A neuroprotective effect of pentoxifylline in rats with diabetic neuropathy: Mitigation of inflammatory and vascular alterations.

BACKGROUND: Treatment of diabetic neuropathic pain does not change the natural history of neuropathy. Improved glycemic control is the recommended treatment in these cases, given that no specific treatment for the underlying nerve damage is available, so far. In the present study, the potential neuroprotective effect of pentoxifylline in streptozotocin (50 mg/kg) induced diabetic neuropathy in rats was investigated. METHODS: Pentoxifylline was administered at doses equivalent to 50, 100 & 200 mg/kg, in drinking water, starting one week after streptozotocin injection and for 7 weeks. Mechanical allodynia, body weight and blood glucose level were assessed weekly. Epidermal thickness of the footpad skin, and neuroinflammation and vascular alterations markers were assessed. RESULTS: Tactile allodynia was less in rats that received pentoxifylline at doses of 100 and 200 mg/kg (60 % mechanical threshold increased by 48 % and 60 %, respectively). The decrease in epidermal thickness of footpad skin was almost completely prevented by the same doses. This was associated with a decrease in spinal tumor necrosis factor alpha (TNFα) and nuclear factor kappa B levels and a decrease in microglial ionized calcium binding adaptor molecule 1 immunoreactivity, compared to the control diabetic group. In sciatic nerve, there was decrease in TNF-α and vascular endothelial growth factor levels and intercellular adhesion molecule immunoreactivity. CONCLUSION: Pentoxifylline showed a neuroprotective effect in streptozotocin-induced diabetic neuropathy, which was associated with a suppression of both the inflammatory and vascular pathogenic pathways that was not associated with a hypoglycemic effect. Thus, it may represent a potential neuroprotective drug for diabetics.

Examining the Impact of the COVID-19 Vaccine on Smokers and Diabetic Individuals: Unveiling the Efficacy and Unraveling Side Effects in Al Jouf Region, KSA.

BACKGROUND: The assessment of the side effects of the COVID-19 vaccine is crucial to inform individuals about the potential risks and benefits of vaccination and to provide appropriate medical care if necessary. The study aimed to assess the effect of the COVID-19 vaccine on smokers and diabetic individuals and to investigate the occurrence of any side effects in the subpopulation of the Al Jouf region, KSA. MATERIALS AND METHODS: The questionnaire had three main sections: the first covered basic information including gender, age, general health status, place, socio-economic position, nationality, smoking, and diabetes. Section 2 included the COVID-19 vaccination status and side effects, and the third section dealt with the dental history. Informed consent was obtained from the recruited individuals. Participants completed a Google self-administered questionnaire. RESULTS: One hundred and twenty participants responded to the survey forms. Similarly, for diabetics versus non-diabetics, there was no statistically significant difference in the type of vaccine received (chi-square value = 3.125, p-value = 0.682). For smokers versus non-smokers, the chi-square test showed a non-significant difference in side effects (chi-square = 2.56, p-value = 0.109), indicating that there was no significant difference in the side effects experienced by smokers and non-smokers. For diabetics versus non-diabetics, the chi-square test showed a non-significant difference in side effects (chi-square = 0.34, p-value = 0.560), indicating that there was no significant difference in the side effects experienced by diabetics and non-diabetics. CONCLUSION: Smokers and diabetics had higher harmful effects than non-smokers and non-diabetics. These findings need larger, robust trials to support treatment decision-making.

Student Perception and Preferences With Social Media for Enhanced Learning in Health Sciences Following Post-COVID-19 Era: A Cross-Sectional Study.

Background During the COVID-19 pandemic, universities worldwide pivoted to distance education, primarily online, using various blended learning tools. In the contemporary era, characterized by widespread high-speed internet and the ubiquity of social media (SM), SM has become an essential tool, especially among students. This study aimed to assess the perception, impact, and preferences of various SM platforms for learning among health sciences students in the post-COVID-19 era. Methodology The study was conducted at constituent colleges of Jouf University and Northern Border University between January and June 2022. Responses from 560 students were assessed using a self-administered, pre-validated questionnaire comprising 31 questions. These questions addressed students' perceptions, preferences, and learning modes derived from SM. Descriptive and inferential statistics evaluated the influence of SM on student learning. Results On average, students spent 3.18 hours daily on SM. YouTube (41.1%) and Instagram (37.1%) emerged as the most preferred platforms for learning. A significant 86.4% of students utilized SM for accessing subject-related texts and watching related videos. Moreover, 78.6% believed that SM platforms enhanced their subject knowledge following lectures. Logistic regression analysis indicated maximum learning benefits for students who used SM between two to three hours daily. Conclusion Social media platforms, when used judiciously, can enhance the learning experience for health sciences students in the post-COVID era. While offering opportunities to acquire new knowledge and skills, care must be taken to prevent misuse, abuse, or related health hazards.

