There is evidence that elevated tissue concentrations of glutamate may contribute to pain and sensitivity in certain musculoskeletal pain conditions. In the present study the food additive monosodium glutamate (MSG) was injected intravenously into rats to determine whether it could significantly elevate interstitial concentrations of glutamate in the masseter muscle and whether MSG administration could excite and/or sensitize slowly conducting masseter afferent fibers through Nmethyl-D-aspartate (NMDA) receptor activation. The interstitial concentration of glutamate after systemic injection of isotonic phosphate-buffered saline (control) or MSG (10 and 50 mg/kg) was measured with a glutamate selective biosensor. The pre-injection baseline interstitial concentration of glutamate in the rat masseter muscle was 24±11 μM. Peak interstitial concentration after injection of 50 mg/kg MSG was 63±18 μM and remained elevated above baseline for ~18 minutes In vivo single unit recording experiments were undertaken to assess the effect of MSG (50 mg/kg) on masseter afferent fibers. Injection of MSG evoked a brief discharge in one afferent fiber, and significantly decreased (~25%) the average afferent mechanical threshold (n=10) during the first 5 min after injection of MSG. Intravenous injection of ketamine (1 mg/kg), 5 minutes prior to MSG, prevented the MSG-induced decreases in the mechanical threshold of masseter afferent fibers. The present results indicate that a 2-3 fold elevation in interstitial glutamate levels in the masseter muscle is sufficient to excite and induce afferent mechanical sensitization through NMDA receptor activation. These findings suggest that modest elevations of interstitial glutamate concentration could alter musculoskeletal pain sensitivity in humans.
1. Hydromorphone-3-glucuronide, dihydromorphine, dihydroisomorphine, dihydromorphine-3-glucuronide and dihydroisomorphine-3-glucuronide were isolated from a cancer patient's urine and identified as metabolites of hydromorphone by comparison with synthetic standards using LC/MS/MS with gradient elution. 2. The relative urinary recovery of dihydroisomorphine-3-glucuronide was estimated to be 17-fold higher than previously reported. 3. Three new metabolites, including hydromorphone-3-sulphate, norhydromorphone and nordihydroisomorphine, were tentatively identified.
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