Intracerebroventricular administration of N-type calcium channel blocker ziconotide displays anticonvulsant, anxiolytic, and sedative effects in rats: A preclinical and pilot study.

ABSTRACT

OBJECTIVE: Ziconotide (ω-conotoxin MVIIA peptide) is a novel analgesic agent acting on voltage-gated calcium channels and is administered intrathecally for neuropathic pain. While antiepileptic activities of other types of calcium channel blockers (T- or L-type) are well established, there is no information regarding the effect of ziconotide as an N-type calcium channel antagonist in pentylenetetrazol-induced seizures or its anxiolytic and sedative activities. The present study is the first to report on these effects. METHODS: To evaluate the anticonvulsant activity of ziconotide in the pentylenetetrazol (60 mg/kg) seizure model, ziconotide was administered intracerebroventricular (i.c.v.) as a single dose (1 µg/rat) or repeatedly (chronic administration 0.1, 0.3, or 1 µg/rat once a day for seven days). The anxiolytic and sedative actions of ziconotide were evaluated with the elevated plus maze, light/dark (LD) box, and pentobarbital-induced sleep tests. Immediately after behavioral testing, the amygdala was completely removed bilaterally to determine corticosterone levels by immunoassay. RESULTS: In all dosing regimens, ziconotide significantly decreased the seizure frequency and also delayed the latency period compared with control. Chronic administration affected the percentage of mortality protection, while a single dose of ziconotide did not. In behavioral tests, ziconotide significantly increased both the number of entries and the percentage of time spent in the open arms of the elevated plus maze. Furthermore, ziconotide significantly increased the latency period and the number of entries into the light compartment during the LD box examination. Chronic administration of ziconotide significantly reduced the latency to sleep and increased sleeping time, whereas these parameters were not affected by a single dose. Additionally, amygdala corticosterone levels were significantly decreased in rats treated with ziconotide compared with control. CONCLUSION: Ziconotide displays beneficial neurobehavioral effects in a model of epilepsy with anxiety as its comorbid event. It seems that at least one of the mechanisms involved in these effects is associated with a decrease in brain corticosterone levels. The main advantage of ziconotide over benzodiazepines (routine anxiolytic and sedative drugs) is that it does not cause tolerance, dependency, and addiction. Therefore, more than ever, it is necessary to improve the convenience of drug delivery protocols and attenuate the adverse effects associated with ziconotide-based therapies.