norbinaltorphimine and Seizures

The present study used pharmacological and gene ablation techniques to examine the involvement of kappa opioid receptors (KOPr) in modulating the convulsant effects of two mechanistically different drugs: cocaine and pentylenetetrazol (PTZ; GABA-A receptor antagonist) in mice. Systemic administration of the selective KOPr-1 agonist, U69593 (0.16-0.6mg/kg; s.c.), failed to modify cocaine-evoked convulsions or cocaine kindling. Similarly, no alteration in responsiveness to cocaine was observed in wild-type mice that received the selective KOPr-1 antagonist, nor-binaltorphimine (nor-BNI; 5mg/kg) or in mice lacking the gene encoding KOPr-1. In contrast to cocaine, U69593 attenuated the seizures induced by acute or repeated PTZ administration. Nor-BNI decreased the threshold for PTZ-evoked seizures and increased seizure incidence during the initial induction of kindling relative to controls. Decreased thresholds for PTZ-induced seizures were also observed in KOPr-1 knock out mice. Together, these data demonstrate an involvement of endogenous KOPr systems in modulating vulnerability to the convulsant effects of PTZ but not cocaine. Furthermore, they demonstrate that KOPr-1 activation protects against acute and kindled seizures induced by this convulsant. Finally, the results of our study suggest that KOPr-1 antagonists will not have therapeutic utility against cocaine-induced seizures, while they may prove beneficial in attenuating several actions of cocaine that have been linked to its abuse.

Topics: Analgesics; Animals; Behavior, Animal; Benzeneacetamides; Cocaine; Dose-Response Relationship, Drug; Drug Interactions; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Naltrexone; Narcotic Antagonists; Pentylenetetrazole; Pyrrolidines; Receptors, Opioid, kappa; Seizures

Although the neurochemical mechanisms contributing to alcohol withdrawal seizures are poorly understood, withdrawal seizures probably reflect neuronal hyperexcitability resulting from adaptation to chronic alcohol. Altered kappa-Opioid receptor (KOP-R) signaling has been observed in multiple seizure types; however, a role for this system in ethanol withdrawal seizures has not been systematically characterized. We hypothesized that pharmacological manipulations of the KOP-R would alter withdrawal in mice selectively bred for differences in ethanol withdrawal severity. Withdrawal Seizure-Prone (WSP) and Withdrawal Seizure-Resistant (WSR) mice were made physically dependent using chronic ethanol vapor inhalation, and the effects of the KOP-R antagonist nor-binaltorphimine or agonist U-50,488H on withdrawal severity were examined. Pretreatment with nor-binaltorphimine significantly increased handling-induced convulsion (HIC) severity in withdrawing WSR mice, with no observable effects in withdrawing WSP mice. In contrast, U-50,488H significantly decreased HIC severity in WSP mice, with no effects in WSR mice. During extended withdrawal (i.e. hours 12+), a rebound hyperexcitability was observed in WSP mice given agonist. Thus, administration of a KOP-R antagonist increased withdrawal severity in mice normally resistant to withdrawal seizures, while a KOP-R agonist reduced convulsion severity in animals susceptible to withdrawal seizures. These observations are consistent with differences in the KOP-R system observed in these lines at the molecular level, and suggest the KOP-R system may be a promising therapeutic target for management of ethanol withdrawal seizures. Finally, these findings underscore the importance of determining the potential for rebound increases in withdrawal severity during later withdrawal episodes.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Alcohol-Induced Disorders, Nervous System; Analgesics, Non-Narcotic; Analgesics, Opioid; Animals; Anticonvulsants; Brain; Central Nervous System Depressants; Disease Models, Animal; Drug Interactions; Drug Synergism; Ethanol; Male; Naltrexone; Receptors, Opioid, kappa; Seizures; Species Specificity; Substance Withdrawal Syndrome; Treatment Outcome

N-Cyclopropylmethyl-[7alpha,8alpha,2', 3']-cyclohexano-1'[S]-hydroxy-6,14-endo-ethenotetrahydronororip avine (BU48) is a novel, ring-constrained analog of buprenorphine. In vivo, BU48 (0.1-10 mg/kg s.c.) produced brief, nonlethal convulsions in mice followed by brief Straub tail and a short period of catalepsy characteristic of BW373U86 and other nonpeptidic delta-receptor agonists. BU48-induced convulsions were sensitive to antagonism by naltrindole (10 mg/kg s.c.) and were also prevented by administration of the putative delta(1) antagonist 7-benzylidenenaltrexone and the putative delta(2) antagonist naltriben, with the latter being more potent. In the abdominal stretch assay in the mouse, only low-efficacy antinociceptive activity of BU48 (0.1-10 mg/kg) was seen. This was reversed by the kappa-opioid antagonist norbinaltorphimine (32 mg/kg s.c.) but not by the delta-opioid antagonist naltrindole (10 mg/kg s.c.). BU48 (10 mg/kg s.c.) acted as a delta-antagonist in this assay. In mouse brain homogenates, BU48 had high (nanomolar) binding affinity for all three opioid receptors in the order mu > delta = kappa. In vitro, the compound acted as a potent (EC(50) = 1.4 nM) kappa-opioid agonist in the guinea pig ileum and a potent (EC(50) = 0.2 nM) delta-opioid agonist in the mouse vas deferens but showed partial agonist activity at the rat cloned delta-opioid (40%) and human cloned kappa-opioid (59%) receptors with very low efficacy at the rat cloned mu-opioid receptor (10%); findings consistent with its in vivo profile. BU48 is the first described compound that produces delta-opioid-mediated convulsions without any evidence of delta-opioid-mediated antinociception and will be a useful tool in investigations of the delta-opioid receptor.

