Modelling disease mitigation at mass gatherings: A case study of COVID-19 at the 2022 FIFA World Cup.

The 2022 FIFA World Cup was the first major multi-continental sporting Mass Gathering Event (MGE) of the post COVID-19 era to allow foreign spectators. Such large-scale MGEs can potentially lead to outbreaks of infectious disease and contribute to the global dissemination of such pathogens. Here we adapt previous work and create a generalisable model framework for assessing the use of disease control strategies at such events, in terms of reducing infections and hospitalisations. This framework utilises a combination of meta-populations based on clusters of people and their vaccination status, Ordinary Differential Equation integration between fixed time events, and Latin Hypercube sampling. We use the FIFA 2022 World Cup as a case study for this framework (modelling each match as independent 7 day MGEs). Pre-travel screenings of visitors were found to have little effect in reducing COVID-19 infections and hospitalisations. With pre-match screenings of spectators and match staff being more effective. Rapid Antigen (RA) screenings 0.5 days before match day performed similarly to RT-PCR screenings 1.5 days before match day. Combinations of pre-travel and pre-match testing led to improvements. However, a policy of ensuring that all visitors had a COVID-19 vaccination (second or booster dose) within a few months before departure proved to be much more efficacious. The State of Qatar abandoned all COVID-19 related travel testing and vaccination requirements over the period of the World Cup. Our work suggests that the State of Qatar may have been correct in abandoning the pre-travel testing of visitors. However, there was a spike in COVID-19 cases and hospitalisations within Qatar over the World Cup. Given our findings and the spike in cases, we suggest a policy requiring visitors to have had a recent COVID-19 vaccination should have been in place to reduce cases and hospitalisations.

Evaluating infectious disease outbreak potential and mitigation effectiveness on cruise ships.

The cruise ship sector is a major part of the tourism industry, and an estimated over 30 million passengers are transformed worldwide each year. Cruise ships bring diverse populations into proximity for many days, facilitating the transmission of respiratory illnesses. The objective of this study is to develop a modeling framework to inform the development of viable disease risk management policies and measures to control disease outbreaks on cruises. Our model, parameterized and calibrated using the data of the COVID-19 outbreak on the Diamond Princess cruise ship in 2020, is used to assess the impact of the mitigation measures such as mask wearing, vaccination, on-board and pre-traveling testing measures. Our results indicate mask wearing in public places as the cheapest and most affordable measure can drop the number of cumulative confirmed cases by almost 50%. This measure along with the vaccination by declining the number of the cumulative confirmed cases by more than 94% is the most effective measure to control outbreaks on cruises. According to our findings, outbreaks are more predominant in the passenger population than the crew members, however, the protection measures are more beneficial if they are applied by both crew members and passengers. Regarding the testing measure, pre-traveling testing is more functional than the on-board testing to control outbreaks on cruises.

Effect of biliary cirrhosis on neurogenic relaxation of rat gastric fundus and anococcygeus muscle: role of nitric oxide pathway.

BACKGROUND: Cirrhosis, associated with a host of hemodynamic abnormalities, could affect the gastrointestinal (GI) tract motility. On the other hand, the nonadrenergic noncholinergic (NANC) neurotransmission has been shown to play a pivotal role in GI tract motility and has been linked with release of nitric oxide (NO) on electrical stimulation. In this study, we investigated the effect of biliary cirrhosis on the neurogenic relaxation of rat gastric fundus and anococcygeus muscle and also the possible role of nitric oxide system in this manner. METHODS: Isolated gastric fundus and anococcygeus strips of sham-operated and biliary cirrhotic (4 weeks after bile duct ligation) rats were mounted under tension in a standard organ bath. Electrical stimulation was applied to obtain NANC-mediated relaxations in precontracted gastric fundus and anococcygeus muscle. The neurogenic relaxations were examined in the presence of different doses of NO synthase inhibitor, N (w)-Nitro-L-Arginine Methyl Ester (L-NAME). The concentration-dependent relaxant responses to the NO donor sodium nitroprusside were also evaluated. RESULTS: The neurogenic relaxation of both gastric fundus and anococcygeus muscle was significantly (P < 0.001) increased in cirrhotic animals. L-NAME (0.03-1,000 µM) inhibited relaxations in both groups in a dose-dependent manner (P < 0.001), but cirrhotic groups were more resistant to the inhibitory effects of L-NAME (P < 0.01). Sodium nitroprusside-mediated relaxations were similar in two groups. CONCLUSIONS: This study for the first time demonstrated that cirrhosis increases the NO-mediated neurogenic relaxation of both rat gastric fundus and anococcygeus muscle, suggesting a crucial role for the neurogenic NO in the pathophysiology of disturbed GI motility in cirrhosis.

