Although accumulating evidence indicates that the immunomodulatory medication
thalidomide exerts
anticonvulsant properties, the mechanisms underlying such effects of
thalidomide are still unknown. Our previous preclinical study suggested that
nitric oxide (NO) signaling may be involved in the
anticonvulsant effects of
thalidomide in a mouse model of clonic seizure. Additionally, several studies have shown a modulatory interaction between
thalidomide and
opioids in
opioids intolerance, nociception and
neuropathic pain. However, it is unclear whether opioidergic transmission or its interaction with NO signaling is involved in the
anticonvulsant effects of
thalidomide. Given the fact that both opioidergic and nitrergic transmissions have bimodal modulatory effects on seizure thresholds, in the present study we explored the involvement of these signaling pathways in the possible
anticonvulsant effects of
thalidomide on the
pentylenetetrazole (PTZ)-induced clonic seizure in mice. Our data showed that acute administration of
thalidomide (5-50 mg/kg, i.
p., 30 min prior PTZ injection) dose-dependently elevated PTZ-induced clonic seizure thresholds. Acute administration of low doses (0.5-3 mg/kg, i.p., 60 min prior PTZ) of
morphine exerted
anticonvulsant effects (P < 0.001), whereas higher doses (15-60 mg/kg, 60 min prior PTZ) had proconvulsant effects (P < 0.01). Acute administration of a non-effective
anticonvulsant dose of
morphine (0.25 mg/kg) prior non-effective dose of
thalidomide (5 mg/kg) exerted a robust (P < 0.01)
anticonvulsant effect. Administration of a non-effective proconvulsant dose of
morphine (7.5 mg/kg) prior
thalidomide (5 mg/kg) didn't affect clonic seizure thresholds. Acute administration of a non-effective dose of the
opioid receptor antagonist naltrexone (1 mg/kg, i.p.) significantly prevented
anticonvulsant effects of
thalidomide (10 mg/kg, i.p.). Pretreatment with non-effective dose of the NO precursor
L-arginine (60 mg/kg, i.p.) significantly (P < 0.01) reduced the
anticonvulsant effects of combined low doses of
morphine (0.25 mg/kg) and
thalidomide (5 mg/kg). Conversely, pretreatment with non-effective doses of either non-selective (
L-NAME, 5 mg/kg, i.p.) or selective neuronal (7-nitroindazole, 30 mg/kg, i.p.)
NO synthase (NOS) inhibitors significantly augmented the
anticonvulsant effects of combined low doses of
thalidomide and
morphine, whereas the inducible NOS inhibitor
aminoguanidine (100 mg/kg, i.p.) did not exert such effect. Our results indicate that opioidergic transmission and its interaction with neuronal NO signaling may contribute to the anti-seizure activity of
thalidomide in the mice PTZ model of clonic seizure.