Wong H, Kang I, Dong X-D, Christidis N, Ernberg M, Svensson P, Cairns B E
Faculty of Pharmaceutical Sciences, The University of British Columbia, 2405 Wesbrook Mall, Vancouver, BC V6T 1Z3, Canada.
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.
Neuroscience. 2014 Jun 6;269:232-44. doi: 10.1016/j.neuroscience.2014.03.054. Epub 2014 Apr 4.
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.
在健康人体中肌肉注射神经生长因子（NGF）会模拟肌筋膜性颞下颌关节紊乱症（M-TMD）的一些症状。我们推测，NGF通过增加外周N-甲基-D-天冬氨酸（NMDA）受体表达诱导长时间的肌筋膜机械性致敏，导致肌肉伤害感受器对内源性谷氨酸的反应增强。向雄性大鼠咬肌注射NGF（25μg/ml，10μl）的行为实验使机械撤针阈值降低1天，而在雌性大鼠中降低5天。这些结果反映了在人类中发现的NGF诱导的机械性致敏的性别差异。肌肉注射竞争性NMDA受体拮抗剂dl-2-氨基-5-磷酸戊酸（APV，0.020g/ml，10μl）可逆转雄性大鼠而非雌性大鼠的机械性致敏。NGF增加了两性中表达NMDA受体2B亚型（NR2B）的大鼠三叉咬肌神经节神经元数量，在注射后3天达到峰值。NR2B表达水平与NGF诱导的机械性致敏之间存在关联。表达NR2B的神经元的平均胞体大小显著增加。在雌性而非雄性大鼠的表达NR2B的咬肌神经节神经元中观察到神经肽（降钙素基因相关肽和P物质）表达增加。在健康男性和女性中，咬肌微生物活检的外周纤维中发现NR2B和P物质的基础表达水平相当。这项研究表明，NGF诱导的咬肌伤害感受器致敏部分是由外周NMDA受体表达增强介导的。外周NMDA受体表达的测量可能作为M-TMD疼痛的生物标志物有用。
