FTO is a major genetic link between breast cancer, obesity, and diabetes.

PURPOSE: Breast cancer (BC), obesity, and type 2 diabetes mellitus (T2DM) are three complex diseases and health problems that are prevalent worldwide. The aim of this study was to investigate the common genetic associations between these diseases by referring back to the previous genome-wide association studies (GWAS). METHODS: To this end, significant GWAS variants and common variants associated with BC, obesity, or diabetes were identified from the GWAS catalog. To perform candidate variants, the 1000-Genomes Project was used to find variants with linkage disequilibrium. Common variants between each category were identified (common candidate haplotypic variants). Finally, these variants and their associated genes were examined for SNP function analysis, gene expression, gene-gene correlation, and pathway analysis. RESULTS: The results identified 7 variants associated with both T2DM and BC, 8 variants associated with both obesity and BC, and 167 variants associating obesity with T2DM. 91 variants and 4 haplotypic blocks such as CTC were identified on the FTO gene associated with obesity, BC, and T2DM. The results of TCGA data showed that FTO in gene expression was correlated with 6 other genes in the DNA repair pathway in BC subjects. CONCLUSIONS: This study suggests that the FTO gene is one of the major genes shared by BC, T2DM, and obesity based on two DNA repair and inflammatory mechanisms. These results may provide a new perspective on the important role of the FTO gene and repair mechanism in the relationship between BC, obesity, and T2DM for future studies.

Metformin and long non-coding RNAs in breast cancer.

Breast cancer (BC) is the second most common cancer and cause of death in women. In recent years many studies investigated the association of long non-coding RNAs (lncRNAs), as novel genetic factors, on BC risk, survival, clinical and pathological features. Recent studies also investigated the roles of metformin treatment as the firstline treatment for type 2 diabetes (T2D) played in lncRNAs expression/regulation or BC incidence, outcome, mortality and survival, separately. This comprehensive study aimed to review lncRNAs associated with BC features and identify metformin-regulated lncRNAs and their mechanisms of action on BC or other types of cancers. Finally, metformin affects BC by regulating five BC-associated lncRNAs including GAS5, HOTAIR, MALAT1, and H19, by several molecular mechanisms have been described in this review. In addition, metformin action on other types of cancers by regulating ten lncRNAs including AC006160.1, Loc100506691, lncRNA-AF085935, SNHG7, HULC, UCA1, H19, MALAT1, AFAP1-AS1, AC026904.1 is described.

Haplotypic variants of COVID-19 related genes are associated with blood pressure and metabolites levels.

The genetic association of coronavirus disease 2019 (COVID-19) with its complications has not been fully understood. This study aimed to identify variants and haplotypes of candidate genes implicated in COVID-19 related traits by combining the literature review and pathway analysis. To explore such genes, the protein-protein interactions and relevant pathways of COVID-19-associated genes were assessed. A number of variants on candidate genes were identified from Genome-wide association studies (GWASs) which were associated with COVID-19 related traits (p ˂ 10-6 ). Haplotypic blocks were assessed using haplotypic structures among the 1000 Genomes Project (r2 ≥ 0.8, D' ≥ 0.8). Further functional analyses were performed on the selected variants. The results demonstrated that a group of variants in ACE and AGT genes were significantly correlated with COVID-19 related traits. Three haplotypes were identified to be involved in the blood metabolites levels and the development of blood pressure. Functional analyses revealed that most GWAS index variants were expression quantitative trait loci and had transcription factor binding sites, exonic splicing enhancers or silencer activities. Furthermore, the proxy haplotype variants, rs4316, rs4353, rs4359, and three variants, namely rs2493133, rs2478543, and rs5051, were associated with blood metabolite and systolic blood pressure, respectively. These variants exerted more regulatory effects compared with other GWAS variants. The present study indicates that the genetic variants and candidate haplotypes of COVID-19 related genes are associated with blood pressure and blood metabolites. However, further observational studies are warranted to confirm these results.

A systematic review and meta-analysis of the global epidemiology of pediatric traumatic spinal cord injuries.

