Headache and mechanical sensitization of human pericranial muscles after repeated intake of monosodium glutamate (MSG)

Temporomandibular Disorders (TMD) affect approximately 10% of the population [1, 2]. The principal symptom of TMD that most often leads patients to seek medical treatment is pain in the temporomandibular joint and/or masticatory muscles [1]. Around 70% of TMD patients report masticatory muscle pain and are described as suffering from myofascial TMD [3]. In the majority of myofascial TMD cases, there is little evidence of ongoing pathological change in masticatory muscles, and, consequently, a number of alternative mechanisms have been proposed to explain pathogenesis of this pain [1, 3]. Of these potential mechanisms, life-style related factors may play an important role in development and maintenance of muscle pain in myofascial TMD. For example, chronic stress has been speculated to lead to parafunctional activities such as repetitive tooth clenching or grinding that then produces strain injury to masticatory muscles leading to pain [4‐6], although the relationship between bruxism and craniofacial pain may be more complex [7, 8]. Diet may be another important life-style related factor contributing the muscle pain in myofascial TMD, as it has been reported that TMD patients alter their diet to avoid exacerbating pain associated with mastication of certain foods [9]. However, very little is currently known about the interaction between food intake and pain in TMD.

Consumption of certain foods is thought to precipitate or aggravate other chronic craniofacial pain conditions. One postulated food trigger for migraine headaches is monosodium glutamate (MSG), which is used as a taste enhancer in many snack and fast foods [10]. Indeed, total dietary consumption of glutamate ranges from 50–200 mg/kg/day [11, 12]. Of note, healthy young men who consumed a single dose of 150 mg/kg MSG had a significant increase in headache and craniofacial muscle sensitivity as well as an elevated systolic blood pressure [13], suggesting that MSG consumption may trigger more types of craniofacial pain than just headaches. A significant amount of systemically administered glutamate is known to be taken up by skeletal muscles, including the masticatory muscles [14]. The resulting elevation of interstitial glutamate concentration sensitizes muscle nociceptors to mechanical stimuli [15]; an effect which could underlie reports of craniofacial muscle pain sensitivity in healthy young men given MSG [13]. Further, there is evidence that glutamate concentrations are elevated in painful regions of masticatory muscles of myofascial TMD patients compared to healthy controls [16].

Although a single 150 mg/kg dose of MSG did result in a demonstrable increase in craniofacial sensitivity in young healthy men, more regular consumption of this quantity of MSG may result in tolerance to the acute sensitizing effects of MSG [13]. On the other hand, chronic daily administration of 150 mg/kg of MSG might lead to the accumulation of MSG in masticatory muscles, which might be manifested by enhanced craniofacial sensitivity reminiscent of symptoms reported by myofascial TMD patients. The current study was therefore conducted to assess the impact of 5 days of consumption of 150 mg/kg MSG on craniofacial pain sensitivity in healthy subjects.

The present study was conducted to probe whether, compared to a single administration, repeated intake of MSG could lead to increased complaints of untoward affects and evidence of accumulation of glutamate. MSG (150 mg/kg) was administered daily for 5 days and pain sensitivity and side effects monitored. Daily intake of this amount of MSG did not result in significant reports of spontaneous pain. However, it did lead to a sustained mechanical sensitization of the masseter muscle that lasted for the duration of MSG administration. This pain sensitizing effect of MSG was not observed in the temporalis muscle, suggesting that the effect was site specific. Daily intake of MSG also caused headaches and dizziness for at least one day out of five in 57% of subjects. Although tolerance to most side effects of MSG administration appeared to occur, as evidenced by a decrease in the frequency of side effect complaints, the frequency of headache reports remained relatively constant over the 5 days of MSG ingestion. This suggests that tolerance to the headache inducing effects of MSG may not occur. There was also no apparent tolerance to the ability of MSG administration to increased systolic and diastolic blood pressure over the 5 days intervention. Baseline salivary concentrations of glutamate remained constant and were not different between the MSG and placebo sessions. These concentrations are similar to a previous study that reported mean saliva concentrations of glutamate of 18±1 μM in 18 subjects [20]. However, administration of MSG tended to increase salivary glutamate concentration each day, which suggests the potential that accumulation might have been occurring. These findings suggest that daily consumption of elevated amounts of MSG increases craniofacial pain symptoms in otherwise healthy subjects.

There are some differences in the response properties of the masseter and temporalis muscles to glutamate that may underlie the finding of a masseter muscle selective mechanical sensitizing effect of MSG. Elevated concentrations of glutamate induce mechanical sensitization of masticatory muscle nociceptors through activation of peripheral NMDA receptors [15, 21]. It has been found that there is a lower expression of NMDA receptors by nociceptors that innervate the temporalis muscle and that the response of temporalis nociceptors to peripheral NMDA receptor activation is less robust than masseter muscle nociceptors [22, 23]. Thus, it is possible that there is also a lower expression of peripheral NMDA receptors by nociceptors that innervate the temporalis muscle in healthy human subjects, which results in the temporalis muscle being less sensitive to orally consumed MSG than the masseter muscle [24].

