded in both challenges to MSG but not placebo in protocol C; however, their symptoms were not reproducible in protocols A through C. These 2 subjects were challenged in protocol D 3 times with placebo and 3 times with 5 g of MSG in the presence of food. Both responded to only one of the MSG challenges in protocol D. The results suggest that large doses of MSG given without food may elicit more symptoms than a placebo in individuals who believe that they react adversely to MSG. However, neither persistent nor serious effects from MSG ingestion are observed, and the responses were not consistent on retesting.
Article
We used the microdialysis technique to study concentrations of substances in the extensor carpi radialis brevis (ECRB) tendon in patients with tennis elbow. In 4 patients (mean age 41 years, 3 men) with a long duration of localized pain at the ECRB muscle origin, and in 4 controls (mean age 36 years, 2 men) with no history of elbow pain, a standard microdialysis catheter was inserted into the ECRB tendon under local anesthesia. The local concentrations of the neurotransmitter glutamate and prostaglandin E2 (PGE2) were recorded under resting conditions. Samplings were done every 15 minutes during a 2-hour period. We found higher mean concentrations of glutamate in ECRB tendons from patients with tennis elbow than in tendons from controls (215 vs. 69 micromoL/L, p < 0.001). There were no significant differences in the mean concentrations of PGE2 (74 vs. 86 pg/mL). In conclusion, in situ microdialysis can be used to study certain metabolic events in the ECRB tendon of the elbow. Our findings indicate involvement of the excitatory neurotransmitter glutamate, but no biochemical signs of inflammation (normal PGE2 levels) in ECRB tendons from patients with tennis elbow.
Article
Animal studies have suggested that tissue injury-related increased levels of glutamate may be involved in peripheral nociceptive mechanisms in deep craniofacial tissues. Indeed, injection of glutamate (0.1-1 M, 10 microl) into the temporomandibular region evokes reflex jaw muscle responses through activation of peripheral excitatory amino acid receptors. It has recently been found that this glutamate-evoked reflex muscle activity is significantly greater in female than male rats. However, it is not known whether peripheral administration of glutamate, in the same concentrations that evoke jaw muscle activity in rats, causes pain in humans or activates deep craniofacial nociceptive afferents. Therefore we examined whether injection of glutamate into the masseter muscle induces pain in male and female volunteers and, since masseter afferent recordings were not feasible in humans, whether glutamate excites putative nociceptive afferents supplying the masseter muscle of male and female rats. Injection of glutamate (0.5 M or 1.0 M, 0.2 ml) into the masseter muscle of both men and women caused significantly higher levels of peak pain, duration of pain, and overall pain than injection of isotonic saline (0.2 ml). In addition, glutamate-evoked peak and overall muscle pain in women was significantly greater than in men. In rats of both sexes, glutamate (10 microl, 0.5 M) evoked activity in a subpopulation of masseter muscle afferents (n = 36) that projected to the subnucleus caudalis, an important relay of noxious input from the craniofacial region. The largest responses to glutamate were recorded in muscle afferents with the slowest conduction velocities (2.5-5 m/s). Further, glutamate-evoked masseter muscle afferent activity was significantly greater in female than in male rats. These results indicate that glutamate injection into the masseter muscle evokes pain responses that are greater in women than men and that one possible mechanism for this difference may be a greater sensitivity to glutamate of masseter muscle afferents in females. These sex-related differences in acute experimental masseter muscle pain are particularly interesting given the higher prevalence of many chronic muscle pain conditions in women.
Article
This investigation describes, to our knowledge, the first experiment where the microdialysis technique was used to study certain metabolic events in human patellar tendons in combination with immunohistochemical analyses of tendon biopsies. In five patients (four men and one woman) with a long duration (range 12‐36 months) of pain symptoms from Jumper's knee (localized tenderness in the patellar tendon verified as tendon changes with ultrasonography or MRI), and in five controls (four men and one woman) with normal patellar tendons, a standard microdialysis catheter was inserted into the patellar tendon under local anestesia. The local concentrations of glutamate (excitatory neurotransmitter) and prostaglandin E 2 (PGE 2 ) were registered under resting conditions. Samplings were done every 15 min during a 2 h period. In all individuals (patients and controls) biopsies were taken for immunohistochemical analyses. The results showed that it was possible to detect and measure the concentrations of glutamate and PGE 2 in the patellar tendon with the use of microdialysis technique. There were significantly higher concentrations of free glutamate, but not PGE 2 , in tendons with tendinosis compared to normal tendons. In the biopsies, there were no inflammatory cell infiltrates, but, for the first time, it was shown that there was immunoreaction for the glutamate receptor NMDAR1 in association with nerve structures in human patellar tendons. These findings altogether indicate that glutamate might be involved in painful Jumper's knee, and further emphasizes that there is no chemical inflammation (normal PGE 2 levels) in this chronic condition. © 2001 Orthopaedic Research Society. Punlished by Elsevier Science Ltd. All rights reserved.
Article
In rats, intradermal or intraarticular injection of glutamate or selective excitatory amino acid receptor agonists acting at peripheral excitatory amino acid receptors can decrease the intensity of mechanical stimulation required to evoke nocifensive behaviors, an indication of hyperalgesia. Since excitatory amino acid receptors have been found on the terminal ends of cutaneous primary afferent fibers, it has been suggested that increased tissue glutamate levels may have a direct sensitizing effect on primary afferent fibers, in particular skin nociceptors. However, less is known about the effects of glutamate on deep tissue afferent fibers. In the present study, a series of experiments were undertaken to investigate the effect of intramuscular injection of glutamate on the excitability and mechanical threshold of masseter muscle afferent fibers in anesthetized rats of both sexes.