Systematic review fracture resistance of endodontically treated posterior teeth restored with fiber reinforced composites- a systematic review.

BACKGROUND: Large cavity designs and access cavities impair endodontically treated tooth fracture resistance. As the tooth's strength is known to reduce significantly after the root canal treatment, occlusal loading as a result of functions such as chewing, biting and certain parafunctional tendencies makes the endodontically treated tooth vulnerable to fracture. Hence, after endodontic treatment, it is vital to give adequate and appropriate restorative material to avoid tooth fractures. Accordingly, the choice of such restorative material should be dictated by the property of fracture resistance. OBJECTIVE: The goal of this study was to conduct a systematic review and critical analysis of available data from in vitro studies examining the fracture resistance of endodontically treated posterior teeth restored with fiber-reinforced composites. METHODOLOGY: The Preferred Reporting Items for Systematic Review and Meta-Analysis (PRIS-MA) Statement was used to guide the reporting of this systematic review A comprehensive literature search was performed using MEDLINE (via PubMed), Scopus, ScienceDirect, Google Scholar, and LILACS. A manual search of the reference lists of the articles was also performed. The databases provided a total of 796 studies from the electronic systematic search. The databases provided a total of 796 studies from the electronic systematic search. Two reviewers scrutinized the papers for eligibility based on inclusion/exclusion criteria and extracted data. The studies were assessed for their potential risk of bias. Based on modified JBI & CRIS (checklist for reporting in vitro studies) guidelines, along with the methodology and treatment objective, we have formulated 13 parameters specifically to assess the risk of bias. A total of 18 studies met the inclusion criteria and were included for qualitative analysis. Considering the high heterogeneity of the studies included, a meta-analysis could not be performed. RESULTS: The majority of the included studies had a moderate or high risk of bias. When compared to traditional hybrid composites, fiber-reinforced composites showed increased fracture resistance of endodontically treated teeth in the majority of investigations. On the other hand, limited evidence was found for the bulk fill composites. Moreover, moderate evidence was found for the fracture resistance of inlays and fiber posts with fiber-reinforced composites for core build-up in endodontically treated teeth. No evidence could be found comparing the fracture resistance of endo crowns and fiber-reinforced composites in endodontically treated teeth. CONCLUSION: According to the research, using fiber-reinforced composites instead of conventional hybrid composites improves the fracture resistance of endodontically treated teeth. However, there was a high risk of bias in the research considered. No judgments could be reached about the superiority of one material over another based-on comparisons between other core restorations.

Cone Beam Computerized Tomographic Analysis of Collum Angle of the Maxillary Central Incisors in Different Types of Malocclusion: Comparative Assessment in Saudi, Jordan and Egypt Subpopulation.

Background: The collum angle (CA) is an extremely significant for patients who are undergoing orthodontic, dental implant restoration, prosthodontic and periodontic treatments. Aim and Objectives: To determine and compare the mean CA for maxillary central incisor in different types of malocclusion utilizing 3D Cone Beam Computerized Tomography (CBCT) images. The additional objectives were to determine and compare the mean CA for maxillary central incisor based upon the demographic characteristics among Saudi, Jordan and Egypt subpopulation and to test for significant differences in the CA of maxillary central incisor with different molar malocclusions. Methodology: A total of 400 CBCT images were included from the radiology archive at the College of Dentistry, Jouf University (Sakaka, Saudi Arabia). The CBCT images were divided into four groups based upon molar classifications. The selected records were used for the measurement of CA of maxillary central incisor using the measurement tool built into 3D:OnDemand software. Statistical analysis was done using independent t test and ANOVA to examine the differences between gender and races. Results: The mean CA for Class II div 2 exhibited significantly higher crown-root variation as compared other groups (p < 0.0001). Males sample showed greater value of CA for each group as compared to the females and this difference was statistically significant for all the groups other than for Class I (p < 0.05). The post hoc pairwise comparisons between the races showed statistically insignificant findings (p > 0.05). Significant difference was found on pairwise comparisons among different malocclusion groups other than for group Class I/Class II div 1 (p < 0.05). Conclusion: The CA of Class II div 2 group was the greatest as compared to other malocclusion groups. Males sample showed greater value of CA for each group as compared to the females and this difference was statistically significant for all the groups other than for Class I. Statistically insignificant difference was noted for the mean CA among different races whereas significant difference was found on pairwise comparisons among different malocclusion groups other than for group Class I/Class II div 1.

