Mizushima Toshiyuki, Obata Koichi, Katsura Hirokazu, Sakurai Jun, Kobayashi Kimiko, Yamanaka Hiroki, Dai Yi, Fukuoka Tetsuo, Mashimo Takashi, Noguchi Koichi
Department of Anatomy and Neuroscience, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan.
J Pharmacol Exp Ther. 2007 Apr;321(1):28-34. doi: 10.1124/jpet.106.116749. Epub 2007 Jan 19.
Alterations in the intracellular signal transduction pathway in primary afferents may contribute to pain hypersensitivity. Recently, we have reported that the phosphorylation of extracellular signal-regulated protein kinase 1/2 (ERK1/2) and p38 mitogen-activated protein kinase (MAPK) occurs in primary afferent neurons in response to noxious stimulation of the peripheral tissue, i.e., activity-dependent activation of ERK1/2 and p38 MAPK in dorsal root ganglion (DRG) neurons. In the present study, we investigated the phosphorylation of ERK5, also known as big MAPK1, in the DRG by noxious stimulation using immunohistochemistry. Capsaicin injection induced phosphorylated ERK5 (p-ERK5) in small-to-medium diameter sensory neurons with a peak at 2 min after capsaicin injection. Furthermore, we examined the p-ERK5 labeling in the DRG after noxious heat and cold stimuli and found a stimulus intensity-dependent increase in the number of activated neurons. Most of these p-ERK5-immunoreactive neurons were small- and medium-sized neurons, which coexpressed transient receptor potential (TRP) ion channel TRPV1 and TRPA1 after noxious heat and cold stimuli, respectively. In contrast, there was no change in ERK5 phosphorylation in the spinal dorsal horn. The i.t. administration of ERK5 antisense oligodeoxynucleotide reversed heat hyperalgesia, but not mechanical allodynia, produced by capsaicin injection. Taken together, these findings suggest that the in vivo activation of the ERK5 signaling pathway in sensory neurons by noxious stimulation may be, at least in part, correlated with functional activity and, further, involved in the development of pain hypersensitivity.
初级传入神经元细胞内信号转导通路的改变可能导致疼痛超敏反应。最近，我们报道细胞外信号调节蛋白激酶1/2（ERK1/2）和p38丝裂原活化蛋白激酶（MAPK）的磷酸化发生在初级传入神经元中，以响应外周组织的伤害性刺激，即背根神经节（DRG）神经元中ERK1/2和p38 MAPK的活性依赖性激活。在本研究中，我们使用免疫组织化学方法，通过伤害性刺激研究了DRG中ERK5（也称为大MAPK1）的磷酸化情况。辣椒素注射在中小直径感觉神经元中诱导磷酸化ERK5（p-ERK5），在辣椒素注射后2分钟达到峰值。此外，我们检查了伤害性热刺激和冷刺激后DRG中的p-ERK5标记，发现激活神经元的数量呈刺激强度依赖性增加。这些p-ERK5免疫反应性神经元大多为中小尺寸神经元，在伤害性热刺激和冷刺激后分别共表达瞬时受体电位（TRP）离子通道TRPV1和TRPA1。相比之下，脊髓背角中ERK5的磷酸化没有变化。鞘内注射ERK5反义寡脱氧核苷酸可逆转辣椒素注射引起的热痛觉过敏，但不能逆转机械性异常性疼痛。综上所述，这些发现表明伤害性刺激在体内激活感觉神经元中的ERK5信号通路可能至少部分与功能活动相关，并且进一步参与疼痛超敏反应的发生。