Cytokine single nucleotide polymorphisms in patients' with gallstone: dose TGF-ß gene variants affect gallstone formation?

Gallstone is a common biliary disorder with several risk factors. Immune responses and inflammatory cytokines are important in this disease; as a result, some cytokines can be detected in bile fluid. In this research, cytokine gene polymorphisms were studied, and their effects on gallstone formation were evaluated. On 158 gallstone patients and 254 normal subjects, by PCR- RFLP method, IL-4-C590T polymorphism and by ARMS-PCR method, IFN-γ T+874A, TNF-α-A308G, IL-6 G-174C and TGF-ß T+869C variants were studied. Pathologic evaluations were done on surgical specimens. There were no significant differences in distribution of evaluated polymorphisms between patient group and normal control group (P > 0.05), except TGF-ß +869T allele (P = 0.04, OR = 1.23, 95 % CI = 1-1.79) which was higher in patients with gallstone. Although the pro-inflammatory cytokines such as TNF-α and IL-6 may promote gallstone formation, in this study no significant correlation between TNF-α and IL-6 polymorphisms and gallstone formation was seen. It is taught that TGF-ß may affect gallbladder cells to promote gallstone formation and higher producer TGF-ß +869T allele can be a risk factor of gallstone disease, so further studies would be more elucidative

The role of 5-HT(3) receptors in the additive anticonvulsant effects of citalopram and morphine on pentylenetetrazole-induced clonic seizures in mice.

Citalopram, a selective serotonin reuptake inhibitor (SSRI), is frequently used in the treatment of major depressive disorders. In addition to its antidepressant features, citalopram shows some anticonvulsive properties at lower doses, whereas higher doses, ingested in cases of suicide, have been associated with seizures. Moreover, some reports support the enhancing effect of morphine on different responses of SSRIs such as analgesic and anticonvulsant properties. Although the exact mechanisms of these additive effects are not yet fully understood, 5-HT(3) receptor has recently been shown to play an important role in the central effects of SSRIs and morphine. In this regard, we used a model of clonic seizures induced by pentylenetetrazole (PTZ) in male NMRI mice to investigate whether morphine and citalopram exhibit additive anticonvulsant effects and, if so, whether this effect is mediated through modulation of 5-HT(3) receptors. In our study, citalopram at lower doses (0.5 and 1 mg/kg, ip) significantly increased the seizure threshold (P<0.01) and at a higher dose (50 mg/kg) had proconvulsive effects. Moreover, morphine at low and noneffective doses had additive effects on the anticonvulsive properties of citalopram. This additive effect was prevented by pretreatment with low and noneffective doses of tropisetron (a 5-HT(3) receptor antagonist) and augmented by 1-(m-chlorophenyl)-biguanide (mCPBG, a 5-HT(3) receptor agonist). Moreover, low doses of morphine (0.1 and 0.5 mg/kg) alone or in combination with potent doses of 5-HT(3) receptor agonist or antagonist could not alter the proconvulsive properties of citalopram at higher dose (50 mg/kg), ruling out the contribution of 5-HT(3) to this effect. In summary, our findings demonstrate that 5-HT(3) receptor mediates the additive anticonvulsant properties of morphine and low-dose citalopram. This could constitute a new approach to augmenting the efficacy and curtailing the adverse effects of citalopram.

Sonographic measurement of uterus and ovaries in premenarcheal healthy girls between 6 and 13 years old: correlation with age and pubertal status.

BACKGROUND: To provide normal references of sonographic uterine and ovarian size in premenarcheal healthy girls aged 6-13 years in different stages of puberty. METHODS: Two hundred forty girls were enrolled into the study (mean age ± SD, 9.5 ± 1.7 years [range, 6-13.5 years]). Pubertal status was classified according to Tanner staging. All subjects underwent pelvic sonographic examination for the measurement of uterine volume, body and cervical length, anteroposterior diameter of fundus, body, and cervix, ovarian volume, and both right and left prominent follicular diameter. RESULTS: A gradual increase with age was observed in all uterine and ovarian measurements. Both uterine and ovarian parameters were significantly correlated to age, height and weight, and stages of puberty. Uterine volume was <3.5 cm(3) in 98% of prepubertal girls, and in stage 2 it was significantly more than in stage 1 (3 ± 3.2 versus 1.7 ± 1.7, respectively) (p < 0.001). Uterine body length was also significantly greater in stage 2 than stage 1 (17.5 ± 4.5 versus 14.6 ± 3.3, respectively) (p < 0.001). CONCLUSION: The reference values for uterus and ovaries were determined in healthy girls. There is a progressive increase in size of internal female genitalia in relation to age, height, weight, and puberty. Uterine volume and body length presented the best correlation with age and stage of puberty.

