Katz Y, Weizman A, Pick C G, Pasternak G W, Liu L, Fonia O, Gavish M
Department of Pharmacology, Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa.
Brain Res. 1994 May 23;646(2):235-41. doi: 10.1016/0006-8993(94)90084-1.
We examined the interactions of D,L-laudanosine, a potentially epileptogenic metabolite of the neuromuscular relaxant atracurium besylate, with gamma-aminobutyric acid (GABA) and opioid binding sites, all of which have been implicated in seizure activity. Laudanosine was almost ineffective at [3H]muscimol binding to high-affinity GABA receptors (IC50 = 100 microM). However, laudanosine displayed an inhibitory effect at the low-affinity GABA receptors labeled by [3H]bicuculline methochloride, with an IC50 value of 10 microM. At the opioid receptor subtype, laudanosine lowered radiolabeled opioid binding at the mu 1, mu 2, delta, kappa 1, and kappa 3 receptors with Ki values of 2.7, 13, 5.5, 21, and 24 microM, respectively, concentrations seen clinically in blood and approaching those measured in cerebrospinal fluid. Saturation studies of mu 1, mu 2, delta, and kappa 3 sites in the presence of laudanosine revealed competitive interactions, with increases in the apparent Kd values but without significant changes in the maximal numbers of binding sites. In addition, we investigated whether the in vitro laudanosine-opioid receptor interaction would also be expressed by analgesic physiologic effects. We found that laudanosine elicited a dose-dependent analgesia in mouse tail-flick assay that was attenuated by coadministration of beta-funaltrexamine (mu 1- and mu 2-selective antagonist) and of naloxonazine (mu 1 antagonist), but not by nor-binaltorphimine (kappa 1-selective antagonist) or naltrindole (delta-selective antagonist), indicating a mu 1 mechanism for analgesia-mediated property of laudanosine. There is evidence suggesting mu 2 activity as well, but this is due to the ability of laudanosine to elicit analgesia when given intrathecally. We also observed cross-tolerance between laudanosine and morphine, as well as a partial effect of laudanosine on gastrointestinal transit. These results suggest an interaction between laudanosine and the low-affinity GABA receptor, as well as opioid mu 1 and mu 2 receptors.
我们研究了神经肌肉松弛剂苯磺阿曲库铵的一种潜在致癫痫代谢产物D，L-劳丹诺辛与γ-氨基丁酸（GABA）和阿片类结合位点的相互作用，所有这些都与癫痫活动有关。劳丹诺辛对[³H]蝇蕈醇结合高亲和力GABA受体几乎无效（IC₅₀ = 100微摩尔）。然而，劳丹诺辛对[³H]荷包牡丹碱甲氯化物标记的低亲和力GABA受体显示出抑制作用，IC₅₀值为10微摩尔。在阿片受体亚型方面，劳丹诺辛降低了放射性标记的阿片类物质在μ₁、μ₂、δ、κ₁和κ₃受体上的结合，其Ki值分别为2.7、13、5.5、21和24微摩尔，这些浓度在临床上可见于血液中，且接近在脑脊液中测得的浓度。在存在劳丹诺辛的情况下对μ₁、μ₂、δ和κ₃位点进行的饱和研究显示出竞争性相互作用，表观Kd值增加，但结合位点的最大数量无显著变化。此外，我们研究了体外劳丹诺辛 - 阿片受体相互作用是否也会通过镇痛生理效应表现出来。我们发现劳丹诺辛在小鼠甩尾试验中引起剂量依赖性镇痛，这种镇痛作用在同时给予β-芬太尼（μ₁和μ₂选择性拮抗剂）和纳洛酮嗪（μ₁拮抗剂）时减弱，但在给予去甲丙氧芬（κ₁选择性拮抗剂）或纳曲吲哚（δ选择性拮抗剂）时未减弱，这表明劳丹诺辛的镇痛介导特性存在μ₁机制。也有证据表明存在μ₂活性，但这是由于劳丹诺辛鞘内给药时引发镇痛的能力。我们还观察到劳丹诺辛和吗啡之间存在交叉耐受性，以及劳丹诺辛对胃肠转运有部分作用。这些结果表明劳丹诺辛与低亲和力GABA受体以及阿片类μ₁和μ₂受体之间存在相互作用。