Do learning style preferences influence the cumulative gross point average and self directed learning hours in dental students: a preliminary study.

BACKGROUND: Learning styles influence the outcome of the student performances based on preliminary data available. To evaluate whether the learning styles discriminate the cumulative gross point average (CGPA) scores and self-directed learning hours (SDL) in an integrated curriculum of dental students. METHODS: Participants in this blinded cross-sectional study were dental students enrolled in the Bachelor of Dental & Oral Surgery program at XXXX College of Dentistry. An online survey (Kolb Learning Style Inventory) was used to collect data. It has four sections: Concrete Experience (CE), Abstract Conceptualization (AC), Reflective Observation (RO), and Active Experimentation (AE). Questionnaire was distributed electronically to students of Academic level 1 to 5, selected by using non-probability quota sampling technique. In addition to learning style assessment the questionnaire also included measures to obtain data such as gender, academic level, CGPA score, and SDL hours of participants. The CGPA scores were categorized into average (3 to 3.6), good (3.7 to 4.2), excellent (4.3 to 4.7) and outstanding (> 4.7) as well as SDL in to three classes as, < 1 h, > 1 but < 3 h and > 3 h. Discriminant function test was computed to assess the effectiveness of discrimination by the learning styles in GPA and SDL. RESULTS: The study's questionnaire was completed by 198 participants (43% females and 57% males). Learning styles were discriminated by excellent category of CGPA scores that presented 72.1% group membership whereas in case of outstanding category presented the least as 17% group membership. Learning styles were discriminated by > 2 but < 3 h category of SDL hours that presented 69.7% group membership. CONCLUSION: Learning styles can be used to discriminate the student academic performances and self-directed learning hours. Among the different category of CGPA participants with outstanding performance represent a good prediction for learning styles preferences. Participants with varying SDL hours also influenced the learning styles.

Enhancement of Skill Competencies in Operative Dentistry Using Procedure-Specific Educational Videos (E-Learning Tools) Post-COVID-19 Era-A Randomized Controlled Trial.

E-learning has completely transformed how people teach and learn, particularly in the last three pandemic years. This study evaluated the effectiveness of additional procedure-specific video demonstrations through E-learning in improving the knowledge and practical preclinical skills acquisition of undergraduate dental students in comparison with live demonstration only. A randomized controlled trial was conducted for the second-year dental students in the College of Dentistry, Jouf University, to evaluate the impact of E-learning-assisted videos on preclinical skill competency levels in operative dentistry. After a brief introduction to this study, the second-year male and female students voluntarily participated in the survey through an official college email. Fifty participants were enrolled in the study after obtaining informed consent. The participants were randomly divided into two groups, twenty-five each. The control group (Group A) was taught using traditional methods, and the intervention group (Group B) used E-learning-assisted educational videos and traditional techniques. An objective structured practical examination (OSPE) was used to assess both groups. The faculty members prepared a structured, standardized form to evaluate students. After OSPE, statistical analysis was done to compare the grades of OSPE between Group A and Group B. Logistic regression analysis was done to express the effect of components of the OSPE on gender, cumulative gross point average (CGPA), Group A and Group B. The results showed a significant difference in the experimental groups after the intervention (p < 0.000). The simulator position parameter demonstrated that the participants had a significant competence level after the intervention by procedure-specific videos (p < 0.000) and an exponential value of 6.494. The participants taught by E-learning-assisted procedure-specific videos and traditional teaching strategies demonstrated an enhanced learning and skill competency level than participants who used only traditional teaching strategies.