Fractal structures arising from interfacial instabilities in bio-oil atomization.

The intriguing multi-scale fractal patterns ubiquitously observed in nature similarly emerge as fascinating structures in two-phase fluid flows of bio-oil breakup and atomization processes. High-resolution microscopy of the two-phase flows under 15 flow conditions (cases of different flow rates of the liquid and co-flowing air streams as well as different degrees of liquid preheating) reveal that the geometrical complexities evolve under the competing/combined action of the instability mechanisms such as Kelvin-Helmholtz, Rayleigh-Taylor and Rayleigh-Plateau leading into the transition from break-up to atomization. A thorough analysis of the higher order moments of statistics evaluated based on the probability density functions from 15,000 fractal dimension samples suggest that a single-value analysis is not sufficient to describe the complex reshaping mechanisms in two-phase flows. Consistently positive skewness of the statistics reveal the role of abrupt two-phase mechanisms such as liquid column rupture, ligament disintegration, liquid sheet bursting and droplet distortions in a hierarchical geometrical entanglement. Further, large kurtosis values at increased flow inertia are found associated with turbulence-induced intermittent geometrical reshaping. Interestingly, the proposed power-law correlation reveals that the global droplet size obtained from laser-diffraction measurements declines as the two-phase geometrical complexity increases.

Administration of lithium and magnesium chloride inhibited tolerance to the anticonvulsant effect of morphine on pentylenetetrazole-induced seizures in mice.

Although morphine has an anticonvulsant effect in several animal models of seizures, its potential clinical application in epilepsy may be hindered by its adverse effects like opioid tolerance. The present study evaluated the development of tolerance to the anticonvulsant effect of morphine in a model of clonic seizures induced with pentylenetetrazole (PTZ) in male Swiss mice. We also examined whether administration of either lithium chloride (LiCl) or magnesium chloride (MgCl(2)) was able to prevent the probable tolerance. Our data demonstrated that the anticonvulsant effect of a potent dose of morphine (1mg/kg) was abolished in chronic morphine-treated mice (mice administered the same dose of morphine intraperitoneally twice daily for 4 days). Four days of pretreatment with low and noneffective doses of MgCl(2) (2 and 5mg/kg) and LiCl (5mg/kg) inhibited the development of tolerance to the anticonvulsant effect of morphine (1mg/kg, ip). Moreover, a single acute injection of the aforementioned agents at the same doses reversed the expression of tolerance to the anticonvulsant effects of morphine (1mg/kg, ip). Chronic 17-day treatment with LiCl (600 mg/L in drinking water) also inhibited the development of tolerance to the anticonvulsant effects of 1mg/kg morphine. These results demonstrate that the anticonvulsant effect of morphine is subject to tolerance after repeated administration. Both development and expression of tolerance are inhibited by either LiCl or MgCl(2). As both LiCl and MgCl(2) can modulate the function of N-methyl-d-aspartate (NMDA) receptors, we discuss how NMDA receptor functioning might be involved in the effects of LiCl and MgCl(2) on the development of tolerance to the anticonvulsant effect of morphine.

Agmatine enhances the anticonvulsant effect of lithium chloride on pentylenetetrazole-induced seizures in mice: Involvement of L-arginine/nitric oxide pathway.

