Xie Y F, Zhang S, Chiang C Y, Hu J W, Dostrovsky J O, Sessle B J
Department of Oral Physiology, Faculty of Dentistry, University of Toronto, 124 Edward Street, Toronto, Ont., Canada M5G 1G6.
Brain Behav Immun. 2007 Jul;21(5):634-41. doi: 10.1016/j.bbi.2006.07.008. Epub 2006 Oct 20.
Central sensitization is a crucial mechanism underlying the increased excitability of nociceptive pathways following peripheral tissue injury and inflammation. We have previously demonstrated that the small-fiber excitant and inflammatory irritant mustard oil (MO) applied to the tooth pulp produces glutamatergic- and purinergic-dependent central sensitization in brainstem nociceptive neurons of trigeminal subnucleus caudalis (Vc). Recent studies have implicated both astrocytes and microglia in spinal nociceptive mechanisms, showing, for example, that inhibition of spinal astroglial metabolism or spinal microglial p38MAPK activation can attenuate hyperalgesia in inflammatory pain models but have not tested effects of glial inhibitors on central sensitization in functionally identified spinal nociceptive neurons. The aim of the present study was to determine whether glial cells are involved in the MO-induced central sensitization in Vc nociceptive neurons, by examining the effects of intrathecally applied SB203580 (SB), an inhibitor of p38MAPK, and fluoroacetate (FA), an inhibitor of the astroglial metabolic enzyme aconitase. During continuous superfusion of phosphate-buffered saline over Vc, MO application to the pulp-induced central sensitization in Vc nociceptive neurons reflected in significant increases in cutaneous mechanoreceptive field (RF) size and responses to noxious mechanical stimuli and a decrease in mechanical activation threshold. The i.t. application of SB or FA markedly attenuated the MO-induced increases in pinch RF size and responses to noxious stimuli and the decrease in activation threshold. Neither SB nor FA application significantly affected the baseline (i.e., pre-MO application) RF and response properties. These results suggest that glial metabolic processes are important in the development of Vc central sensitization.
中枢敏化是外周组织损伤和炎症后伤害性感受通路兴奋性增加的关键机制。我们之前已经证明，将小纤维兴奋性和炎性刺激物芥子油（MO）应用于牙髓会在三叉神经尾侧亚核（Vc）的脑干伤害性神经元中产生谷氨酸能和嘌呤能依赖性中枢敏化。最近的研究表明星形胶质细胞和小胶质细胞都参与脊髓伤害性感受机制，例如，研究表明抑制脊髓星形胶质细胞代谢或脊髓小胶质细胞p38丝裂原活化蛋白激酶（p38MAPK）激活可减轻炎症性疼痛模型中的痛觉过敏，但尚未测试胶质细胞抑制剂对功能明确的脊髓伤害性神经元中枢敏化的影响。本研究的目的是通过研究鞘内注射p38MAPK抑制剂SB203580（SB）和星形胶质细胞代谢酶乌头酸酶抑制剂氟乙酸（FA）的作用，来确定胶质细胞是否参与MO诱导的Vc伤害性神经元中枢敏化。在对Vc持续灌流磷酸盐缓冲盐水期间，将MO应用于牙髓会诱导Vc伤害性神经元中枢敏化，表现为皮肤机械感受野（RF）大小显著增加、对有害机械刺激的反应增强以及机械激活阈值降低。鞘内注射SB或FA可显著减轻MO诱导的捏压RF大小增加和对有害刺激的反应以及激活阈值的降低。注射SB和FA均未显著影响基线（即应用MO前）的RF和反应特性。这些结果表明胶质细胞代谢过程在Vc中枢敏化的发生中起重要作用。
