TY - JOUR
T1 - Interactions between laudanosine, GABA, and opioid subtype receptors
T2 - implication for laudanosine seizure activity
AU - Katz, Yeshayaku
AU - Weizman, Abraham
AU - Pick, Chaim G.
AU - Pasternak, Gavril W.
AU - Liu, Linda
AU - Fonia, Ora
AU - Gavish, Moshe
N1 - Funding Information:
This study was supported in part by Grants DA06241 and K02 DA000138 from the National Institute on Drug Abuse (to G.W.P.), Core Grant CA 8748 from the National Cancer Institute (to the M.S.K.C.C.), and a grant from the Fund for the Promotion of Research at the Technion (to M.G.). This paper is submitted in partial fulfillment of the requirements for the D,Sc. degree of Y.K. at the Technion-Israel Institute of Technology. We thank Miss Ruth Singer for typing and editing the manuscript.
PY - 1994/5/23
Y1 - 1994/5/23
N2 - 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.
AB - 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.
KW - Analgesia
KW - Laudanosine
KW - Opioid receptor
UR - http://www.scopus.com/inward/record.url?scp=0028217868&partnerID=8YFLogxK
U2 - 10.1016/0006-8993(94)90084-1
DO - 10.1016/0006-8993(94)90084-1
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AN - SCOPUS:0028217868
SN - 0006-8993
VL - 646
SP - 235
EP - 241
JO - Brain Research
JF - Brain Research
IS - 2
ER -