After nearly 60years, lithium is still the mainstay in the treatment of mood disorders. In addition to its antimanic and antidepressant effects, lithium also has anticonvulsant properties. Similar to lithium, agmatine plays a protective role in the central nervous system against seizures and has been reported to enhance the effect of different antiepileptic agents. Moreover, both agmatine and lithium have modulatory effects on the L-arginine/nitric oxide pathway. This study was designed to investigate: (1) whether agmatine and lithium exert a synergistic effect against clonic seizures induced by pentylenetetrazole and (2) whether or not this synergistic effect is mediated through inhibition of the L-arginine/nitric oxide pathway. In our study, acute administration of a single potent dose of lithium chloride (30mg/kg ip) increased seizure threshold, whereas pretreatment with a low and independently noneffective dose of agmatine (3mg/kg) potentiated a subeffective dose of lithium (10mg/kg). N(G)-L-arginine methyl ester (L-NAME, nonspecific nitric oxide synthase inhibitor) at 1 and 5mg/kg and 7-nitroindazole (7-NI, preferential neuronal nitric oxide synthase inhibitor) at 15 and 30mg/kg augmented the anticonvulsant effect of the noneffective combination of lithium (10mg/kg ip) and agmatine (1mg/kg), whereas several doses (20 and 40mg/kg) of aminoguanidine (inducible nitric oxide synthase inhibitor) failed to alter the seizure threshold of the same combination. Furthermore, pretreatment with independently noneffective doses (30 and 60mg/kg) of L-arginine (substrate for nitric oxide synthase) inhibited the potentiating effect of agmatine (3mg/kg) on lithium (10mg/kg). Our findings demonstrate that agmatine and lithium chloride have synergistic anticonvulsant properties that may be mediated through the L-arginine/nitric oxide pathway. In addition, the role of constitutive nitric oxide synthase versus inducible nitric oxide synthase is prominent in this phenomenon.

Voltage-dependent calcium channel and NMDA receptor antagonists augment anticonvulsant effects of lithium chloride on pentylenetetrazole-induced clonic seizures in mice.

Although lithium is still a mainstay in the treatment of bipolar disorder, its underlying mechanisms of action have not been completely elucidated. Several studies have shown that lithium can also modulate seizure susceptibility in a variety of models. In the present study, using a model of clonic seizures induced with pentylenetetrazole (PTZ) in male Swiss mice, we investigated whether there is any interaction between lithium and either calcium channel blockers (CCBs: nifedipine, verapamil, and diltiazem) or N-methyl-D-aspartate (NMDA) receptor antagonists (ketamine and MK-801) in modulating seizure threshold. Acute lithium administration (5-100mg/kg, ip) significantly (P<0.01) increased seizure threshold. CCBs and NMDA receptor antagonists also exerted dose-dependent anticonvulsant effects on PTZ-induced seizures. Noneffective doses of CCBs (5mg/kg, ip), when combined with a noneffective dose of lithium (5mg/kg, ip), exerted significant anticonvulsant effects. Moreover, co-administration of a noneffective dose of either MK-801 (0.05mg/kg, ip) or ketamine (5mg/kg, ip) with a noneffective dose of lithium (5mg/kg, ip) significantly increased seizure threshold. Our findings demonstrate that lithium increases the clonic seizure threshold induced by PTZ in mice and interacts with either CCBs or NMDA receptor antagonists in exerting this effect, suggesting a role for Ca(2+) signaling in the anticonvulsant effects of lithium in the PTZ model of clonic seizures in mice.

Inverse cascade of the vortical structures near the contact line of evaporating sessile droplets.

Microscopic imaging as well as the particle image velocimetry (PIV) are carried out to evaluate the concentration, velocity and vorticity fields near the contact line of the nano-particles-laden evaporating sessile droplets. After the onset of the linear thermocapillary instabilities due to the Marangoni perturbations, the non-linear state sets in and the micro-scale jet-like vortex structures are ejected from the contact line towards the center of the droplet. Afterwards, the jet-like vortical structures expand in the spanwise directions and start to interact with the neighbouring structures. Two types of the inverse cascade mechanisms are found to occur. In the first kind, the vortices of the similar length scale merge and continuously produce larger vortices and corresponding wavelength growth. The second inverse cascade mechanism takes place due to the entrainment of the smaller vortices into the larger structures. Both inverse cascade processes are identified as the continuous feeding of the kinetic energy from the smaller scales to the larger scales. For individual micro-jets the velocity field characterizes the jet-like vortex structures ejected from the contact line towards the droplet center opposing the bulk flow from the center towards the contact line. In addition, the vorticity field overlaid by the velocity streamlines identify the sense of rotation of the low pressure zones on either side of the micro-jet as well as the high pressure stagnation point at the tip.

Co-existence effect of tricalcium phosphate and bioactive glass on biological and biodegradation characteristic of Poly L-Lactic Acid (PLLA) in trinary composite scaffold form.

