Authors' reply to the comment by Fernstrom

We appreciate Dr. Fernstrom’s (Fernstrom, 2017) interest in our original research paper entitled ‘Increased pain and muscle glutamate concentration after single ingestion of monosodium glutamate by myofascial temporomandibular disorders patients’ (Shimada et al., 2016). Dr. Fernstrom raises a concern in his comment that it is not possible, based on the experimental paradigm used in the study, to extrapolate our findings to “normal” monosodium glutamate (MSG) consumption. He concludes that it would not be possible to get the same exposure to glutamate in the “Western” diet that was achieved by oral ingestion of a liquid containing 150 mg/kg of MSG. While we do agree that our study was purely experimental and used a large dose of dissolved MSG as a simple means of delivering an oral glutamate dose, we are not convinced that exposure to large amounts of glutamate cannot occur in a normal diet. Glutamaterich foods include soups and packaged sauces, which are certainly consumed as liquids (Freeman, 2006). Further, a single fast food meal of a hamburger and milk shake has been reported to elevate serum glutamate concentrations for about 6 h, with peak concentrations reaching ~250% of baseline concentrations by 2 h after consumption (Stegink et al., 1983). Therefore, we think that there are circumstances even in the ‘Western’ diet where consumption of glutamate rich foods could lead to substantially elevated tissue glutamate concentrations. Should this occur, then craniofacial pain sensitivity could be increased, at least transiently (BaadHansen et al., 2010; Shimada et al., 2016). Although Dr. Fernstrom suggests a time to peak of around 60 min after oral MSG ingestion based on his own work, other studies that used continuous plasma sampling after ingestion of an MSG dose similar to the one used in our study reported that peak plasma glutamate concentrations occurred between 20 and 30 min post ingestion of MSG (Graham et al., 2000). In addition to metabolism, it has been shown that excess glutamate in the plasma is cleared by skeletal muscle and it has been suggested that skeletal muscle is a major sink for glutamate (Graham et al., 2000). This is clearly demonstrated in our study results, where interstitial concentrations of glutamate in the masseter muscle were found to be significantly elevated between 20 and 40 min after MSG ingestion. We believe this is an important point and based on direct measurements with the use of microdialysis. Moreover, this elevation of interstitial glutamate concentration coincides with a reported increase in muscle sensitivity that occurs 30 min after ingestion of 150 mg/kg of MSG (Baad-Hansen et al., 2010), and substantially exceeds the concentration required to mechanically sensitize muscle nociceptors (Cairns et al. 2007). If it is true that skeletal muscle plays an important role in the clearance of glutamate from the plasma, then it may be too early to assume that only a substantial elevation of plasma concentration of glutamate will lead to an increase in the concentration of free glutamate in the muscle. Nevertheless, we do not exclude that other mechanisms that may include localized glutamate release or altered glutamate signalling may explain the apparent association between elevated free glutamate concentrations in masticatory muscle and myofascial TMD. Finally, Dr. Fernstrom indicated that he has no conflict of interest in his comment; however, we believe it may be appropriate to note that he has served for many years as a consultant for the Ajinomoto Company Inc, a manufacturer of MSG (Fernstrom and Fernstrom, 2007; Fernstrom, 2016).