Effects of gestational and breastfeeding caffeine exposure in adenosine A1 agonist-induced antinociception of infant rats.

OBJECTIVES: Caffeine is extensively consumed as a psychostimulant drug, acting on A1 and A2A adenosine receptors blockade. Chronic exposure to caffeine during gestation and breast-feeding may be involved in infant rat's behavioral and biochemical alterations. Our goal was to evaluate the effect of chronic caffeine exposure during gestation and breast-feeding in the functionality of adenosine A1 receptors in infant rats at P14. NTPDase and 5'-nucleotidase activities were also evaluated. METHODS: Mating of adult female Wistar rats was confirmed by presence of sperm in vaginal smears. Rats were divided into three groups on the first day of pregnancy: (1) control: tap water, (2) caffeine: 0.3 g/L until P14, and (3) washout caffeine: caffeine was changed to tap water at P7. Evaluation of nociceptive response was performed at P14 using hot plate (HP) and tail-flick latency (TFL) tests. A1 receptor involvement was assessed using caffeine agonist (CPA) and antagonist (DPCPX). Enzymatic activities assays were conducted in the spinal cord. RESULTS: Gestational and breastfeeding exposure to caffeine (caffeine and washout groups) did not induce significant alterations in thermal nociceptive thresholds (HP and TF tests). Both caffeine groups did not show analgesic response induced by CPA when compared to the control group at P14, indicating chronic exposure to caffeine in the aforementioned periods inhibits the antinociceptive effects of the systemic A1 receptor agonist administration. No effect was observed upon ectonucleotidase activities. CONCLUSIONS: Our results demonstrate that chronic caffeine exposure in gestational and breastfeeding alters A1-mediated analgesic response in rats.

A Framework for Understanding the Relationship between Descending Pain Modulation, Motor Corticospinal, and Neuroplasticity Regulation Systems in Chronic Myofascial Pain.

Myofascial pain syndrome (MPS) is a leading cause of chronic musculoskeletal pain. However, its neurobiological mechanisms are not entirely elucidated. Given the complex interaction between the networks involved in pain process, our approach, to providing insights into the neural mechanisms of pain, was to investigate the relationship between neurophysiological, neurochemical and clinical outcomes such as corticospinal excitability. Recent evidence has demonstrated that three neural systems are affected in chronic pain: (i) motor corticospinal system; (ii) internal descending pain modulation system; and (iii) the system regulating neuroplasticity. In this cross-sectional study, we aimed to examine the relationship between these three central systems in patients with chronic MPS of whom do/do not respond to the Conditioned Pain Modulation Task (CPM-task). The CPM-task was to immerse her non-dominant hand in cold water (0-1°C) to produce a heterotopic nociceptive stimulus. Corticospinal excitability was the primary outcome; specifically, the motor evoked potential (MEP) and intracortical facilitation (ICF) as assessed by transcranial magnetic stimulation (TMS). Secondary outcomes were the cortical excitability parameters [current silent period (CSP) and short intracortical inhibition (SICI)], serum brain-derived neurotrophic factor (BDNF), heat pain threshold (HPT), and the disability related to pain (DRP). We included 33 women, (18-65 years old). The MANCOVA model using Bonferroni's Multiple Comparison Test revealed that non-responders (n = 10) compared to responders (n = 23) presented increased intracortical facilitation (ICF; mean ± SD) 1.43 (0.3) vs. 1.11 (0.12), greater motor-evoked potential amplitude (µV) 1.93 (0.54) vs. 1.40 (0.27), as well a higher serum BDNF (pg/Ml) 32.56 (9.95) vs. 25.59 (10.24), (P < 0.05 for all). Also, non-responders presented a higher level of DRP and decreased HPT (P < 0.05 for all). These findings suggest that the loss of net descending pain inhibition was associated with an increase in ICF, serum BDNF levels, and DRP. We propose a framework to explain the relationship and potential directionality of these factors. In this framework we hypothesize that increased central sensitization leads to a loss of descending pain inhibition that triggers compensatory mechanisms as shown by increased motor cortical excitability.

Repetitive Transcranial Magnetic Stimulation for Fibromyalgia: Systematic Review and Meta-Analysis.