The purpose of this study is to analyze the co-existence effect of 30 wt.% TCP-BG phases on degradation and precipitation behaviors of PLLA based composite scaffold in biological media. First, phase separation method was used to synthesize of the pure PLLA and the trinary composite scaffolds, and second they were immersed in SBF solution for 45 days. Subsequently, the degradation and precipitation characteristic were investigated by analyzing of pH value and weight changes of the immersed samples, the ability of biological products formation and the change of relative molecular weight of PLLA matrix as function of the degradation time. Finally, the experimental data of relative molecular weight change were verified by Han and Pan model and comparisons were made between them. Results have represented precipitation of huge amount of carbonate apatite on surface of the composite scaffold, and also the acidity of SBF media changes moderately which is prove better bioactivity properties compare to the pure PLLA scaffold. The results of comparison with the model point to quiet good agreement between them in early stage of degradation. So, the consequences suggest that the TCP-BG/PLLA composite scaffold have great potential to be applied in bone replacements or repairs.

The Potential Use of Methotrexate in the Treatment of Cutaneous Leishmaniasis: In Vitro Assays against Sensitive and Meglumine Antimoniate-resistant Strains of Leishmania tropica.

BACKGROUND: The present study aimed to evaluate the effect of methotrexate (MTX) alone and in combination with meglumine antimoniate (MA, Glucantime) against sensitive and MA-resistant Leishmania tropica stages in vitro. METHODS: The present study was carried out in 2014 in Leishmaniasis Research Center at School of Medicine, Kerman University of Medical sciences, Kerman, Iran. The effects of MTX alone and along with MA on promastigote and amastigote stages of sensitive (SS) and MA-resistant (RS) L. tropica strains have been evaluated using a colorimetric MTT assay and in a macrophage model, respectively. In addition, the inhibitory effect of MTX on the Leishmania invasion of murine macrophages was assessed in promastigotes of both strains of L. tropica. Sensitive and MA resistant L. tropica are referred to those isolates that are responsive or non-responsive to one or two courses of treatment by MA systemically and/or intralesionally, respectively. RESULTS: The findings of OD and IC50 showed that MTX plus MA (SS: 16.1 µg/ml, RS: 39.8 µg/ml) had a higher anti-leishmanial effect than MA (SS: 52.2 µg/ml, RS: 170 µg/ml) or MTX alone (SS: 22.2 µg/ml, RS: 51.4 µg/ml) on promastigotes of both strains of L. tropica. The MTX plus MA caused a significant decrease (P<0.05) in the mean infection rate (MIR) and the mean number of amastigotes in each macrophage compared with positive control. Infectivity of promastigotes is significantly (P<0.05) reduced when it was preincubated with MTX. CONCLUSION: This study indicated high potency and a synergistic effect of MTX on MA in inhibiting the growth rateof promastigote and amastigote stages of sensitive and meglumine antimoniate-resistant L. tropica. Further works are needed to evaluate the anti-leishmanial effects of MTX on L. tropica using a clinical setting.

Rapid antidepressant effects of repeated doses of ketamine compared with electroconvulsive therapy in hospitalized patients with major depressive disorder.

Accumulating evidence suggests that N-methyl-d-aspartate receptor (NMDAR) antagonists (e.g. ketamine) may exert rapid antidepressant effects in MDD patients. In the present study, we evaluated the rapid antidepressant effects of ketamine compared with the electroconvulsive therapy (ECT) in hospitalized patients with MDD. In this blind, randomized study, 18 patients with DSM-IV MDD were divided into two groups which received either three intravenous infusions of ketamine hydrochloride (0.5 mg/kg over 45 min) or ECT on 3 test days (every 48 h). The primary outcome measure was the Beck Depression Inventory (BDI) and Hamilton Depression Rating Scale (HDRS), which was used to rate overall depressive symptoms at baseline, 24 h after each treatment, 72 h and one week after the last (third) ketamine or ECT. Within 24 h, depressive symptoms significantly improved in subjects receiving the first dose of ketamine compared with ECT group. Compared to baseline level, this improvement remained significant throughout the study. Depressive symptoms after the second dose ketamine was also lower than the second ECT. This study showed that ketamine is as effective as ECT in improving depressive symptoms in MDD patients and have more rapid antidepressant effects compared with the ECT.

A role for opioid system in the proconvulsant effects of sildenafil on the pentylenetetrazole-induced clonic seizure in mice.

