NGF-induced mechanical sensitization of the masseter muscle is mediated through peripheral NMDA receptors.
Intramuscular injection of nerve growth factor (NGF) in healthy humans mimics some of the symptoms of myofascial temporomandibular disorders (M-TMD). We hypothesized that NGF induces a prolonged myofascial mechanical sensitization by increasing peripheral N-methyl-d-aspartate (NMDA) receptor expression, leading to an enhanced response of muscle nociceptors to endogenous glutamate. Behavioral experiments with an injection of NGF (25 μg/ml, 10 μl) into the masseter muscle reduced the mechanical withdrawal threshold for 1 day in male rats and 5 days in female rats. These results mirror the sex-related differences found in NGF-induced mechanical sensitization in humans. Intramuscular injection with the competitive NMDA receptor antagonist dl-2-amino-5-phosphonovaleric acid (APV, 0.020 g/ml, 10 μl) reversed the mechanical sensitization in male but not in female rats. NGF increased the number of NMDA receptor subtype 2B (NR2B)-expressing rat trigeminal masseter ganglion neurons in both sexes, which peaked at 3 days post injection. There was an association between the levels of NR2B expression and NGF-induced mechanical sensitization. The average soma size of NR2B-expressing neurons increased significantly. Increased expression of neuropeptides (CGRP and SP) was observed in NR2B-expressing masseter ganglion neurons in female but not in male rats. In healthy men and women, comparable basal expression levels of NR2B and SP were found in peripheral fibers from masseter muscle microbiopsies. This study suggests that NGF-induced sensitization of masseter nociceptors is mediated, in part, by enhanced peripheral NMDA receptor expression. Measurement of peripheral NMDA receptor expression may be useful as a biomarker for M-TMD pain.
Faculty of Pharmaceutical Sciences, The University of British Columbia, 2405 Wesbrook Mall, Vancouver, BC V6T 1Z3, Canada.
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Wong
Faculty of Pharmaceutical Sciences, The University of British Columbia, 2405 Wesbrook Mall, Vancouver, BC V6T 1Z3, Canada.
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Kang
Faculty of Pharmaceutical Sciences, The University of British Columbia, 2405 Wesbrook Mall, Vancouver, BC V6T 1Z3, Canada; College of Stomatology, Tianjin Medical University, Tianjin 300070, China.
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Dong
Orofacial Pain and Jaw Function, Department of Dental Medicine, Karolinska Institute, Huddinge, Sweden.
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Christidis
Orofacial Pain and Jaw Function, Department of Dental Medicine, Karolinska Institute, Huddinge, Sweden.
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Ernberg
Section of Clinical Oral Physiology, Department of Dentistry, Aarhus University, Aarhus, Denmark; Center for Sensory Motor Interaction, Aalborg University, Aalborg, Denmark.
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Svensson
Faculty of Pharmaceutical Sciences, The University of British Columbia, 2405 Wesbrook Mall, Vancouver, BC V6T 1Z3, Canada; Center for Sensory Motor Interaction, Aalborg University, Aalborg, Denmark. Electronic address: brcairns@mail.ubc.ca.
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Cairns
D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D000818:Animals; D048429:Cell Size; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005260:Female; D006801:Humans; D006930:Hyperalgesia / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology*; D008406:Masseter Muscle / Q000187:drug effects / Q000503:physiopathology*; D020932:Nerve Growth Factor; D009474:Neurons / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D009619:Nociceptors / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology; D010812:Physical Stimulation; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012727:Sex Characteristics; D013045:Species Specificity; D014110:Touch; D012668:Trigeminal Ganglion / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*
D018691:Excitatory Amino Acid Antagonists; C121001:NR2B NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D015763:2-Amino-5-phosphonovalerate; D020932:Nerve Growth Factor
masseter muscle; nerve growth factor; nociceptors; sensitization; temporomandibular disorders; trigeminal