Interactions between laudanosine, GABA, and opioid subtype receptors: Implication for laudanosine seizure activity Journal Article
| Authors: | Katz, Y.; Weizman, A.; Pick, C. G.; Pasternak, G. W.; Liu, L.; Fonia, O.; Gavish, M. |
| Article Title: | Interactions between laudanosine, GABA, and opioid subtype receptors: Implication for laudanosine seizure activity |
| Abstract: | We examined the interactions of d,l-laudanosine, a potentially epileptogenic metabolite of the neuromuscular relaxant atracurium besylate, with γ-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 μM). However, laudanosine displayed an inhibitory effect at the low-affinity GABA receptors labeled by [3H]bicuculline methochloride, with an IC50 value of 10 μM. At the opioid receptor subtype, laudanosine lowered radiolabeled opioid binding at the μ1, μ2, δ, κ1, and κ3 receptors with Ki values of 2.7, 13, 5.5, 21, and 24 μM, respectively, concentrations seen clinically in blood and approaching those measured in cerebrospinal fluid. Saturation studies of μ1, μ2, δ, and κ3 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 β-funaltrexamine (μ1- and μ2-sselective antagonist) and of naloxonazine (μ1 antagonist), but not by nor-binaltophimine (κ1-selective antagonist) or naltrindole (δ-selective antagonist), indicating a μ1 mechanism for analgesia-mediated properly of laudanosine. There is evidence suggesting μ2 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 μ1 and μ2 receptors. © 1994. |
| Keywords: | controlled study; nonhuman; mouse; animal; mice; animal tissue; pain; animal experiment; mice, inbred strains; kinetics; brain; spinal cord; gamma-aminobutyric acid; cell membrane; rats; seizure; rats, sprague-dawley; morphine; analgesia; receptors, opioid, mu; receptor binding; tail flick test; injections, spinal; opiate receptor; beta funaltrexamine; enkephalin[2,5 dextro penicillamine]; naltrindole; opioid receptor; seizures; cerebral ventricles; receptor subtype; binding, competitive; injections, intraventricular; isoquinolines; receptors, opioid, delta; 3,4 dichloro n methyl n [2 (1 pyrrolidinyl)cyclohexyl]benzeneacetamide methanesulfonate; naloxone benzoylhydrazone; naloxonazine; enkephalin[2 dextro alanine 4 methylphenylalanine 5 glycine]; bicuculline; subcutaneous drug administration; receptors, opioid; intracerebroventricular drug administration; norbinaltorphimine; male; priority journal; article; receptors, opioid, kappa; support, non-u.s. gov't; support, u.s. gov't, p.h.s.; 4 aminobutyric acid receptor; substance withdrawal syndrome; enkephalin[2 dextro alanine 5 dextro leucine]; laudanosine; muscimol; gaba antagonists; receptors, gaba |
| Journal Title: | Brain Research |
| Volume: | 646 |
| Issue: | 2 |
| ISSN: | 0006-8993 |
| Publisher: | Elsevier Science, Inc. |
| Date Published: | 1994-05-23 |
| Start Page: | 235 |
| End Page: | 241 |
| Language: | English |
| DOI: | 10.1016/0006-8993(94)90084-1 |
| PROVIDER: | scopus |
| PUBMED: | 8069669 |
| DOI/URL: | |
| Notes: | Export Date: 14 January 2019 -- Article -- Source: Scopus |
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