Despite being relatively rare, pediatric traumatic spinal cord injury (TSCI) is a debilitating event with high morbidity and long-term damage and dependency. This study aims to provide insight on the epidemiological characteristics of pediatric TSCI worldwide. The studies were included if they provided data for the pediatric population with the diagnosis of TSCI. Information sources included PubMed, Embase, Web of Science, and Scopus. All databases were searched from 1990 to April 2023. The quality of included studies was evaluated by Joanna Briggs Institute Critical Appraisal Tools. The results of the meta-analysis were presented as forest plots. PROSPERO Registration code: CRD42020189757. We identified 87 studies from 18 developed and 11 developing countries. Of the 87 studies evaluated, 52 studies were considered medium quality, 27 studies were considered high quality, and 8 studies were considered low quality. In developed countries, the proportion of TSCIs occurring in patients aged 0-15 years was 3% (95% CI: 2.2%; 3.9%), while in developing countries, it was 4.5% (95% CI: 2.8%; 6.4%). In developed countries, the pooled incidence of pediatric TSCI was 4.3/millions of children aged 0-15/year (95% CI: 3.1; 6.0/millions children aged 0-15/year) and boys comprised 67% (95% CI: 63%; 70%) of cases. The most prevalent level of injury was cervical (50% [95% CI: 41%; 58%]). The frequency of SCI Without Obvious Radiological Abnormality (SCIWORA) was 35% (95% CI: 18%; 54%) among children 0-17 years. The most common etiology in developed countries was transport injuries (50% [95% CI: 42%; 57%]), while in developing countries falls were the leading cause (31% [95% CI: 20%; 42%]). The most important limitation of our study was the heterogeneity of studies in reporting age subgroups that hindered us from age-specific analyses.   Conclusion: Our study provided accurate estimates for the epidemiology of pediatric TSCI. We observed a higher proportion of pediatric TSCI cases in developing countries compared to developed countries. Furthermore, we identified distinct epidemiological characteristics of pediatric TSCI when compared to adult cases and variations between developing and developed countries. Recognizing these unique features allows for the implementation of cost-effective preventive strategies aimed at reducing the incidence and burden of TSCI in children. What is Known: • Pediatric Traumatic Spinal Cord Injury (TSCI) can have profound physical and social consequences for affected children, their families, and society as a whole. • Epidemiological insights are vital for they provide the data and understanding needed to the identification of vulnerable populations, aiding in the development of targeted prevention strategies and effective resource allocation. What is New: • The estimated incidence of pediatric TSCI in developed countries is 4.3 cases per million children aged 0-15. The proportion of pediatric TSCI cases in relation to all-age TSCI cases is 3% in developed countries and 4.5% in developing countries. • The etiology of TSCI in pediatric cases differs between developing and developed countries. In developed countries, transport injuries are the most prevalent cause of pediatric TSCI, while falls are the least common cause. Conversely, in developing countries, falls are the leading cause of pediatric TSCI.

Risk of permanent medical impairment after road traffic crashes: A systematic review.

PURPOSE: To systematically review the risk of permanent disability related to road traffic injuries (RTIs) and to determine the implications for future research regarding permanent impairment following road traffic crashes. METHODS: We conducted this systematic review according to the preferred reporting items for systematic reviews and meta-analysis statement. An extended search of the literature was carried out in 4 major electronic databases for scientific research papers published from January 1980 to February 2020. Two teams include 2 reviewers each, screened independently the titles/abstracts, and after that, reviewed the full text of the included studies. The quality of the studies was assessed using the strengthening the reporting of observational studies in epidemiology (STROBE) checklist. A third reviewer was assessed any discrepancy and all data of included studies were extracted. Finally, the data were systematically analyzed, and the related data were interpreted. RESULTS: Five out of 16 studies were evaluated as high-quality according to the STROBE checklist. Fifteen studies ranked the initial injuries according to the abbreviated injury scale 2005. Five studies reported the total risk of permanent medical impairment following RTIs which varied from 2% to 23% for car occupants and 2.8% to 46% for cyclists. Seven studies reported the risk of permanent medical impairment of the different body regions. Eleven studies stated the most common body region to develop permanent impairment, of which 6 studies demonstrated that injuries of the cervical spine and neck were at the highest risk of becoming permanent injured. CONCLUSION: The finding of this review revealed the necessity of providing a globally validated method to evaluate permanent medical impairment following RTIs across the world. This would facilitate decision-making about traffic injuries and efficient management to reduce the financial and psychological burdens for individuals and communities.

Role of genetic polymorphisms in recurrent aphthous stomatitis: A systematic review and meta-analysis.