Effect of N95 filtering facepiece respirators on dental health professionals with an emphasis on pulmonary function and heart rate: an intrasubject comparison.

Despite the ubiquitous use of N95 filtering facepiece respirators (N95 FFR), published literature on the topic remains scarce, especially in relation to dental professionals. This study assesses the impact of N95 FFRs on blood oxygen saturation and heart rate of dental health professionals while performing procedures requiring varying degrees of physical exertion in an aerosol-rich environment. A total of 51 participants, consisting of 43 men and eight women aged between 23 and 31 years were recruited into the study. All subjects were well-versed in wearing personal protective equipment (PPE). A clinical grade pulse oximeter was used with a clamp placed around the fingertip or the earlobe of the participant. The selection of N95 FFR was based on fit and leakage. All data were collected once from the same participants using a surgical mask as a control. Data were collected again from the same subjects after 1, 2, and 3 hours of use. There were significant differences in both oxygen saturation (SpO2) and heart rate between the two groups after 1, 2, and 3 hours of wearing the respective masks. In healthy young individuals, wearing an N95 FFR for an extended period of time during clinical dental procedures reduced the SpO2level and increased the heart rate compared with a standard surgical mask. However, SpO2 levels remained within a healthy range of more than 95%, and heart rate was within acceptable limits.

Novel Approach to Dental Biofilm Management through Guided Biofilm Therapy (GBT): A Review.

Dental biofilm plays a very crucial role in the etiopathogenesis of periodontal andperi-implant diseases. Over the past decade, tremendous research has been carried outto know the structure of biofilm and the mechanism by which it causes the destruction of supporting tissues of tooth or implant. Periodontal or peri-implant therapy usually begins with primarily removing thebiofilm and is considered as non-surgical mechanical debridement. Although scaling and root planing (SRP) is regarded as a gold standard for mechanical plaque debridement, various other means of biofilm removal have constantly been evolving. These may vary from different scaling systems such as vector systems to decontamination of pockets with LASER therapy. Nowadays, a new concept has emerged known as "guided biofilm therapy" (GBT). It is beneficial in removing the biofilm around the tooth and implant structures, resulting in better or comparable clinical outcomes than SRP. These results were substantiated with the reduction in the microbial load as well as the reduction in the inflammatory cytokines. This review will highlight the various aspects of GBT used in periodontal and peri-implant disease.

Evaluation of temporomandibular disorders among dental students of Saudi Arabia using Diagnostic Criteria for Temporomandibular Disorders (DC/TMD): a cross-sectional study.

BACKGROUND: Temporomandibular disorders (TMD) are a broad category of conditions arising from the various components of the temporomandibular joint complex. Bio-psychosocial model is the most accepted theory describing the etiopathogenesis of TMD. Dental students are vulnerable to psychological disorders, including anxiety, depression, and stress. Hence, the aim of the current study was to evaluate the prevalence and possible risk factors of TMD among dental students of various academic levels and explore the association of TMDs with demographic, academic, and psychosocial parameters. METHODS: A total of 246 students of a Saudi Arabia dental school were chosen for the study. After getting consent, all students were examined according to the Diagnostic Criteria for Temporomandibular Disorders, including Axis I and II components. RESULTS: The overall cross-sectional prevalence of TMD was found to be 36.99%. Pain arising from the jaw, temple, and the peri-auricular area were the most commonly reported symptoms and elicited signs during examination. Among the pain-related TMD, myalgia was the commonest diagnosed condition, whereas disc displacement with reduction was found prevalent in the intra-articular disorder category. Female (OR = 1.94; P = 0.004), married (OR = 1.74; P = 0.04), and students in clinical academic levels (OR = 1.65; P = 0.03) were found to have significantly increased risk of TMD. Among the psychosocial parameters, anxiety (OR = 1.55; P = 0.04) and parafunctional behaviours (OR = 2.10; P < 0.001) were shown to increase the risk of developing TMD. Students with any TMD reported to have significantly higher pain intensity levels (OR = 1.68; P = 0.01) and jaw functional limitations (OR = 1.45; P = 0.008). CONCLUSION: Dental students, especially in clinical levels were shown to pose a higher risk of developing TMD, hence strategies such as academic counselling and objective evaluation via rubrics should be planned to modify the administration of the curriculum, training methods and evaluation process.