BACKGROUND: Fibromyalgia (FM) is a prevalent chronic pain syndrome with few effective therapeutic options available. Repetitive transcranial magnetic stimulation (rTMS) is an emerging therapeutic alternative for this condition; however, results have been mixed. OBJECTIVES: To evaluate the efficacy of rTMS on FM, a comprehensive systematic review and meta-analysis were performed. METHODS: Relevant published, English and Portuguese language, randomized clinical trials (RCT) comparing rTMS (irrespective of the stimulation protocol) to sham stimulation for treating FM pain intensity, depression, and/or quality of life (QoL) were identified, considering only those with low risk for bias. Trials available until April 2014 were searched through MEDLINE, EMBASE, the Cochrane Library Databases, and other 26 relevant medical databases covering from every continent. The outcomes for pain, depression, and QoL assessed closest to the 30th day after rTMS treatment were extracted, and changes from baseline were calculated to compare the effects of rTMS vs. placebo. RESULTS: One hundred and sixty-three articles were screened, and five with moderate to high quality were included. rTMS improved QoL with a moderate effect size (Pooled SMD = -0.472 95%CI = -0.80 to -0.14); it showed a trend toward reducing pain intensity (SMD = -0.64 95%CI = -0.31 to 0.017), but did not change depressive symptoms. CONCLUSION: In comparison with sham stimulation, rTMS demonstrated superior effect on the QoL of patients with FM 1 month after starting therapy. However, further studies are needed to determine optimal treatment protocols and to elucidate the mechanisms involved with this effect, which does not seem to be mediated by changes in depression, but that may involve pain modulation. Level of evidence 1b.

Cognitive effects and autonomic responses to transcranial pulsed current stimulation.

Transcranial pulsed current stimulation (tPCS) is emerging as an option in the field of neuromodulation; however, little is known about its effects on cognition and behavior and its neurophysiological correlates as indexed by autonomic responses. Our aim was to identify the effects of tPCS on arithmetic processing and risk-taking behavior, and to further categorize physiological autonomic responses by heart rate variability (HRV) and electrodermal activity measurements before, during, and after exposure to task performance and stimulation. Thirty healthy volunteers were randomized to receive a single session of sham or active stimulation with a current intensity of 2 mA and a random frequency between 1 and 5 Hz. Our results showed that tPCS has a modest and specific effect on cognitive performance as indexed by the cognitive tasks chosen in this study. There was a modest effect of active tPCS only on performance facilitation on a complex-level mathematical task as compared to sham stimulation. On autonomic responses, we observed that HRV total power increased while LF/HF ratio decreased in the tPCS active group compared to sham. There were no group differences for adverse effects. Based on our results, we conclude that tPCS, in healthy subjects, has a modest and specific cognitive effect as shown by the facilitation of arithmetical processing on complex mathematical task. These effects are accompanied by modulation of the central autonomic network providing sympathetic-vagal balance during stressful conditions. Although behavioral results were modest, they contribute to the understanding of tPCS effects and cognitive enhancement.

Neuroplastic Effects of Transcranial Direct Current Stimulation on Painful Symptoms Reduction in Chronic Hepatitis C: A Phase II Randomized, Double Blind, Sham Controlled Trial.

INTRODUCTION: Pegylated Interferon Alpha (Peg-IFN) in combination with other drugs is the standard treatment for chronic hepatitis C infection (HCV) and is related to severe painful symptoms. The aim of this study was access the efficacy of transcranial direct current stimulation (tDCS) in controlling the painful symptoms related to Peg-IFN side effects. MATERIALS AND METHODS: In this phase II double-blind trial, twenty eight (n = 28) HCV subjects were randomized to receive either 5 consecutive days of active tDCS (n = 14) or sham (n = 14) during 5 consecutive days with anodal stimulation over the primary motor cortex region using 2 mA for 20 min. The primary outcomes were visual analogue scale (VAS) pain and brain-derived neurotrophic factor (BDNF) serum levels. Secondary outcomes were the pressure-pain threshold (PPT), the Brazilian Profile of Chronic Pain: Screen (B-PCP:S), and drug analgesics use. RESULTS: tDCS reduced the VAS scores (P < 0.003), with a mean pain drop of 56% (p < 0.001). Furthermore, tDCS was able to enhance BDNF levels (p < 0.01). The mean increase was 37.48% in the active group. Finally, tDCS raised PPT (p < 0.001) and reduced the B-PCP:S scores and analgesic use (p < 0.05). CONCLUSIONS: Five sessions of tDCS were effective in reducing the painful symptoms in HCV patients undergoing Peg-IFN treatment. These findings support the efficacy of tDCS as a promising therapeutic tool to improve the tolerance of the side effects related to the use of Peg-IFN. Future larger studies (phase III and IV trials) are needed to confirm the clinical use of the therapeutic effects of tDCS in such condition. TRIAL REGISTRATION: Brazilian Human Health Regulator for Research with the approval number CAAE 07802012.0.0000.5327.

