Aley K O, Martin A, McMahon T, Mok J, Levine J D, Messing R O
Departments of Medicine and Oral Surgery, National Institutes of Health Pain Center at the University of California, San Francisco, San Francisco, California 94143, USA.
J Neurosci. 2001 Sep 1;21(17):6933-9. doi: 10.1523/JNEUROSCI.21-17-06933.2001.
Inflammatory pain, characterized by a decrease in mechanical nociceptive threshold (hyperalgesia), arises through actions of inflammatory mediators, many of which sensitize primary afferent nociceptors via G-protein-coupled receptors. Two signaling pathways, one involving protein kinase A (PKA) and one involving the epsilon isozyme of protein kinase C (PKCepsilon), have been implicated in primary afferent nociceptor sensitization. Here we describe a third, independent pathway that involves activation of extracellular signal-regulated kinases (ERKs) 1 and 2. Epinephrine, which induces hyperalgesia by direct action at beta(2)-adrenergic receptors on primary afferent nociceptors, stimulated phosphorylation of ERK1/2 in cultured rat dorsal root ganglion cells. This was inhibited by a beta(2)-adrenergic receptor blocker and by an inhibitor of mitogen and extracellular signal-regulated kinase kinase (MEK), which phosphorylates and activates ERK1/2. Inhibitors of G(i/o)-proteins, Ras farnesyltransferases, and MEK decreased epinephrine-induced hyper-algesia. In a similar manner, phosphorylation of ERK1/2 was also decreased by these inhibitors. Local injection of dominant active MEK produced hyperalgesia that was unaffected by PKA or PKCepsilon inhibitors. Conversely, hyperalgesia produced by agents that activate PKA or PKCepsilon was unaffected by MEK inhibitors. We conclude that a Ras-MEK-ERK1/2 cascade acts independent of PKA or PKCepsilon as a novel signaling pathway for the production of inflammatory pain. This pathway may present a target for a new class of analgesic agents.
炎症性疼痛以机械性伤害性感受阈值降低（痛觉过敏）为特征，是由炎症介质的作用引起的，其中许多炎症介质通过G蛋白偶联受体使初级传入伤害感受器敏感化。有两条信号通路与初级传入伤害感受器敏感化有关，一条涉及蛋白激酶A（PKA），另一条涉及蛋白激酶C的ε同工酶（PKCε）。在此，我们描述了第三条独立的信号通路，该通路涉及细胞外信号调节激酶（ERK）1和2的激活。肾上腺素通过直接作用于初级传入伤害感受器上的β2 - 肾上腺素能受体诱导痛觉过敏，它能刺激培养的大鼠背根神经节细胞中ERK1/2的磷酸化。这一过程被β2 - 肾上腺素能受体阻滞剂以及有丝分裂原和细胞外信号调节激酶激酶（MEK，其可磷酸化并激活ERK1/2）的抑制剂所抑制。G(i/o) - 蛋白抑制剂、Ras法尼基转移酶抑制剂和MEK抑制剂均可减轻肾上腺素诱导的痛觉过敏。同样，这些抑制剂也能降低ERK1/2的磷酸化水平。局部注射显性活性MEK所产生的痛觉过敏不受PKA或PKCε抑制剂的影响。相反，由激活PKA或PKCε的药物所产生的痛觉过敏不受MEK抑制剂的影响。我们得出结论，Ras - MEK - ERK1/2级联反应独立于PKA或PKCε发挥作用，是产生炎症性疼痛的一条新的信号通路。该通路可能成为一类新型镇痛药的作用靶点。
