Activation of Peripheral NMDA Receptors Contributes to Human Pain and Rat Afferent Discharges Evoked by Injection of Glutamate into the Masseter Muscle

1 Department of Anesthesia, Harvard Medical School/Children's Hospital, Boston Massachusetts, 02115 2 Department of Clinical Oral Physiology, Dental School, Århus University, DK-8000 Århus C, Denmark 3 Laboratory for Experimental Pain Research, Center for Sensory-Motor Interaction, Aalborg University, DK-9220, Denmark 4 Department of Anesthesia, Aalborg Hospital, DK-9000 Aalborg, Denmark 5 Faculty of Dentistry, University of Toronto, Toronto, Ontario, M5G 1G6 Canada Submitted 10 April 2003; accepted in final form 16 June 2003 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. Address for reprint requests and other correspondence: L. Arendt-Nielsen, Laboratory for Experimental Pain Research, Center for Sensory-Motor Interaction, Aalborg University, Fredrik Bajers Vej 7D3, DK-9220, Denmark (E-mail: LAN{at}smi.auc.dk ).