Opioid peptide pharmacology and immunocytochemistry in an animal model of self-sustaining status epilepticus.
In a model of self-sustaining status epilepticus induced in rats by 30 min intermittent stimulation of the perforant path through chronically implanted electrodes, a decrease in dynorphin-like immunoreactivity in the dentate gyrus and CA3 was observed 3 h and 24 h after the induction of status epilepticus. Enkephalin-like immunoreactivity decreased 3 h but not 24 h after perforant path stimulation. Injection into the hilus of the dentate gyrus 10 min prior to stimulation of the kappa-receptor agonist dynorphin-A(1-13), the delta-receptor antagonists ICI-174864 and naltrindole, as well as i.p. injection of naloxone prevented the development of status epilepticus. Perihilar administration of the delta-agonist [D-Ser2]Leu-enkephalin-Thr6 or the kappa-antagonist nor-Binaltorphimine, but not of the mu-agonist [D-Ala2,N-Me-Phe4,Gly-ol5]-Enkephalin, facilitated the establishment of self-sustaining status epilepticus. Injection into the hilus of dynorphin-A(1-13) after the end of perforant path stimulation, stopped established status epilepticus, while administration of naloxone, naltrindole and ICI-174864 were ineffective. We conclude that kappa-opioids in the hippocampus counteract initiation and maintenance of status epilepticus, while delta-opioids promote initiation, but not maintenance of seizure activity. These data are important for the understanding the mechanisms which underlie initiation and maintenance of status epilepticus and for the development of new approaches for its effective management.
Mazarati
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A
Epilepsy Research Laboratory, Sepulveda Veteran Administration Medical Center, CA 91343, USA.
Liu
H
H
Wasterlain
C
C
D000200:Action Potentials / Q000502:physiology; D000700:Analgesics / Q000494:pharmacology; D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D004195:Disease Models, Animal; D004399:Dynorphins / Q000494:pharmacology; D004558:Electric Stimulation; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D004743:Enkephalin, Leucine / Q000031:analogs & derivatives / Q000494:pharmacology; D004745:Enkephalins / Q000494:pharmacology; D007150:Immunohistochemistry; D008297:Male; D009270:Naloxone / Q000494:pharmacology; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009474:Neurons / Q000737:chemistry / Q000502:physiology; D018847:Opioid Peptides / Q000494:pharmacology*; D010446:Peptide Fragments / Q000494:pharmacology; D019580:Perforant Pathway / Q000166:cytology; D051381:Rats; D017208:Rats, Wistar; D017465:Receptors, Opioid, delta / Q000502:physiology*; D017473:Receptors, Opioid, kappa / Q000502:physiology*; D013226:Status Epilepticus / Q000139:chemically induced* / Q000503:physiopathology*
D000700:Analgesics; D000701:Analgesics, Opioid; D004745:Enkephalins; D009292:Narcotic Antagonists; D018847:Opioid Peptides; D010446:Peptide Fragments; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; C051843:binaltorphimine; D009270:Naloxone; D004743:Enkephalin, Leucine; D009271:Naltrexone; C026843:dynorphin (1-13); D004399:Dynorphins; C034318:enkephalin, Ser(2), Leu(5), Thr(6)-; C040643:N,N-diallyl-tyrosyl-alpha-aminoisobutyric acid-phenylalanyl-leucine; C055382:naltrindole