Assessing the Prevalence and Association of Pulp Stones with Cardiovascular Diseases and Diabetes Mellitus in the Saudi Arabian Population-A CBCT Based Study.

The detection of pulp stone in a patient suffering from undiagnosed systemic diseases can be an early diagnostic indicator. Thus, the aim of the study was to assess the prevalence of pulp stones in the Saudi Arabian population with cardiovascular diseases and diabetes mellitus. In a retrospective study, we included cone-beam computed tomography (CBCT) scans of 73 patients with cardiovascular disease and 76 patients with diabetes mellitus as group I and II, respectively. Group III comprised of CBCT scan of 80 healthy controls. From a total of 229 scans, 4807 teeth were screened for pulp stones throughout the arches. A chi-square test was used for comparing the prevalence of pulp stones among the groups. Univariable and multivariable analysis was done to evaluate the independent risk indicators for pulp stones. The tooth-wise prevalence of pulp stones in group I, II, and III was found to be 16.65%, 9.01%, and 3.86%, respectively. Patient-wise (p < 0.01) and tooth-wise (p < 0.01) prevalence was recorded significantly highest in the cardiovascular group followed by the diabetic group. The control group had the least prevalence. Significantly (p < 0.01) higher number of pulp stones were found in cardiovascular patients with age > 50 years compared to other groups. Similarly, a significantly increased number of pulp stones were seen in the 1st molar (p < 0.05) and the maxillary jaw (p < 0.05) of patients with cardiovascular diseases. Subjects with cardiovascular disease and diabetes were found to have 2.94 times (p < 0.001; CI 1.54-3.10) and 1.81 times (p < 0.01; CI 0.48-2.06) higher risk of having pulp stones in comparison to healthy subjects. The first molar has 2.20 times (p < 0.001; CI 0.84-2.45) increased the risk of having pulp stones compared to other tooth types. Systemic disease such as cardiovascular disease and diabetes mellitus poses a higher risk for the development of pulp stones. Among the systemic disease group, patients in the cardiovascular group showed a higher risk for pulp stones and also reported the maximum number of pulp stones compared to the diabetic and healthy subjects.

Comparative Evaluation of Dental Implant Failure among Healthy and Well-Controlled Diabetic Patients-A 3-Year Retrospective Study.

Diabetes mellitus is known to compromise the various aspects of homeostasis, including the immune response and the composition of oral microflora. One of the oral manifestations of diabetes mellitus is tooth loss and the survival rate of dental implants chosen as a treatment modality for its rehabilitation is controversial. The current study aims to evaluate and compare the failure rate of dental implants between well-controlled diabetic and healthy patients. A retrospective study of case-control design was conceptualized with 121 well-controlled diabetic and 136 healthy individuals. Records of subjects who had undergone oral rehabilitation with dental implants between the periods of January 2013 to January 2016 were retrieved. Post-operative evaluation was carried out for all patients for about three years to assess the immediate and long-term success of the procedure. From a total of 742 dental implants, 377 were placed in well-controlled diabetic patients (case group) and 365 in healthy subjects (control group). A comparable (9.81%), but non-significant (p = 0.422) failure rate was found in the case group in comparison to the control group (9.04%). A non-significant (p = 0.392) raised number (4.98%) of failure cases were reported among females in comparison to males (4.44%). In respect to arch, the mandibular posterior region was reported as the highest failure cases (3.09%; p = 0.411), with 2.29% of cases reported in the mandibular anterior (p = 0.430) and maxillary posterior (p = 0.983) each. The maxillary anterior region was found to have the least number (1.75%; p = 0.999) of failure cases. More (4.98%; p = 0.361) cases were reported to fail during the functional loading stage in contrast to osseointegration (4.44%; p = 0.365). A well-controlled diabetic status does not impose any additional risk for individuals undergoing dental implant therapy.

Equivalent intraperitoneal doses of ibuprofen supplemented in drinking water or in diet: a behavioral and biochemical assay using antinociceptive and thromboxane inhibitory dose-response curves in mice.

