The delta opioid receptor agonist, SNC80, has complex, dose-dependent effects on pilocarpine-induced seizures in Sprague-Dawley rats.
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.
Bausch
Suzanne B
SB
Department of Pharmacology, Uniformed Services University, Bethesda, MD 20814, USA. sbausch@usuhs.mil
Garland
Joshua P
JP
Yamada
Jaclyn
J
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
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