INTERACTIONS BETWEEN LAUDANOSINE, GABA, AND OPIOID SUBTYPE RECEPTORS - IMPLICATION FOR LAUDANOSINE SEIZURE ACTIVITY

We examined the interactions of D,L-laudanosine, a potentially epilept ogenic metabolite of the neuromuscular relaxant atracurium besylate, w ith gamma-aminobutyric acid (GABA) and opioid binding sites, all of wh ich have been implicated in seizure activity. Laudanosine was almost i neffective at [H-3]muscimol binding to high-affinity GABA receptors (I C50 = 100 mu M). However, laudanosine displayed an inhibitory effect a t the low-affinity GABA receptors labeled by [H-3]bicuculline methochl oride, with an IC50 value of 10 mu M. At the opioid receptor subtype, laudanosine lowered radiolabeled opioid binding at the mu(1), mu(2), d elta, k(1), and K-3 receptors with K-i values of 2.7, 13, 5.5, 21, and 24 mu M, respectively, concentrations seen clinically in blood and ap proaching those measured in cerebrospinal fluid. Saturation studies of mu(1), mu(2), delta, and k(3) sites in the presence of laudanosine re vealed competitive interactions, with increases in the apparent K-d va lues 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 physi ologic effects. We found that laudanosine elicited a dose-dependent an algesia in mouse tail-flick assay that was attenuated by coadministrat ion of beta-funaltrexamine (mu(1)- and mu(2)-selective antagonist) and of naloxonazine (mu(1) antagonist), but not by nor-binaltorphimine (K -1-selective antagonist) or naltrindole (delta-selective antagonist), indicating a mu(1) mechanism for analgesia-mediated property of laudan osine. There is evidence suggesting mu(2), activity as well, but this is due to the ability of laudanosine to elicit analgesia when given in trathecally. We also observed cross-tolerance between laudanosine and morphine, as well as a partial effect of laudanosine on gastrointestin al transit. These results suggest an interaction between laudanosine a nd the low-affinity GABA receptor, as well as opioid mu(1) and mu(2), receptors.