There was a very consistent, albeit relatively small, increase in both systolic and diastolic blood pressure after oral intake of MSG each day. There is recent evidence that increased dietary intake of glutamate over a 5 year period is correlated with an increase in systolic blood pressure, which was more pronounced in women than in men [25]. It is also important to consider whether MSG-induced increases in blood pressure account for the increased incidence of headaches observed in the present as well as previous studies [13, 14]. Although earlier work suggested that elevated blood pressure causes headaches [26‐28], more recent work does not support a strong association. For example, in a large population of Icelandic men and women, it was found that elevated systolic blood pressure was inversely correlated with migraine headache in both men and women [29]. There is also no difference in mean or systolic blood pressure in women with chronic daily headache and women without this condition [30]. These findings suggest that mechanisms other than hypertension may explain MSG-induced headaches.

Glutamate has also been shown to dilate intracranial and extracranial blood vessels through a peripheral NMDA receptor mechanism that involves the release of nitric oxide [31‐33]. Many therapeutically employed vasodilators appear to cause headaches as one of their side effects [34]. For example, infusion of nitroglycerin reliably induces a headache, which is thought to be due to dilation of extracerebral arteries [35, 36]. In a recent study in migraine headache patients, infusion of calcitonin gene related peptide (CGRP), a potent neuropeptide vasodilator and migraine headache inducer, was shown to induce vasodilation of arteries only on the side of the migraine headache pain [37]. On the other hand, vasodilation itself is not able to induce pain that occurs only when periovascular nerve endings are sensitized. This shows that a neural factor, i. e. sensitization, seems to be related to chronic MSG administration [38]. We speculate that it could be vasodilation of extracranial blood vessels through peripheral NMDA receptor activation that mediates MSG headaches [39].

Baseline salivary concentrations of glutamate did not increase over the 5 days of MSG intake, however, post MSG glutamate concentrations increased over the 5 day period. Glutamate has an apparent half-life of about 30 min, which suggests that it would be completely cleared from the blood within 4 hrs of ingestion of MSG [14]. Previously, it was reported that a single oral dose of 150 mg/kg MSG resulted in peak blood glutamate concentrations of a little over 400 μM, which occurred 30-45 min after ingestion [14]. This suggests that salivary glutamate concentrations are about 25-50% of blood concentrations. It has been suggested that as much as 40% of a 150 mg/kg oral dose of MSG is removed by and stored in skeletal muscle [14, 40]. Increased peak levels in the saliva over the 5 days could reflect saturation of storage sites in the skeletal muscle. Animal research suggests that after systemic administration of MSG (50 mg/kg i.v.) there is a rapid rise in glutamate concentration in the masseter muscle that is associated with significant mechanical sensitization of muscle nociceptors [15]. It is likely that oral MSG consumption increases glutamate concentration in the masseter muscle of human subjects and that this underlies the mechanical sensitization of the masseter muscle seen in the present study.

Although the MSG was dissolved in sugar free lemon soda, which we have previously found masks the taste of MSG [13], the vast majority of subjects correctly identified the substance administered to them when asked at the end of each 5 days session. Considering the significant increase in adverse effects, which occurred during MSG ingestion, this result is understandable. Nevertheless, it does mean that we cannot consider this study truly blind, and this lack of subject blinding might have influenced findings that relied on psychophysical assessments, such as PPT and PPTol, and reporting of side effects. However, it should be noted that even though PPT and PPTol were assessed in two jaw closing muscles, significant differences were only found for the masseter muscle. This suggests that even if subjects thought they knew what they were receiving their responses were not reflective of any systematic bias. Also, the administration of placebo can induce adverse effects such as headache, which complicates clarification of adverse reactions induced by MSG [41]. Though adverse effects of headache in the placebo week also could be observed in the result of the present study, it was seen to a significantly lesser extent than in the MSG week. This may imply that an accumulation of MSG by oral administration could be a factor best avoided by TMD and headache patients. Mechanical sensitization of masseter muscles is one of the typical symptoms of TMD and there is a well-known overlap between painful TMD and headache [42].

In conclusion, the present study suggests that individuals who consume elevated amounts of MSG in their diet are more likely to suffer from headaches and have masseter muscle sensitivity, two symptoms associated with myofascial TMD. Although far from definitive, the present findings may indicate that there is a link between diet and susceptibility to the development of chronic orofacial pain conditions that include TMD and headache. If future studies can confirm a link, dietary modification could become an important part of treatment aimed at ameliorating symptoms associated with these chronic craniofacial pain conditions.