Yanagidate Fumi, Strichartz Gary R
Pain Research Center, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115-6110, USA.
Anesthesiology. 2006 Apr;104(4):805-14. doi: 10.1097/00000542-200604000-00027.
Central terminals of primary nociceptors release neurotransmitters glutamate and substance P, which bind to ionotropic or metabotropic receptors on spinal neurons to induce cellular responses. Extracellular signal-regulated kinases are activated by these receptors and are important modulators of pain at the dorsal horn. The authors investigated these pathways as potential targets for antinociceptive actions of local anesthetics.
The effects of bupivacaine on the activation of extracellular receptor-activated kinase (phosphorylation to pERK) in rat spinal cord slices, induced by presynaptic release (capsaicin), by presynaptic or postsynaptic ionotropic or metabotropic receptor activation, or by activation of intracellular protein kinase C or protein kinase A and also by a receptor-independent Ca2+ ionophore, were quantitated by immunohistochemistry, counting pERK-positive neurons in the superficial dorsal horn.
Capsaicin (3 microm, 10 min)-stimulated pERK was reduced by bupivacaine (IC50 approximately 2 mm, approximately 0.05%), which similarly suppressed pERK induced by the ionotropic glutamate receptors for N-methyl-D-aspartate and (S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid but not that induced by the metabotropic receptors for glutamate, bradykinin, or substance P. Extracellular receptor-activated kinase activation by the Ca2+ ionophore ionomycin was also sensitive to bupivacaine, but direct activation by protein kinase A or protein kinase C was not.
Bupivacaine inhibits pERK activation resulting from different modes of Ca2+ influx through the plasma membrane. This represents a postsynaptic mechanism of analgesia that occurs in parallel with impulse inhibition during neuraxial blockade.
初级伤害感受器的中枢终末释放神经递质谷氨酸和P物质，它们与脊髓神经元上的离子型或代谢型受体结合以诱导细胞反应。细胞外信号调节激酶被这些受体激活，是背角疼痛的重要调节因子。作者研究了这些途径作为局部麻醉药抗伤害感受作用的潜在靶点。
通过免疫组织化学，计数浅表背角中pERK阳性神经元，定量布比卡因对大鼠脊髓切片中由突触前释放（辣椒素）、突触前或突触后离子型或代谢型受体激活、或细胞内蛋白激酶C或蛋白激酶A激活以及由受体非依赖性Ca2+离子载体诱导的细胞外受体激活激酶（磷酸化为pERK）的激活的影响。
辣椒素（3 μmol，10分钟）刺激的pERK被布比卡因降低（IC50约为2 mmol，约0.05%），布比卡因同样抑制由N-甲基-D-天冬氨酸和（S）-α-氨基-3-羟基-5-甲基-4-异恶唑丙酸的离子型谷氨酸受体诱导的pERK，但不抑制由谷氨酸、缓激肽或P物质的代谢型受体诱导的pERK。Ca2+离子载体离子霉素激活的细胞外受体激活激酶对布比卡因也敏感，但蛋白激酶A或蛋白激酶C的直接激活则不敏感。
布比卡因抑制因通过质膜的不同Ca2+内流模式导致的pERK激活。这代表了一种突触后镇痛机制，在神经轴阻滞期间与冲动抑制同时发生。
