N-methyl-d-aspartate receptor (
NMDA-R)/
nitric oxide (NO) pathway is involved in the intensification of the
analgesic effect of
opioids and the reduction of the intensity of
opioids tolerance and dependence. In the current study, we investigated the involvement of
NMDA-R/NO pathway in chronic
morphine-treated mice in both the development of tolerance to the
analgesic effect of
morphine and in
pentylenetetrazole (PTZ)-induced seizure threshold. Chronic treatment with
morphine (30 mg/kg) exhibited increased seizure resistance in
morphine-induced tolerant mice. The development of
morphine tolerance was withdrawn when used concomitantly with NOS inhibitors and
NMDA-R antagonist, suggesting that the development of tolerance to the
anticonvulsant effect of
morphine (30 mg/kg) is mediated through the
NMDA-R/NO pathway. A dose-dependent biphasic seizure modulation of
morphine was demonstrated in the acute treatment with
morphine; acute treatment at a dose of 0.5 mg/kg shows the
anticonvulsant effect and at a dose of 30 mg/kg shows proconvulsant effect. However, a different pattern was observed in the mice treated chronically with
morphine: they demonstrated tolerance in the tail-flick test; five consecutive days of chronic treatment with a high dose of
morphine (30 mg/kg) showed
anticonvulsant effect while a low dose of
morphine (0.5 mg/kg) showed a proconvulsant effect. The
anticonvulsant effect of
morphine was inhibited completely by the concomitant administration of
NO synthase (NOS) inhibitors including nonspecific NOS inhibitor (
L-NAME, 10 mg/kg), inducible NOS inhibitor (
aminoguanidine, 50 mg/kg), and neuronal NOS inhibitor (7-nitroindazole (7-NI), 15 mg/kg) for five consecutive days. Besides, five days injection of
NMDA-R antagonist (
MK-801, 0.05 mg/kg) significantly inhibited the
anticonvulsant effect of
morphine on the PTZ-induced
clonic seizures. The results revealed that chronic treatment with
morphine leads to the development of tolerance in mice, which in turn may cause an
anticonvulsant effect in a high dose of
morphine via the
NMDA-R/NO pathway.