Periodontal disease and high doses of inhaled corticosteroids alter NTPDase activity in the blood serum of rats.

BACKGROUND: Certain drugs such as glucocorticoids may interfere with the modulation of periodontal disease. In contrast, corticosteroid treatment has been associated with a protective effect with regard to periodontal breakdown, depending on the dose, pathway, and exposure time. Considering the potential relevance of nucleotidases in coordinating the cardiovascular system and inflammation processes, the aim of this study was to investigate the nucleotidase activities in the blood serum of rats with periodontal disease exposed chronically to inhaled corticosteroids. METHODS: Adult male Wistar rats (n=26) were randomly assigned to one of the following four study groups: a control group that received no intervention; a periodontal disease group that received saline solution; a 'low dose' group that received 30 µg of budesonide daily; and a corresponding 'high dose' group that received 100 µg daily over a 15-day time course. The hydrolysis of ATP, ADP, and AMP were analysed in blood serum. RESULTS: Periodontal disease diminished the hydrolysis of ATP and enhanced the hydrolysis of ADP. Repeated administration of either a low or high dose in the periodontal disease model of inhaled corticosteroids reversed the observed increase in ADP hydrolysis, and only the repeated administration of low doses of inhaled corticosteroids was able to reverse the decrease in the hydrolysis of ATP induced by periodontal disease. CONCLUSION: The variables investigated in this study may be involved in the pathophysiology of periodontal disease and may participate in the mechanisms that mediate the development of some of the side effects of inhaled corticosteroids.

Association of anxiety with intracortical inhibition and descending pain modulation in chronic myofascial pain syndrome.

BACKGROUND: This study aimed to answer three questions related to chronic myofascial pain syndrome (MPS): 1) Is the motor cortex excitability, as assessed by transcranial magnetic stimulation parameters (TMS), related to state-trait anxiety? 2) Does anxiety modulate corticospinal excitability changes after evoked pain by Quantitative Sensory Testing (QST)? 3) Does the state-trait anxiety predict the response to pain evoked by QST if simultaneously receiving a heterotopic stimulus [Conditional Pain Modulation (CPM)]? We included females with chronic MPS (n = 47) and healthy controls (n = 11), aged 19 to 65 years. Motor cortex excitability was assessed by TMS, and anxiety was assessed based on the State-Trait Anxiety Inventory. The disability related to pain (DRP) was assessed by the Profile of Chronic Pain scale for the Brazilian population (B:PCP:S), and the psychophysical pain measurements were measured by the QST and CPM. RESULTS: In patients, trait-anxiety was positively correlated to intracortical facilitation (ICF) at baseline and after QST evoked pain (ß = 0.05 and ß = 0.04, respectively) and negatively correlated to the cortical silent period (CSP) (ß = -1.17 and ß = -1.23, respectively) (P <0.05 for all comparisons). After QST evoked pain, the DRP was positively correlated to ICF (ß = 0.02) (P < 0.05). Pain scores during CPM were positively correlated with trait-anxiety when it was concurrently with high DRP (ß = 0.39; P = 0.02). Controls' cortical excitability remained unchanged after QST. CONCLUSIONS: These findings suggest that, in chronic MPS, the imbalance between excitatory and inhibitory descending systems of the corticospinal tract is associated with higher trait-anxiety concurrent with higher DRP.

The relationship between cortical excitability and pain catastrophizing in myofascial pain.

UNLABELLED: Pain catastrophizing regularly occurs in chronic pain patients. It has been suggested that pain catastrophizing is a stable, person-based construct. These findings highlight the importance of investigating catastrophizing in conceptualizing specific approaches for pain management. One important area of investigation is the mechanism underlying pain catastrophizing. Therefore, this study explored the relationship between a neurophysiological marker of cortical excitability, as assessed by transcranial magnetic stimulation, and catastrophizing, as assessed by the Brazilian Portuguese Pain Catastrophizing Scale, in patients with chronic myofascial pain syndrome. The Pain Catastrophizing Scale is a robust questionnaire used to examine rumination, magnification and helplessness that are associated with the experience of pain. We include 24 women with myofascial pain syndrome. The Brazilian Portuguese Pain Catastrophizing Scale and cortical excitability were assessed. Functional and behavioral aspects of pain were evaluated with a version of the Profile of Chronic Pain scale and by multiple pain measurements (eg, pain intensity, pressure pain threshold, and other quantitative sensory measurements). Intracortical facilitation was found to be significantly associated with pain catastrophizing (ß = .63, P = .001). Our results did not suggest that these findings were influenced by other factors, such as age or medication use. Furthermore, short intracortical inhibition showed a significant association with pressure pain threshold (ß = .44, P = .04). This study elaborates on previous findings indicating a relationship between cortical excitability and catastrophizing. The present findings suggest that glutamatergic activity may be associated with mechanisms underlying pain catastrophizing; thus, the results highlight the need to further investigate the neurophysiological mechanisms associated with pain and catastrophizing. PERSPECTIVE: This study highlights the relationship between cortical excitability and catastrophizing. Cortical measures may illuminate how catastrophizing responses may be related to neurophysiological mechanisms associated with chronic pain.