There are several lines of evidence that opioidergic and nitrergic systems could modulate the seizure threshold. We previously have shown that sildenafil had proconvulsant effects in a model of clonic seizure induced by pentylenetetrazole (PTZ) or bicuculline. In the present study, we examined whether the opioid system participates in the action of sildenafil on the PTZ-induced clonic seizures in mice. Sildenafil (1, 5, 10 and 20 mg/kg, i.p.) significantly decreased the seizure threshold in a dose-dependent manner, whereas morphine had both anticonvulsant and proconvulsant effects at low (0.5, 1, and 3 mg/kg, s.c.) and high (60 mg/kg, s.c.) doses. A sub-effective dose of sildenafil (5 mg/kg) combined with a dose of morphine (7.5 mg/kg) which was sub-effective for its proconvulsant effects significantly decreased the seizure threshold. Although naltrexone at 0.5 and 1 mg/kg had no effect on the seizure threshold, it significantly prevented both the proconvulsant effects of sildenafil as well as the anticonvulsant and proconvulsant effects of morphine on the PTZ-induced seizure thresholds. Our data suggested a role for opioidergic system in the proconvulsant effects of sildenafil on the PTZ-induced clonic seizures in mice.

Additive anticonvulsant effects of agmatine and lithium chloride on pentylenetetrazole-induced clonic seizure in mice: involvement of α2-adrenoceptor.

After 60 years, lithium is still the mainstay in the treatment of mood disorders and widely used in clinic. In addition to its mood stabilizer effects, lithium also shows some anticonvulsant properties. Similar to lithium, agmatine also plays a protective role in the CNS against seizures and has been reported to enhance the effect of different antiepileptic agents. Moreover, both agmatine and lithium have modulatory effects on α(2)-adrenoceptors. So, we designed this study: 1) to investigate whether agmatine and lithium show an additive effect against clonic seizures induced by pentylenetetrazole; 2) to assess whether this additive effect is mediated through the α(2)-adrenoceptor or not. In our study, acute administration of a single effective dose of lithium chloride (30 mg/kg, i.p.) increased the seizure threshold. Pre-treatment with low and, per se, non-effective doses of agmatine (1 and 3mg/kg) potentiated a sub-effective dose of lithium (10mg/kg). Interestingly, the anticonvulsant effects of these effective combinations of lithium and agmatine were prevented by pre-treatment with low and non-effective doses of yohimbine [α(2)-adrenoceptor antagonist] (0.1 and 0.5mg/kg). On the other hand, clonidine [α(2)-adrenoceptor agonist] augmented the anticonvulsant effect of a sub-effective combination of lithium (5mg/kg i.p.) and agmatine (1mg/kg) at relatively low doses (0.1 and 0.25mg/kg). In summary, our findings demonstrate that agmatine and lithium chloride exhibit additive anticonvulsant properties which seem to be mediated through α(2)-adrenoceptor.

Inhibition of NMDA receptor/NO signaling blocked tolerance to the anticonvulsant effect of morphine on pentylenetetrazole-induced seizures in mice.

Although morphine has anticonvulsant effect in several animal models of seizure, its potential clinical application in epilepsy may be hindered by its adverse effects like the phenomenon of opioid tolerance. The present study evaluated the development of tolerance to the anticonvulsant effect of morphine in a model of clonic seizure induced by pentylenetetrazole (PTZ) in male Swiss mice. We also examined whether N-methyl-d-aspartate (NMDA) receptor/nitrergic system blockage was able to prevent the probable tolerance. Our data demonstrated that anticonvulsant effects of a potent dose of morphine (1mg/kg) was abolished in chronic morphine-treated mice (with the same dose of morphine twice daily, 4 days, i.p.). Chronic pretreatment with low and non-effective doses of different NMDA antagonists ifenprodil (0.5mg/kg), MK-801 (0.05mg/kg) and ketamine (0.5mg/kg) as well as the non-selective nitric oxide (NO) synthase inhibitor l-NAME (2mg/kg) inhibited the development of tolerance to the anticonvulsant effect of morphine (1mg/kg). Moreover, a single acute injection of the above mentioned agents at the same doses reversed the expression of tolerance to the anticonvulsant effects of morphine (1mg/kg). These results demonstrate that anticonvulsant effect of morphine can be subject to tolerance after repeated administration. Both development and expression of tolerance are inhibited by NMDA receptor/nitrergic system blockage, suggesting a role for NMDA receptor/NO signaling in the development of tolerance to the anticonvulsant effect of morphine.