title: The delta opioid receptor agonist, SNC80, has complex, dose-dependent effects on pilocarpine-induced seizures in Sprague-Dawley rats.
abstract: Delta opioid receptor (DOR) selective agonists hold promise clinically as analgesics, but their effects on seizures remain controversial. In this study we examined the effects of the DOR agonist, (+)-4-[(alpha R)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethyl-benzamide (SNC80), on behavioral seizures and hippocampal histopathology in the pilocarpine model of temporal lobe epilepsy. Systemic administration of SNC80 (30 or 60 mg/kg) alone elicited brief seizures within minutes of injection in about half of all rats. When SNC80 (30 or 60 mg/kg) was given prior to pilocarpine administration, trends toward increased latencies to first seizure and status epilepticus (SE) were seen, which correlated with the incidence of a prior, brief SNC80-induced seizure. Significant dose-dependent effects of SNC80 also were observed. Prior administration of SNC80 (30 mg/kg) significantly decreased the number of rats exhibiting acute pilocarpine-induced seizures and overall seizure severity compared to rats given pilocarpine alone, suggesting that SNC80 was anticonvulsant. SNC80 (60 mg/kg) also decreased overall seizure severity. However, SNC80 (60 mg/kg) doubled the total seizure time and the number of rats exhibiting prolonged SE compared to pilocarpine alone, further suggesting that SNC80 has pro-convulsant properties. Significant effects of SNC80 on pilocarpine-induced seizures did not correlate with the occurrence of a prior SNC80-induced seizure. The degree of hilar neuron loss and mossy fiber sprouting correlated strongly with prolonged SE rather than dose of SNC80 (> or =60 min), suggesting that SNC80 did not dramatically alter pilocarpine-induced seizures in the absence of behavioral modifications. Our results demonstrate that the DOR agonist, SNC80, has complex, dose-dependent effects on pilocarpine-induced seizures.
authors.affiliation: Department of Pharmacology, Uniformed Services University, Bethesda, MD 20814, USA. sbausch@usuhs.mil
authors.forename: Suzanne B
authors.initials: SB
authors.lastname: Bausch
authors.forename: Joshua P
authors.initials: JP
authors.lastname: Garland
authors.forename: Jaclyn
authors.initials: J
authors.lastname: Yamada
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage; D001549:Benzamides / Q000008:administration & dosage*; D003292:Convulsants / Q000008:administration & dosage; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions / Q000502:physiology; D004833:Epilepsy, Temporal Lobe / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D006624:Hippocampus / Q000187:drug effects / Q000503:physiopathology; D008297:Male; D019599:Mossy Fibers, Hippocampal / Q000187:drug effects / Q000503:physiopathology; D018721:Muscarinic Agonists / Q000494:pharmacology; D009294:Narcotics / Q000009:adverse effects; D010862:Pilocarpine; D010879:Piperazines / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects / Q000502:physiology; D017465:Receptors, Opioid, delta / Q000819:agonists* / Q000378:metabolism; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology
chemical_list: D000927:Anticonvulsants; D001549:Benzamides; D003292:Convulsants; D018721:Muscarinic Agonists; D009294:Narcotics; D010879:Piperazines; D017465:Receptors, Opioid, delta; D010862:Pilocarpine; C088464:4-(alpha-(4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl)-N,N-diethylbenzamide