A Phase II, Randomized, Double-Blind, Placebo Controlled, Dose-Response Trial of the Melatonin Effect on the Pain Threshold of Healthy Subjects.

BACKGROUND: Previous studies have suggested that melatonin may produce antinociception through peripheral and central mechanisms. Based on the preliminary encouraging results of studies of the effects of melatonin on pain modulation, the important question has been raised of whether there is a dose relationship in humans of melatonin on pain modulation. OBJECTIVE: The objective was to evaluate the analgesic dose response of the effects of melatonin on pressure and heat pain threshold and tolerance and the sedative effects. METHODS: Sixty-one healthy subjects aged 19 to 47 y were randomized into one of four groups: placebo, 0.05 mg/kg sublingual melatonin, 0.15 mg/kg sublingual melatonin or 0.25 mg/kg sublingual melatonin. We determine the pressure pain threshold (PPT) and the pressure pain tolerance (PPTo). Quantitative sensory testing (QST) was used to measure the heat pain threshold (HPT) and the heat pain tolerance (HPTo). Sedation was assessed with a visual analogue scale and bispectral analysis. RESULTS: Serum plasma melatonin levels were directly proportional to the melatonin doses given to each subject. We observed a significant effect associated with dose group. Post hoc analysis indicated significant differences between the placebo vs. the intermediate (0.15 mg/kg) and the highest (0.25 mg/kg) melatonin doses for all pain threshold and sedation level tests. A linear regression model indicated a significant association between the serum melatonin concentrations and changes in pain threshold and pain tolerance (R(2)  = 0.492 for HPT, R(2)  = 0.538 for PPT, R(2)  = 0.558 for HPTo and R(2)  = 0.584 for PPTo). CONCLUSIONS: The present data indicate that sublingual melatonin exerts well-defined dose-dependent antinociceptive activity. There is a correlation between the plasma melatonin drug concentration and acute changes in the pain threshold. These results provide additional support for the investigation of melatonin as an analgesic agent. Brazilian Clinical Trials Registry (ReBec): (U1111-1123-5109). IRB: Research Ethics Committee at the Hospital de Clínicas de Porto Alegre.

Effects of restraint stress on the daily rhythm of hydrolysis of adenine nucleotides in rat serum.

BACKGROUND: Adenosine 5-triphosphate (ATP) and its breakdown products ADP and adenosine can act as extracellular messengers in a range of biological processes. Extracellular adenine nucleotides are metabolized by a number of enzymes including NTPDases and 5'-nucleotidase, which are considered to be the major regulators of purinergic signaling in the blood. Previous work by our group demonstrated that ATPase and ADPase activities in rat serum exhibit a 24-h temporal pattern, with higher enzyme activity during the dark (activity) phase. It was found that stress can cause disruptions in biological circadian rhythms and in the cardiovascular system. Therefore, the aim of the present study was to examine the influence of acute stress exposure upon temporal patterns of NTPDase and 5-nucleotidase enzyme activities in rat blood serum. METHODS: Adult male Wistar rats were divided into 4 groups: ZT0, ZT6, ZT12 and ZT18. Each group was subdivided in 4 groups: control, immediately, 6 h and 24 h after one hour of restraint stress. ATP, ADP and AMP hydrolysis were assayed in the serum. RESULTS: All stressed groups showed significant decreases in all enzyme activities at ZT 12 and ZT 18 when compared with control. CONCLUSION: Acute stress provokes a decrease in nucleotidase activities dependent on the time that this stress occurs and this effect appears to persist for at least 24 hours. Stress can change levels of nucleotides, related to increased frequency of cardiovascular events during the activity phase. Altered levels of nucleotides in serum may be involved in cardiovascular events more frequent during the activity phase in mammals, and with their etiology linked to stress.