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 (R2 = 0.492 for HPT, R2 = 0.538 for PPT, R2 = 0.558 for HPTo and R2 = 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

<p>Abstract</p> <p>Background</p> <p>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.</p> <p>Methods</p> <p>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.</p> <p>Results</p> <p>All stressed groups showed significant decreases in all enzyme activities at ZT 12 and ZT 18 when compared with control.</p> <p>Conclusion</p> <p>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.</p

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 (β = 0.05 and β = 0.04, respectively) and negatively correlated to the cortical silent period (CSP) (β = -1.17 and β = -1.23, respectively) (P <0.05 for all comparisons). After QST evoked pain, the DRP was positively correlated to ICF (β = 0.02) (P < 0.05). Pain scores during CPM were positively correlated with trait-anxiety when it was concurrently with high DRP (β = 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

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

Demographic data and psychological profiles (n = 61).

†<p>Compared by ANOVA; € compared using Chi-Square.</p

Flow and number of patients in each phase of the study.

<p>Flow and number of patients in each phase of the study.</p

Effect of serum plasma melatonin of all of the volunteers on pressure pain threshold (A) and heat pain threshold (B) (n = 61).

<p>Effect of serum plasma melatonin of all of the volunteers on pressure pain threshold (A) and heat pain threshold (B) (n = 61).</p

Dose-concentration curve comparing the mean concentration achieved at 30 min following sublingual doses of 0.05, 0.15 or .25 mg/kg (n = 61).

<p>Serum plasma melatonin level at 30(P<0.05) at the time points. (*) Differences between placebo and melatonin. (**) Differences between 0.05, 0.15, and 0.25 mg/kg doses. All comparisons were made using a regression analysis model, followed by Bonferroni test for post-hoc multiple comparisons. <i>F(3∶57)</i> = 127; (P<0.0001); <i>R²</i> = 0.86.</p

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.This research was supported in part by a grant from BrainGear Inc. LMQ appreciates the mentoring support offered by Dr. Lee Hadlington and Dr. Mark Scase from De Montfort University