Interaction of morphine tolerance with pentylenetetrazole-induced seizure threshold in mice: The role of NMDA-receptor/NO pathway.

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 The development of morphine tolerance was withdrawn when used concomitantly with NOS inhibitors and NMDA-R antagonist, suggesting that the development of tolerance to the anticonvulsant effect of morphine (30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.

Efficacy of nano- and microemulsion-based topical gels in delivery of ibuprofen: an in vivo study.

AIM: Nanoemulsion has shown many advantages in drug delivery systems. In this study, for the first time, analgesic and anti-inflammatory properties of a nanomelusion of almond oil with and without ibuprofen was compared with corresponding microemulsion and commercial topical gel of the drug using formalin and carrageenan tests, respectively. METHOD: Almond oil (oil phase) was mixed with Tween 80 and Span 80 (surfactants), and ethanol (co-surfactant) and them distilled water (aqueous phase) was then added to the mixture at once. Prepared nanoemulsions were pre-emulsified into a 100 ml beaker using magnet/stirrer (1000 rpm). Then, using a probe ultrasonicator (Hielscher UP400s, Hielscher, Ringwood, NJ) the nanoemulsions were formed. RESULTS: The optimised nanoemulsion formulation containing 2.5% ibuprofen, showed improved analgesic and anti-inflammatory effects compared with commercial product and corresponding microemulsion product containing 5% ibuprofen (i.e. twice the content of ibuprofen in the nanoemulsion) in vivo. The nanoemulsion preparation showed superior analgesic activities during chronic phase. Also, it decreased the inflammation from the first hour, while the microemulsion and the commercial product started to show their anti-inflammatory effects after 2 and 3 h, respectively. CONCLUSION: Our finding suggests that the size of the emulsion particles must be considered as an important factor in topical drug delivery systems.