The atypical neuroleptics clozapine and olanzapine differ regarding their antinociceptive mechanisms and potency.

Using the mouse tail-flick assay, we evaluated the antinociceptive effect and the interaction with the opioid, adrenergic, and serotonergic systems of the two "atypical" neuroleptic agents clozapine and olanzapine. Clozapine induced a potent antinociceptive effect in a dose-dependent manner with ED50 of 8.7 mg/kg. This effect was antagonized by the nonselective opioid antagonist naloxone (p < 0.05), implying an opioid mechanism of action involved in clozapine-induced antinociception. Further evaluation demonstrated the involvement of micro1-, micro2-, kappa1- opioid receptor subtypes and of alpha2-adrenoreceptors in clozapine antinociception but not the serotonin receptors. Olanzapine induced a weak antinociceptive effect. The highest effect found was a 50% antinociception following an injection of 10 mg/kg. As the olanzapine dose increased beyond 10 mg/kg, latencies declined almost back to baseline. Yohimbine (an alpha2-adrenoreceptor antagonist) significantly reduced olanzapine's antinociceptive effect almost completely (to 10%; p < 0.05), while both naloxone and metergoline (a nonselective 5-HT receptor antagonist) reduced it only partially. These results indicate the possible involvement of the alpha2-adrenoreceptors in olanzapine antinociception and to a less extent the involvement of opioid and serotonergic receptors. Although both clozapine and olanzapine are dibenzodiazepines with similar "atypical" antipsychotic properties, it seems that they differ notably not only regarding their hematological side effects, but regarding their interaction with the opioid system as well.