Ma W, St-Jacques B, Rudakou U, Kim Y N
Douglas Mental Health University Institute, McGill University, Montréal, QC, Canada.
Department of Psychiatry, McGill University, Montréal, QC, Canada.
Eur J Pain. 2017 Apr;21(4):575-593. doi: 10.1002/ejp.959. Epub 2016 Oct 14.
Persistent peripheral sensitization contributes to chronic pain. Plasticity of nociceptive dorsal root ganglion (DRG) neurons (nociceptors) induced by pro-inflammatory mediators contributes to sensitization. Prostaglandin E2 (PGE2) enriched in injured tissues is known not only directly to sensitize DRG neurons, but also to potentiate sensitizing effects of other pain mediators such as capsaicin and its receptor transient receptor potential vanilloid-1 (TRPV1). It remains unknown whether PGE2 potentiates TRPV1 activity by stimulating its synthesis, cell surface and axonal trafficking in DRG neurons.
Combined biochemical, morphological, pharmacological and behavioral approaches have been used to address this issue in both in vitro and in vivo models.
PGE2 increased TRPV1 externalization in cultured rat DRG neurons in a time- and concentration-dependent manner, an event blocked by an inhibitor of protein synthesis or anterograde export. EP1 and EP4, but not EP2 and EP3, mediated this event. EP1 agonist-induced TRPV1 externalization was suppressed by inhibitors of CaMKII, PLC, PKC and PKCε, while EP4 agonist-induced TRPV1 externalization by inhibitors of cAMP/PKA and ERK/MAPK. Pre-exposure to PGE2 potentiated release of calcitonin gene-related peptide from cultured DRG neurons evoked by subsequent capsaicin stimulation. This event was blocked by an inhibitor of protein synthesis or export, suggesting that PGE2-induced TRPV1 synthesis and externalization is coupled to enhanced TRPV1 activity. Pre-exposure to PGE2 not only prolonged tactile allodynia evoked by subsequent capsaicin challenge, but also increased TRPV1 levels in L4-6 DRG, sciatic nerves and plantar skin.
Our data indicate that facilitating TRPV1 synthesis, cell surface and axonal trafficking is a novel mechanism underlying PGE2 potentiation of TRPV1 activity.
持续性外周敏化作用会导致慢性疼痛。促炎介质诱导的伤害性背根神经节（DRG）神经元（伤害感受器）可塑性会导致敏化。富集于受损组织中的前列腺素E2（PGE2）不仅已知可直接使DRG神经元敏化，还能增强其他疼痛介质（如辣椒素及其受体瞬时受体电位香草酸受体1（TRPV1））的敏化作用。PGE2是否通过刺激其在DRG神经元中的合成、细胞表面和轴突运输来增强TRPV1活性尚不清楚。
已采用生物化学、形态学、药理学和行为学相结合的方法在体外和体内模型中解决这一问题。
PGE2以时间和浓度依赖性方式增加培养的大鼠DRG神经元中TRPV1的外向化，这一事件被蛋白质合成或顺行输出抑制剂所阻断。EP1和EP4介导了这一事件，而EP2和EP3则未介导。CaMKII抑制剂、PLC抑制剂、PKC抑制剂和PKCε抑制剂可抑制EP1激动剂诱导的TRPV1外向化，而cAMP/PKA抑制剂和ERK/MAPK抑制剂可抑制EP4激动剂诱导的TRPV1外向化。预先暴露于PGE2可增强随后辣椒素刺激诱发的培养DRG神经元中降钙素基因相关肽的释放。这一事件被蛋白质合成或输出抑制剂所阻断，表明PGE2诱导的TRPV1合成和外向化与增强的TRPV1活性相关。预先暴露于PGE2不仅延长了随后辣椒素激发诱发的触觉异常性疼痛，还增加了L4-6 DRG、坐骨神经和足底皮肤中TRPV1的水平。
我们的数据表明，促进TRPV1合成、细胞表面和轴突运输是PGE2增强TRPV1活性的一种新机制。