Recurrent aphthous stomatitis (RAS) is one of the most common oral ulcerative diseases with unknown etiology. Identifying the genetic markers can improve medical care and prevention of RAS. Genetics variants inflammatory agents are associated with the risk of RAS. Thus, this meta-analysis aimed to investigate the genetic polymorphisms in RAS. Electronic literature search was carried out on Scopus, PubMed, and Web of Science (WOS). The references of relevant reviews were also manually checked. The observational studies till the end of 2020 were included. Odds ratio (OR) was estimated by fixed and random effect model. Seventeen polymorphisms in 23 studies were included in analysis. Pooled analysis performed for 12 polymorphisms (IL-2+166, IL-2-330, IL-4-590, IL-4 RA1902, IL-6-597, TNF-α-308, NLRP3(rs4612666, rs10754558), MMP2- rs2285053, MMP9- rs11697325, MMP9- rs3918242, MMP9- rs17576, IL-1a-889, IL-10-819, and IL-12+1188). The meta-analyses carried out for six polymorphisms (IL-1ß-511, IL-1ß+3954, IL-6-174, IL-10-592, IL-10-1082, and serotonin transporter). There were following significant results for IL-10, 819 in allelic:1.46(1.04-2.05) and homozygote: 1.61(1.08-2.39) models, serotonin Transporter in allelic:0.53(0.40-0.71), recessive:0.56(0.35-0.90), dominant:0.35(0.22-0.57) and homozygote:0.30(0.17-0.54) models. IL-1ß-511 in dominant 0.69(0.50-0.95) and overdominant 0.73(0.55-0.96) models, IL-1ß+3954 in allelic 1.25(1.05-1.50), homozygote 1.67(1.05-2.63) and dominant 1.26(1.01-1.57) models, IL-6-174 in dominant 2.24(1.36-3.67), IL-10-592 in homozygote 0.41(0.23-0.72) and dominant 0.55(0.33-0.93), IL-10-1082 in allelic 1.19(1.01-1.39) and dominant 1.29(1.02-1.64). In conclusion, serotonin transporter(L/S), IL-10-819(T/C), IL-10-592(C/A), IL-10-1082(G/A), IL-1ß-511(C/T), IL-6-174(G/C), and IL-1ß+3954 (T/C) polymorphisms are associated with susceptibility to RAS. These variants could be potential predictors of RAS and could be used for the developing clinically effective genetic panel for RAS.

Interactive relationship between Trp metabolites and gut microbiota: The impact on human pathology of disease.

Tryptophan (Trp), an α-amino acid, is the precursor of serotonin (5-hydroxytryptamine, 5-HT), which is involved in a variety of features of metabolic function and human nutrition. Evidence highlights the role of Trp metabolites (exclusively 5-HT) in the gastrointestinal (GI) tract; however, the mechanisms of action involved in the release of 5-HT in the GI tract are still unknown. Considering the fact that variations of 5-HT may facilitate the growth of certain GI disorders, gaining a better understanding of the function and release of 5-HT in the GI tract would be beneficial. Additionally, investigating Trp metabolism may clarify the relationship between Trp and gut microbiota. It is believed that other metabolites of Trp (mostly that of the kynurenine pathway) may play a significant role in controlling gut microbiota function. In this review, we have attempted to summarize the current research investigating the relationship of gut microbiota, Trp and 5-HT metabolism (with particular attention paid to their metabolite type, as well as a discussion of the research methods used in each study). Taking together, regarding the role that Trp/5-HT plays in a range of physical and mental diseases, the gut bacterial types, as well as the related disorders, have been exclusively considered.

Cognitive appraisals of disability in persons with traumatic spinal cord injury: a scoping review.

