Hirota K, Okawa H, Appadu B L, Grandy D K, Lambert D G
University Department of Anaesthesia, Leicester Royal Infirmary, UK.
Br J Anaesth. 2000 Nov;85(5):740-6. doi: 10.1093/bja/85.5.740.
Local anaesthetics potentiate epidural or intrathecal opioid analgesia via a poorly defined mechanism. In this study, we have examined the interaction of local anaesthetics (lidocaine, bupivacaine and its optical isomers, tetracaine, procaine and prilocaine) with recombinant mu-, kappa-, and delta-opioid receptors expressed in Chinese hamster ovary cells (CHO-mu, kappa, and delta, respectively). Lidocaine produced a concentration-dependent displacement of radiolabelled opioid antagonist [3H]diprenorphine ([3H]DPN) binding with the following rank order of inhibitor constant (Ki): kappa (210 microM) > mu (552 microM) > delta (1810 microM). Procaine, prilocaine, tetracaine and bupivacaine also displaced [3H]DPN binding in CHO-mu with Ki values of 244, 204, 43 and 161 microM respectively. Lidocaine produced a concentration-dependent and naloxone-insensitive inhibition of cAMP formation in all cell lines including untransfected cells. Concentration producing 50% inhibition of maximum was mu, 1.32 mM; kappa, 2.41 mM; delta, 1.27 mM; untransfected, 2.78 mM. When lidocaine (300 microM) was co-incubated with spiradoline (kappa-selective) and [D-Ala2, MePhe4, Gly(ol)5] enkephalin (DAMGO mu-selective) in CHO-kappa and mu cells we did not observe an additive interaction for cAMP formation. In contrast, there was an apparent inhibitory action of the combination at the kappa receptor. This study suggests that clinical concentrations of local anaesthetics interact with mu and kappa but not delta opioid receptors. As there was no synergism between local anaesthetics and opioids we suggest that the interaction of these agents in the clinical setting does not occur at the cellular level.
局部麻醉药通过一种尚不明确的机制增强硬膜外或鞘内阿片类药物的镇痛作用。在本研究中，我们检测了局部麻醉药（利多卡因、布比卡因及其旋光异构体、丁卡因、普鲁卡因和丙胺卡因）与在中国仓鼠卵巢细胞（分别为CHO-mu、kappa和delta）中表达的重组μ-、κ-和δ-阿片受体的相互作用。利多卡因产生了放射性标记的阿片拮抗剂[3H]二丙诺啡（[3H]DPN）结合的浓度依赖性置换，其抑制常数（Ki）的排序如下：κ（210μM）>μ（552μM）>δ（1810μM）。普鲁卡因、丙胺卡因、丁卡因和布比卡因也能置换CHO-mu中的[3H]DPN结合，其Ki值分别为244、204、43和161μM。利多卡因在包括未转染细胞在内的所有细胞系中产生了浓度依赖性且对纳洛酮不敏感的cAMP形成抑制作用。产生最大抑制50%的浓度分别为：μ，1.32 mM；κ，2.41 mM；δ，1. .27 mM；未转染细胞，2.78 mM。当利多卡因（300μM）与螺哌多林（κ选择性）和[D-Ala2，MePhe4，Gly(ol)5]脑啡肽（DAMGOμ选择性）在CHO-κ和μ细胞中共孵育时，我们未观察到cAMP形成的相加相互作用。相反，该组合在κ受体处有明显的抑制作用。本研究表明，临床浓度的局部麻醉药与μ和κ阿片受体相互作用，但不与δ阿片受体相互作用。由于局部麻醉药和阿片类药物之间没有协同作用，我们认为这些药物在临床环境中的相互作用并非发生在细胞水平。
