title: Pharmacological and genetic manipulation of kappa opioid receptors: effects on cocaine- and pentylenetetrazol-induced convulsions and seizure kindling.
abstract: 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.
authors.affiliation: Integrative Neuroscience Section, Behavioral Neuroscience Branch, NIH/NIDA Intramural Research Program, 5500 Nathan Shock Drive, Baltimore, MD 21224, USA. kaminskr@mail.nih.gov
authors.forename: Rafal M
authors.initials: RM
authors.lastname: Kaminski
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Witkin
authors.forename: Toni S
authors.initials: TS
authors.lastname: Shippenberg
mesh_terms: D000700:Analgesics / Q000627:therapeutic use; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D044482:Benzeneacetamides / Q000627:therapeutic use; D003042:Cocaine; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009271:Naltrexone / Q000008:administration & dosage / Q000031:analogs & derivatives; D009292:Narcotic Antagonists / Q000008:administration & dosage; D010433:Pentylenetetrazole; D011759:Pyrrolidines / Q000627:therapeutic use; D017473:Receptors, Opioid, kappa / Q000235:genetics*; D012640:Seizures / Q000139:chemically induced* / Q000235:genetics* / Q000517:prevention & control
chemical_list: D000700:Analgesics; D044482:Benzeneacetamides; D009292:Narcotic Antagonists; D011759:Pyrrolidines; D017473:Receptors, Opioid, kappa; C116587:kappa(1) opioid receptor; C051844:norbinaltorphimine; D009271:Naltrexone; D003042:Cocaine; C045444:U 69593; D010433:Pentylenetetrazole