STUDY DESIGN: Scoping review. OBJECTIVES: To describe the meaning of cognitive appraisals, their relation with outcome. measures, and adapted appraisal scales after Spinal Cord Injury (SCI) in the existing literature. METHODS: This review was performed according to the Arksey and O'Malley (2005) framework that consisted of five steps: setting the review question, searching the literature, selecting and classifying the studies, charting the data, and summarizing the results. Published articles from 1990 to 16 May 2020 related to cognitive appraisal, persons with traumatic SCI (TSCI), and persons older than 18 years were identified by searching by key terms in four databases (PubMed, Web of Science, Scopus, and Embase). RESULTS: The included studies (n = 26) were categorized into three categories. Categories focused on the meanings of cognitive appraisals following TSCI (i.e., appraisals being complex and context-related, or in general definition how persons with TSCI interpret their disability and how they evaluate the resources available to respond to it), the relationship between cognitive appraisals and physical/psychological/social/ outcomes, and appraisals of disability (including the use of appraisals as a predictor of subsequent positive or negative consequences). CONCLUSIONS: The results demonstrated that a cognitive appraisal of TSCI is critical to longer-term rehabilitation outcomes. A combination of physical and psychological-based interventions can help to modify negative or dysfunctional appraisals. Cognitive appraisal in TSCI seems to vary from person to person. To predict it and develop a rehabilitation plan, future research needs to focus on the relationship between cognitive appraisal and person-related factors, including demographic characteristics.

ADA gene haplotype is associated with coronary-in-stent-restenosis.

BACKGROUND: Cardiovascular diseases (CVDs) are the most common and the first cause of death worldwide. While some studies have investigated the association of the Adenosine Deaminase (ADA) gene with CDVs, its roles on in-stent restenosis (ISR) has not been studied. METHODS AND RESULTS: In this study, we investigated the role of ADA gene variants in both genetic and haplotype models on the risk of ISR. 91 samples were included in this study. The subjects were divided into two groups regarding having or not-having ISR (n = 40 ISR+ and n = 51 ISR-). The genotyping for G22A (rs73598374) and A4223C (rs452159) polymorphisms was performed using PCR-RFLP method. Statistical analysis was performed by SPSS v. 20 and Haploview 4.2 softwares. The basic demographic conditions in ISR groups were statistically similar. There was a significant association between A allele of rs452159 ISR groups after adjustment (allelic model: P value = 0.028, OR(95%CI) = 0.366(0.149-0.899)), while rs73598374 polymorphism shows no significant association with ISR. In haplotype analysis, the GA (G:rs73598374/A:rs452159) haplotype decreased the risk of ISR (P value = 00.025, OR(95%CI) = 0.382(0.161-0.907)). CONCLUSIONS: This study suggests that A allele of ADA rs452159 polymorphism and GA (G:rs73598374/A:rs452159) haplotype may be related to decreased risk of ISR in CAD patients receiving drug-eluting stent and offers more observational studies on ADA variants in other populations to generate a potential haplotype panel for ISR risk assessment.

Association of MTHFR C677T polymorphism with elevated homocysteine level and disease development in vitiligo.

Increasing evidence on the association of MTHFR gene polymorphism and serum homocysteine levels with autoimmune diseases such as vitiligo has made the MTHFR gene a very interesting candidate to be evaluated in different ethnicities and populations. We aimed to evaluate the levels of serum homocysteine and vitamin B12 and their associations with MTHFR C677T polymorphism in the Iranian population. This case-control study included 104 patients with vitiligo and 100 age- and sex-matched healthy control subjects. Serum vitamin B12 and homocysteine levels were measured by a chemiluminescence assay. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis was used for genotyping the polymorphism. The mean serum homocysteine levels were significantly higher in cases than controls and associated with disease activity (p < .001). Furthermore, the homozygous MTHFR C677T variant genotype was associated with vitiligo development (adjusted OR: 3.52, 95% CI: 1.09-11.32, p = .02) and elevated homocysteine level (p < .001). There was no association between serum vitamin B12 levels and the MTHFR C677T genotype. The homozygous variant MTHFR C677T may be considered as a risk factor for both elevated homocysteine levels and the development of vitiligo in the Iranian population. Although these results are not conclusive, they could elucidate the contribution of genetic and immune-mediated inflammatory factors to the pathogenesis of vitiligo.

Long-time effects of prenatal morphine, tramadol, methadone, and buprenorphine exposure on seizure and anxiety in immature rats.