Background. Ibuprofen is used chronically in different animal models of inflammation by administration in drinking water or in diet due to its short half-life. Though this practice has been used for years, ibuprofen doses were never assayed against parenteral dose-response curves. This study aims at identifying the equivalent intraperitoneal (i.p.) doses of ibuprofen, when it is administered in drinking water or in diet. Methods. Bioassays were performed using formalin test and incisional pain model for antinociceptive efficacy and serum TXB2 for eicosanoid inhibitory activity. The dose-response curve of i.p. administered ibuprofen was constructed for each test using 50, 75, 100 and 200 mg/kg body weight (b.w.). The dose-response curves were constructed of phase 2a of the formalin test (the most sensitive phase to COX inhibitory agents), the area under the 'change in mechanical threshold'-time curve in the incisional pain model and serum TXB2 levels. The assayed ibuprofen concentrations administered in drinking water were 0.2, 0.35, 0.6 mg/ml and those administered in diet were 82, 263, 375 mg/kg diet. Results. The 3 concentrations applied in drinking water lay between 73.6 and 85.5 mg/kg b.w., i.p., in case of the formalin test; between 58.9 and 77.8 mg/kg b.w., i.p., in case of the incisional pain model; and between 71.8 and 125.8 mg/kg b.w., i.p., in case of serum TXB2 levels. The 3 concentrations administered in diet lay between 67.6 and 83.8 mg/kg b.w., i.p., in case of the formalin test; between 52.7 and 68.6 mg/kg b.w., i.p., in case of the incisional pain model; and between 63.6 and 92.5 mg/kg b.w., i.p., in case of serum TXB2 levels. Discussion. The increment in pharmacological effects of different doses of continuously administered ibuprofen in drinking water or diet do not parallel those of i.p. administered ibuprofen. It is therefore difficult to assume the equivalent parenteral daily doses based on mathematical calculations.

Prophylactic L-arginine and ibuprofen delay the development of tactile allodynia and suppress spinal miR-155 in a rat model of diabetic neuropathy.

Diabetic neuropathy (DN) is a common complication of diabetes mellitus that is hardly reversible at the late stages. Since treatment of neuropathic pain is predominantly symptomatic, a prophylactic measure would be useful. Both ibuprofen and L-arginine exert antiallodynic effects on chronic constriction injury (CCI)-induced cold allodynia. Furthermore, ibuprofen is effective in CCI-induced mechanical allodynia. The aim of the study was to assess the antiallodynic effect of prophylactic ibuprofen and L-arginine in streptozotocin-induced DN in rats and to further investigate the role of spinal miR-155 and nitric oxide (NO) in this effect. Tactile allodynia was assessed weekly by von Frey filaments. Oral daily administration of ibuprofen, L-arginine and their combination, for 4 weeks starting 1 week after streptozotocin injection (ie, before the development of tactile allodynia), resulted in a significant decrease of tactile allodynia compared with the control diabetic group. This was evident in the fifth week of the experiment. The 3 treatments prevented the decrease in muscle fiber diameter and epidermal thickness, seen in the control diabetic group. Furthermore, ibuprofen, L-arginine and their combination prevented the increase in the spinal NO level and miRNA-155, seen in the control diabetic group. In conclusion, both ibuprofen and L-arginine delayed the development of behavioral and histologic changes of DN, with concomitant suppression of spinal miR-155 and NO level. L-arginine being tolerable may be useful prophylactically in diabetic patients.

Nitric oxide is involved in ibuprofen preemptive analgesic effect in the plantar incisional model of postsurgical pain in mice.

