Department of Anesthesiology and Pain Medicine, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu City, Gifu 501-1194, Japan.
Department of Anesthesiology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan.
Eur J Pharmacol. 2014 Jul 5;734:132-6. doi: 10.1016/j.ejphar.2014.03.048. Epub 2014 Apr 12.
Local anesthetics, which are widely known to be neuronal voltage-gated Na(+) channel blockers, also affect a variety of other ion channels, N-methyl-d-asparate (NMDA) receptors and α-amino-3-hydroxy-5-methyl-4-izoxazolepropionic acid (AMPA) receptors. Glutamate, which is released from presynaptic fibers, activates extracellular signal-regulated kinase (ERK) through NMDA and AMPA receptors in spinal dorsal horn neurons. ERK plays a key role in central sensitization, which contributes to the chronicity of pain. We investigated the effects of four representative local anesthetics, lidocaine, tetracaine, levobupivacaine, and ropivacaine on ERK phosphorylation induced by capsaicin, which releases glutamate from presynaptic neurons, NMDA, AMPA, or ionomycin, a calcium ionophore, in dorsal neurons. We observed capsaicin-induced phosphorylation of ERK, which was suppressed by lidocaine, tetracaine, or ropivacaine, but not by levobupivacaine. NMDA-induced phosphorylation of ERK was suppressed by lidocaine, tetracaine, or levobupivacaine, but not by ropivacaine. AMPA-induced phosphorylation of ERK was suppressed by lidocaine or tetracaine, but not by levobupivacaine or ropivacaine. Finally, ionomycin-induced ERK phosphorylation was suppressed by lidocaine, tetracaine, or ropivacaine, but not by levobupivacaine. Our results suggest that local anesthetics contribute to the prevention of the incidence of persistent postsurgical pain with varying intensities and through different mechanisms of action.
局部麻醉剂被广泛认为是神经元电压门控 Na(+)通道阻滞剂，也会影响多种其他离子通道、N-甲基-D-天冬氨酸 (NMDA) 受体和α-氨基-3-羟基-5-甲基-4-异恶唑丙酸 (AMPA) 受体。谷氨酸从前突触纤维释放出来，通过脊髓背角神经元中的 NMDA 和 AMPA 受体激活细胞外信号调节激酶 (ERK)。ERK 在中枢敏化中起关键作用，这有助于疼痛的慢性化。我们研究了四种代表性的局部麻醉剂，利多卡因、丁卡因、左旋布比卡因和罗哌卡因对辣椒素诱导的 ERK 磷酸化的影响，辣椒素从前突触神经元释放谷氨酸，NMDA、AMPA 或离子霉素，一种钙离子载体，在背角神经元中。我们观察到辣椒素诱导的 ERK 磷酸化，被利多卡因、丁卡因或罗哌卡因抑制，但被左旋布比卡因不抑制。NMDA 诱导的 ERK 磷酸化被利多卡因、丁卡因或左旋布比卡因抑制，但被罗哌卡因不抑制。AMPA 诱导的 ERK 磷酸化被利多卡因或丁卡因抑制，但被左旋布比卡因或罗哌卡因不抑制。最后，离子霉素诱导的 ERK 磷酸化被利多卡因、丁卡因或罗哌卡因抑制，但被左旋布比卡因不抑制。我们的结果表明，局部麻醉剂通过不同的作用机制对预防持续术后疼痛的发生有不同的作用强度。