Purpose: This study aimed to investigate seizures and anxiety-like behaviors in immature rats prenatally exposed to opiate drugs.Materials and methods: Pregnant rats were randomly divided into five groups: saline, morphine, tramadol, methadone, and buprenorphine. Administrations were performed intraperitoneally once a day for the last seven days of pregnancy. Neonatal rats were subdivided into ten groups, split according to sex. Anxiety-like behavior was tested on postnatal day (PD) 19. On PD 20, seizure was induced by PTZ injection.Results: Morphine in male rats had an increased time to onset (p < 0.005), whereas there was a decreased number of tonic-clonic seizures in females (p < 0.05). Tramadol had an increased duration of tonic-clonic seizures compared to morphine and methadone in males (p < 0.005). Moreover, tramadol decreased open arm time and locomotor activity in males more than in females (p < 0.05). Methadone decreased open arm time in males (p < 0.05). Furthermore, buprenorphine and tramadol decreased open arm entrance in male rats (p < 0.05).Conclusions: It was demonstrated that prenatal tramadol significantly increases both the duration of seizures and anxiety-like behaviors in immature male rats, whereas morphine decreases both of them. The effects of tramadol on seizure and anxiety-like behavior may be due to the comorbid occurrence of the symptoms of these two disorders.

Association of microRNA gene polymorphisms with Type 2 diabetes mellitus: A systematic review and meta-analysis.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a metabolic disorder with growing prevalence and increasing economic burden. Based on the role of genetics and epigenetic factors on T2DM, we aimed to carry a systematic review and meta-analysis for all miRNA gene polymorphisms and risk of T2DM. MATERIALS AND METHODS: A computerized literature search was carried out on PubMed, Web of Science, Scopus, Embase, as well as references of relevant review/meta-analysis. Key search terms were "Diabetes Mellitus, Type 2," "MicroRNAs," and "Polymorphism, Single Nucleotide." All types of observational studies from January 1, 1992, to November 30, 2019, were included, without language restriction. Data analysis was performed using R programming language (3.5.2). Level of heterogeneity was obtained by Cochran's Q test (P < 0.05), and subgroup analysis was performed based on ethnicity. RESULTS: Thirty-two polymorphisms from fifteen articles were included. Meta-analysis was carried out based on minor allele frequencies. Seven studies with 2193 cases and 3963 controls were included for rs2910164 polymorphism. In subgroup analysis, there were significant results in Caucasian population in dominant model (odds ratio [OR] =1.12; 95% confidence interval [CI]: 0.83-1.51), homozygote model (OR = 1.78; 95% CI: 1.06-3.00), heterozygote model (OR = 1.77; 95% CI: 1.03-3.05), and recessive model (OR = 1.78; 95% CI: 1.07-2.96). Four studies with 2085 cases and 1933 controls were included for rs895819 polymorphism. Overall, there was no significant result for association with rs895819, but subgroup analysis revealed that minor allele significantly decreased the risk of T2DM in Caucasians by recessive model (OR = 0.34; 95% CI: 0.18-0.66), dominant model (OR = 0.70; 95% CI: 0.52-0.94), homozygote model (OR = 0.32; 95% CI: 0.16-0.62), heterozygote model (OR = 0.37; 95% CI: 0.19-0.74), allelic model (OR = 0.67; 95% CI: 0.52-0.85). CONCLUSION: The minor allele of rs2910164 may increase the risk of T2DM by leading to lower level of miR-146a. In contrast, minor allele of rs895819 may decrease the risk of T2DM by leading to higher level of miR-27a.

Association of interleukin-6 polymorphisms with obesity: A systematic review and meta-analysis.

Obesity is a common metabolic disorder with increasing trend all around the world. Owing to the role of pro-inflammatory cytokines on obesity, we aimed to investigate the role of interleukin-6 (IL-6) polymorphisms on risk of obesity. Electronic literatures were searched in Web of Science, PubMed, Embase, and Scopus. The references of relevant reviews and included studies were also manually checked. All types of observational studies from 1 January 1992 to 28 February 2018 were included. Odds ratio (OR) was estimated by fixed and random effect model. Subgroup analysis was carried out based on age statues. Pooling analysis of eligible studies have been considered for rs2069845 and rs1800796, and no significant results were observed. Minor allele of IL-6 rs1800797polymorphism decreased the risk of obesity/overweight in allelic 0.74 (0.59-0.92), dominant 0.65 (0.49-0.85), and over-dominant 0.66 (0.51-0.87) models. Fourteen eligible studies were included for rs1800795. According to BMI, C allele showed increased risk of obesity in genetic models containing homozygote model 1.47 (1.02-2.12) for body mass index (BMI) ≥ 25 vs. BMI < 25, recessive model 1.32 (1.07-1.63) for BMI ≥ 30 vs. BMI < 25, and homozygote model 1.35 (1.10-1.66) for BMI ≥ 30 vs. BMI < 30. In overall definition of obesity more significant results were observed, including homozygote model in obese vs. normal 1.71 (1.14-2.56). Similarly, subgroups analysis revealed additional significant results. Minor alleles of rs1800795 raised and rs1800797 reduced the risk of obesity, while rs1800796 and rs2069845 may not be associated. However, more observational studies are recommended to confirm these results.

