Possible involvement of nitrergic and opioidergic systems in the modulatory effect of acute chloroquine treatment on pentylenetetrazol induced convulsions in mice

• Chloroquine exerts modulatory effects on pentylenetetrazol-induced seizures.
• Nitrergic and opioid systems are involved in the effects of chloroquine.
• Neuronal nitric oxide synthase mediates the chloroquine modulatory role.

Chloroquine has long been used for the treatment of malaria and rheumatological disorders. Accumulating evidence suggests potential use of chloroquine as a neuroprotective agent. Several studies have reported that endogenous opioids and nitric oxide (NO) system mediate the chloroquine effects. In the present study, the involvements of endogenous opioids and NO in the modulatory effects of chloroquine on pentylenetetrazol-induced seizures were assessed in mice. Chloroquine 5 mg/kg significantly increased the seizure threshold, but this effect was reversed with naltrexone 1 mg/kg. Acute co-administration of l-NAME (non-selective NO synthase (NOS) inhibitor, 5 mg/kg) or 7-NI (selective neuronal NOS inhibitor, 40 mg/kg) with the effective dose of chloroquine completely inhibited its anticonvulsant effects. Acute single injection of a sub-effective dose of l-arginine (NO precursor, 60 mg/kg) with a sub-effective dose of chloroquine 2.5 mg/kg increased the seizure threshold but administration of l-arginine 60 mg/kg with chloroquine 10 mg/kg decreased the seizure threshold. Moreover, the combination of the lower doses of naltrexone (0.1 mg/kg) and 7-NI (15 mg/kg) showed additive effects in blocking the chloroquine-induced anticonvulsant properties. Chloroquine 5 mg/kg enhanced the hippocampal nitrite levels. Chloroquine at the dose of 20 mg/kg decreased the seizure threshold. This effect was inhibited through l-NAME (5 mg/kg), 7-NI (40 mg/kg) and naltrexone (1 mg/kg) administration with this dose of chloroquine. In conclusion, NO signaling probably through neuronal NOS, but not inducible NOS could be involved in the opioid-dependent anticonvulsant effects of chloroquine in this model of seizures in mice. It seems that nitric oxide and opioid systems are involved in modulatory effect of chloroquine on seizures induced by pentylenetetrazol.