Control of postoperative pain is far from satisfactory. Yet, non-steroidal anti-inflammatory drugs (NSAIDs) remain an important choice. The production of nitric oxide (NO), which plays an important role in the development and maintenance of inflammatory hyperalgesia, is inhibited by NSAIDs. Monoamines also play a key role in the modulation of nociception. The aim of the present work is to study the involvement of NO and monoamines in the antinociceptive mechanism of ibuprofen in postsurgical pain in mice. Surgical incision resulted in mechanical allodynia and increased spinal NO levels. The nitric oxide synthase inhibitor l-NAME (50mg/kg), administered intraperitoneally (i.p.), 30min before the incision decreased the development of postsurgical mechanical allodynia and reduced spinal NO levels. Ibuprofen (100 and 300mg/kg, i.p.), administered 30min before the incision, dose-dependently decreased both spinal NO levels and the development of mechanical allodynia. Administration of ibuprofen (100mg/kg i.p.), 20min following surgery, did not significantly reduce spinal NO level and resulted in a smaller antiallodynic effect. l-Arginine (600mg/kg i.p.), administered 20min before ibuprofen administration, restored both spinal NO level and mechanical allodynia in ibuprofen-treated mice. The selective alpha-2 adrenoceptor blocker yohimbine (4mg/kg i.p.), administered 30min before ibuprofen, also blocked ibuprofen effect on both mechanical allodynia and spinal NO level. These results suggest that inhibition of NO synthesis is involved in the analgesic activity of ibuprofen in post-surgical pain. Alpha-2 adrenoceptors are also involved in the analgesic activity of ibuprofen and NO may be involved in this mechanism.

Ibuprofen suppresses depressive like behavior induced by BCG inoculation in mice: role of nitric oxide and prostaglandin.

Prostaglandins (PGs) and nitric oxide (NO) may be involved in the pathophysiology of depression. Since NSAIDs decrease PGs and NO production, they may have an antidepressant effect. The aim of the present work was to explore a possible antidepressant action of ibuprofen in the new model of Bacillus Calmette-Guerin (BCG) induced depression. Mice injected with BCG (10(7) CFU/mouse intraperitoneally) showed an increase in the total immobility time during the forced swim test (FST) and the tail suspension test (TST) and an increase in cerebral PGE2 and NO levels. Fluoxetine administered in drinking water at a dose of 80 mg/l, 5 days before BCG and for 2 more weeks resulted in significant decrease in total immobility time during FST and TST and in cerebral PGE2 and NO levels. Both ibuprofen (200 mg/l) and L-NAME (1 g/l) administered in drinking water 24 h before BCG and for 2 more weeks resulted in decrease in the total immobility time during FST and TST and in cerebral PGE2 and NO levels, which was comparable to fluoxetine's effect. On the other hand, l-arginine administered at a dose of 6 g/l in drinking water together with ibuprofen or fluoxetine reversed their effect on FST, TST and cerebral PGE2 and NO levels. Immunohistochemistry showed a decrease in COX-1 and i-NOS immunoreactivity in the CA1 and CA3 areas of the hippocampus following ibuprofen treatment. These results suggest that ibuprofen may have an antidepressant effect through inhibition of PGE2 and NO production, especially in depression secondary to chronic inflammation.

Nitric oxide is negatively correlated to pain during acute inflammation.

BACKGROUND: The role that nitric oxide (NO) plays in modulating pain in the periphery is unclear. We show here, the results of two independent clinical studies (microdialysis and gene expression studies) and a pilot dose finding study (glyceryl trinitrate study), to study the role of NO in the early phase of acute inflammatory pain following oral surgery. The effect of ketorolac on NO production and nitric oxide synthase (NOS) gene expression was also studied. RESULTS: Microdialysis samples showed significantly higher levels of NO at the first 100 min compared to the last 80 minutes in the placebo treated group. In the ketorolac group, on the other hand, NO levels gradually decreased over the first 60 min but were similar to placebo over the later 100-180 min, with no significant change in NO level over time. The levels of NO were negatively correlated to pain intensity scores. Local infusion of the NO donor glyceryl trinitrate at the site of surgery, showed a small analgesic effect that did not reach statistical significance in the sample size used. While the gene expression of iNOS and eNOS were not up-regulated, 3 hours after surgery, nNOS was downregulated in both treatment groups and eNOS gene expression was significantly lower in the ketorolac group compared to the placebo group. Further, there was a positive correlation between the change in gene expression of nNOS and eNOS in the placebo group but not in the ketorolac group. CONCLUSION: We suggest that at this early stage of inflammatory pain in man, NO is analgesic in the periphery. Further, ketorolac down-regulates eNOS gene expression.

Kinin B1 receptors contributes to acute pain following minor surgery in humans.

