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.