Nanomaterial based electrochemical sensing of the biomarker serotonin: a comprehensive review.

This review (with 131 references) summarizes the progress made in the past years in the field of nanomaterial based sensing of serotonin (5-HT). An introduction summarizes the significant role of 5-HT as a biomarker for several major diseases, methods for its determination and the various kinds of nanomaterials for use in electrochemical sensing process relies principally on a precise choice of electrodes. The next main section covers nanomaterial based methods for sensing 5-HT, with subsections on electrodes modified with carbon nanotubes, graphene related materials, gold nanomaterials, and by other nanomaterials. A concluding section discusses future perspectives and current challenges of 5-HT determination. Graphical abstract Conceptual design of electrochemical sensing process of the biomarker serotonin by using nanomaterials and the role of 5-HTas biomarker in the body from preclinical to clincal.

Proconvulsant effects of tramadol and morphine on pentylenetetrazol-induced seizures in adult rats using different routes of administration.

Tramadol is frequently used as a pain reliever. However, it has been sometimes noted to have the potential to cause seizures. Because of its dual mechanism of action (both opioid and nonopioid), the adverse effect profile of tramadol can be different in comparison with single-mechanism opioid analgesics, such as morphine. In the present study, the facilitatory effects of tramadol and morphine on pentylenetetrazol-induced seizures using different routes of administration were compared in rats. Adult female rats were divided into six groups and continuously received saline, morphine, or tramadol on a daily basis for 15 days [gavage (PO) or intraperitoneal (IP)]. An increasing dose of morphine and tramadol was used to prevent resistance to repetitive dose (20-125 mg/kg). Following one week of withdrawal period and 30 min before the seizure induction (PTZ=80 mg/kg, IP), each group of rats was further divided into subgroups that received saline, morphine, or tramadol for the second time on the 22nd day of the experiment. Results showed that, while morphine, tramadol, and their administration had different effects on seizure behaviors, both acute and chronic administrations of morphine and tramadol potentiated PTZ-induced seizures. However, there was no significant difference between morphine and tramadol in terms of seizure severity. Effects of morphine and tramadol on PTZ-induced seizures were also stable following one week of withdrawal. In conclusion, this study indicated similar severity in the proconvulsant effect of morphine and tramadol on PTZ-induced seizures, which might depend on their similar effects on GABAergic pathways.

Chronic morphine and tramadol re-exposure induced an anti-anxiety effect in prepubertal rats exposed neonatally to the same drugs.

Anxiety disorders are among the most common mental disorders. Drugs that are often administered to manage medical problems cause rebound anxiety. The use of morphine and tramadol has increased in recent decades. In the present study, the effects of morphine and tramadol exposure during the neonatal and prepubertal periods on anxiety-like behaviours in prepubertal rats were investigated. Male neonate rats were injected subcutaneously with saline, morphine or tramadol (3-21 mg/kg) on a daily basis from postnatal Day (P) 8 to P14. On P22, rats were divided into seven groups (saline/saline, saline/tramadol, saline/morphine, tramadol/saline, tramadol/tramadol, morphine/saline and morphine/morphine) and were injected with saline, tramadol or morphine for seven consecutive days. All rats were tested in an elevated plus maze (EPM) on P24 (acute effects), P27 (chronic effects) and P29. Locomotor activity was increased by the second and third exposure to the EPM. Re-exposure to chronic morphine and tramadol resulted in increased locomotor activity, whereas acute and chronic administration of these drugs induced no notable difference. Anxiety decreased markedly after re-exposure to tramadol and this anxiolytic-like behaviour was more dominant in EPM re-exposure in rats that had received higher doses of tramadol. Re-exposure to tramadol elicited a stronger anxiolytic-like behaviour than re-exposure to morphine. It can be concluded that repeated morphine and tramadol administration during the neonatal period followed by re-exposure to these drugs at an immature stage produces considerable anxiolytic-like behaviour. Exposure to chronic morphine and tramadol during the neonatal period may affect the developing brain, which may induce long-term changes in the opioid response.