BACKGROUND: Kinins play an important role in regulation of pain and hyperalgesia after tissue injury and inflammation by activating two types of G-protein-coupled receptors, the kinin B1 and B2 receptors. It is generally accepted that the B2 receptor is constitutively expressed, whereas the B1 receptor is induced in response to inflammation. However, little is known about the regulatory effects of kinin receptors on the onset of acute inflammation and inflammatory pain in humans. The present study investigated the changes in gene expression of kinin receptors and the levels of their endogenous ligands at an early time point following tissue injury and their relation to clinical pain, as well as the effect of COX-inhibition on their expression levels. RESULTS: Tissue injury resulted in a significant up-regulation in the gene expression of B1 and B2 receptors at 3 hours post-surgery, the onset of acute inflammatory pain. Interestingly, the up-regulation in the gene expression of B1 and B2 receptors was positively correlated to pain intensity only after ketorolac treatment, signifying an interaction between prostaglandins and kinins in the inflammatory pain process. Further, the gene expression of both B1 and B2 receptors were correlated. Following tissue injury, B1 ligands des-Arg9-BK and des-Arg10-KD were significantly lower at the third hour compared to the first 2 hours in both the placebo and the ketorolac treatment groups but did not differ significantly between groups. Tissue injury also resulted in the down-regulation of TRPV1 gene expression at 3 hours post-surgery with no significant effect by ketorolac treatment. Interestingly, the change in gene expression of TRPV1 was correlated to the change in gene expression of B1 receptor but not B2 receptor. CONCLUSIONS: These results provide evidence at the transcriptional level in a clinical model of tissue injury that up-regulation of kinin receptors are involved in the development of the early phase of inflammation and inflammatory pain. The up-regulation of B1 receptors may contribute to acute inflammatory pain through TRPV1 activation.

Mechanisms of non-opioid analgesics beyond cyclooxygenase enzyme inhibition.

Non-opioid analgesics including both selective and non-selective cyclooxygenase (COX) inhibitors and acetaminophen are the most widely used treatments for pain. Inhibition of COX is thought to be largely responsible for both the therapeutic and adverse effects of this class of drugs. Accumulating evidence over the past two decades has demonstrated effects of non-opioids beyond the inhibition of COX and prostaglandin synthesis that might also explain their therapeutic and adverse effects. These include their interaction with endocannabinoids, nitric oxide, monoaminergic, and cholinergic systems. Moreover, the recent development of microarray technology that allows the study of human gene expression suggests multiple pathways that may be related to the analgesic and anti-inflammatory effects of non-opioids. The present review will discuss the multiple actions of non-opioids and their interactions with these systems during inflammation and pain, suggesting that COX inhibition is an incomplete explanation for the actions of non-opioids and proposes the involvement of multiple selective targets for their analgesic, as well as, their adverse effects.

Upregulation of IL-6, IL-8 and CCL2 gene expression after acute inflammation: Correlation to clinical pain.

Tissue injury initiates a cascade of inflammatory mediators and hyperalgesic substances including prostaglandins, cytokines and chemokines. Using microarray and qRT-PCR gene expression analyses, the present study evaluated changes in gene expression of a cascade of cytokines following acute inflammation and the correlation between the changes in the gene expression level and pain intensity in the oral surgery model of tissue injury and acute pain. Tissue injury resulted in a significant upregulation in the gene expression of interleukin-6 (IL-6; 63.3-fold), IL-8 (8.1-fold), chemokine (C-C motif) ligand 2 (CCL2; 8.9-fold), chemokine (C-X-C motif) ligand 1 (CXCL1; 30.5-fold), chemokine (C-X-C motif) ligand 2 (CXCL2; 26-fold) and annexin A1 (ANXA1; 12-fold). The upregulation of IL-6 gene expression was significantly correlated to the upregulation of IL-8, CCL2, CXCL1 and CXCL2 gene expression. Interestingly, the tissue injury-induced upregulation of IL-6, IL-8 and CCL2 gene expression, was positively correlated to pain intensity at 3h post-surgery, the onset of acute inflammatory pain. However, ketorolac treatment did not have a significant effect on the gene expression of IL-6, IL-8, CCL2, CXCL2 and ANXA1 at the same time point of acute inflammation. These results demonstrate that the upregulation of IL-6, IL-8 and CCL2 gene expression contributes to the development of acute inflammation and inflammatory pain. The lack of effect of ketorolac on the expression of these gene products may be related to the ceiling analgesic effects of non-steroidal anti-inflammatory drugs.