Topics: Analgesics, Opioid; Animals; Benzamides; Brain; Buprenorphine; Convulsants; Electric Stimulation; Guanosine 5'-O-(3-Thiotriphosphate); Guinea Pigs; Ileum; In Vitro Techniques; Male; Mice; Muscle Contraction; Muscle, Smooth; Naltrexone; Narcotic Antagonists; Pain Measurement; Piperazines; Radioligand Assay; Rats; Receptors, Opioid, delta; Receptors, Opioid, kappa; Seizures; Vas Deferens

Involvement of the kappa opioid receptor in regulation of the pilocarpine-induced seizures and neurodegeneration was studied in mice. Administration of pilocarpine (400 mg/kg i.p.) resulted in a sequence of behavioral alterations including motor limbic seizures. Pretreatment of mice with the selective kappa opioid receptor agonist U69,593 (2 and 20 mg/kg i.p.) or PD117,302 (0.1 and 1 mg/kg i.p.) increased the latency of motor seizures and decreased the seizure severity and mortality. Those effects were abolished in animals pretreated with the specific kappa opioid receptor antagonist nor-binaltorphimine (Nor-BNI, 10 mg/kg i.p.). Examination of frontal forebrain sections by light microscopy revealed widespread damage, especially within the hippocampal formation, in pilocarpine-treated mice. Both U69,593 and PD117,503 protected the integrity of hippocampal neurons, especially in the CA1 region, that effect being reversed by Nor-BNI. The above data indicate that activation of the kappa opioid receptor exerts an inhibitory effect on the pilocarpine-induced limbic seizures and neurotoxicity.

Topics: Analgesics; Animals; Benzeneacetamides; Brain; Injections, Intraperitoneal; Mice; Naltrexone; Pilocarpine; Pyrroles; Pyrrolidines; Receptors, Opioid, kappa; Seizures; Thiophenes

The kappa-selective opioid antagonist, norbinaltorphimine (Nor-BNI), was tested against convulsions and mortality induced by the excitatory amino acids, N-methyl-D-aspartic acid (NMDA), (R,S)-alpha-amino-3- hydroxy-5-methyl-4-isoxazole propionate (AMPA) and kainic acid and the gamma-aminobutyric acid antagonist, bicuculline. Nor-BNI (10-40 nmol; intracerebroventricularly, i.c.v.) protected against NMDA (0.5-2.0 nmol i.c.v.)-induced convulsions and NMDA (2 nmol i.c.v.) and AMPA (2 nmol i.c.v.)-induced mortality. The opioid antagonist, naloxone (10 nmol i.c.v.), had no protecting activity. In vitro, Nor-BNI competed with the binding of the specific NMDA receptor ligand, [3H]D,L-(E)-2-amino-4-propyl- 5-phosphono-3-pentenoic acid ([3H]CGP 39653, 10 nM; IC50 of 1.63 +/- 0.20 microM) to mouse brain membrane preparations. The results indicate that the protecting activities of Nor-BNI are mediated by NMDA receptor-related mechanisms.

Topics: 2-Amino-5-phosphonovalerate; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Bicuculline; Binding, Competitive; Brain; Ibotenic Acid; Injections, Intraventricular; Kainic Acid; Male; Mice; N-Methylaspartate; Naltrexone; Receptors, N-Methyl-D-Aspartate; Seizures

The selective kappa-opioid receptor agonist CI-977, stereoselectively antagonised clonic seizures induced by slow i.v. infusion of N-methyl-DL-aspartate in the mouse. It was found to be more efficacious and 10-fold more potent than the competitive N-methyl-D-aspartic acid receptor antagonist CPP (3-(+/-)-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid). The anticonvulsant action of CI-977 was antagonised by norbinaltorphimine indicating a specific interaction with the kappa-receptor. The effect of CI-977 but not that of CPP was also antagonised by the glycine/NMDA receptor agonist D-serine. These results provide evidence for a possible interaction between the kappa-receptor and the glycine/NMDA receptor.

Topics: Animals; Anticonvulsants; Benzofurans; Dizocilpine Maleate; In Vitro Techniques; Mice; Mice, Inbred Strains; Naltrexone; Piperazines; Pyrrolidines; Radioligand Assay; Rats; Receptors, N-Methyl-D-Aspartate; Receptors, Opioid; Receptors, Opioid, kappa; Seizures; Stereoisomerism

The opioid antagonist properties of nor-binaltorphimine (nor-BNI; 17,17'-Bis(cyclopropylmethyl)-6,6',7,7'-tetradehydro-4,5:4', 5'-diepoxy-6,6'-(imino) [7,7'-bimorphinan]-3,3',14,14'-tetrol) were evaluated in vivo in the rat maximal electroshock (MES) seizure model. Following s.c. or i.c.v. pretreatment, nor-BNI selectively antagonized the anticonvulsant effects of the kappa opioid U50, 488, significantly increasing its ED50 by 2.3 and 4.5 fold, respectively. In contrast, pretreatment with nor-BNI (s.c. or i.c.v.) failed to antagonize the anticonvulsant effects of the selective mu opioid, DAMGO. At the doses and injection routes used, nor-BNI itself had no apparent effect on overt behavior or MES-induced convulsions. These data support the earlier suggestion that the anticonvulsant effects of U50,488 are mediated by kappa opioid receptors and confirm 1) the selectivity of nor-BNI as a kappa antagonist and 2) its applicability as a pharmacological tool in the differentiation of multiple opioid receptors.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Anticonvulsants; Electroshock; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalins; Male; Naltrexone; Pyrrolidines; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, Opioid, kappa; Seizures