Joanna Ripoll Rozisky

Reversal of chronic stress-induced pain by transcranial direct current stimulation (tDCS) in an animal model.

Transcranial direct current stimulation (tDCS) has been suggested as a therapeutic tool for pain syndromes. Although initial results in human subjects are encouraging, it still remains unclear whether the effects of tDCS can reverse maladaptive plasticity associated with chronic pain. To investigate this question, we tested whether tDCS can reverse the specific behavioral effects of chronic stress in the pain system, and also those indexed by corticosterone and interleukin-1β levels in serum and TNFα levels in the hippocampus, in a well-controlled rat model of chronic restraint stress (CRS). Forty-one adult male Wistar rats were divided into two groups control and stress. The stress group was exposed to CRS for 11 weeks for the establishment of hyperalgesia and mechanical allodynia as shown by the hot plate and von Frey tests, respectively. Rats were then divided into four groups control, stress, stress+sham tDCS and stress+tDCS. Anodal or sham tDCS was applied for 20min/day over 8 days and the tests were repeated. Then, the animals were killed, blood collected and hippocampus removed for ELISA testing. This model of CRS proved effective to induce chronic pain, as the animals exhibited hyperalgesia and mechanical allodynia. The hot plate test showed an analgesic effect, and the von Frey test, an anti-allodynic effect after the last tDCS session, and there was a significant decrease in hippocampal TNFα levels. These results support the notion that tDCS reverses the detrimental effects of chronic stress on the pain system and decreases TNFα levels in the hippocampus.

Cafeteria diet-induced obesity plus chronic stress alter serum leptin levels

Obesity is a disease that has become a serious public health issue worldwide, and chronic stressors, which are a problem for modern society, cause neuroendocrine changes with alterations in food intake. Obesity and chronic stress are associated with the development of cardiovascular diseases and metabolic disorders. In this study, a rat model was used to evaluate the effects of a hypercaloric diet plus chronic restraint stress on the serum leptin and lipids levels and on the weight of specific adipose tissue (mesenteric, MAT; subcutaneous, SAT and visceral, VAT). Wistar rats were divided into the following 4 groups: standard chow (C), hypercaloric diet (HD), stress plus standard chow (S), and stress plus hypercaloric diet (SHD). The animals in the stress groups were subjected to chronic stress (placed inside a 25 cm × 7 cm plastic tube for 1h per day, 5 days per week for 6 weeks). The following parameters were evaluated: the weight of the liver, adrenal glands and specific adipose tissue; the delta weight; the Lee index; and the serum levels of leptin, corticosterone, glucose, total cholesterol, and triglycerides. The hypercaloric diet induced obesity in rats, increasing the Lee index, weight, leptin, triglycerides, and cholesterol levels. The stress decreased weight gain even in animals fed a hypercaloric diet but did not prevent a significant increase in the Lee index. However, an interaction between the independent factors (hypercaloric diet and stress) was observed, which is demonstrated by the increased serum leptin levels in the animals exposed to both protocols.

Long-term effect of morphine administration in young rats on the analgesic opioid response in adult life

Neonates, infants and children are often exposed to pain from invasive procedures during intensive care and during the post‐operative period. Opioid anesthesia and post‐operative opioid analgesia have been used in infants and result in clinical benefits. The objectives of this study were to verify the effect of repeated 5 μg morphine administration (subcutaneous), once a day for 7 days in 8‐day‐old rats, at P8 until P14. To verify the long‐term effect of morphine, the animals were submitted to a second exposure of 5 mg/kg (intraperitoneal) of morphine at P80 until P86. Animals that received morphine for 7 days, at P14 did not develop tolerance, however at P80, rats demonstrated greater morphine analgesia. At P86, after 7 days of morphine administration, animals showed classical tolerance. These findings may have important implications for the human neonate, suggesting a possible explanation for the differences in the requirements of morphine observed in the youngest patients.

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.

Transcranial direct current stimulation (tDCS) reverts behavioral alterations and brainstem BDNF level increase induced by neuropathic pain model: Long-lasting effect

INTRODUCTION Neuropathic pain (NP) is a chronic pain modality that usually results of damage in the somatosensory system. NP often shows insufficient response to classic analgesics and remains a challenge to medical treatment. The transcranial direct current stimulation (tDCS) is a non-invasive technique, which induces neuroplastic changes in central nervous system of animals and humans. The brain derived neurotrophic factor plays an important role in synaptic plasticity process. Behavior changes such as decreased locomotor and exploratory activities and anxiety disorders are common comorbidities associated with NP. OBJECTIVE Evaluate the effect of tDCS treatment on locomotor and exploratory activities, and anxiety-like behavior, and peripheral and central BDNF levels in rats submitted to neuropathic pain model. METHODS Rats were randomly divided: Ss, SsS, SsT, NP, NpS, and NpT. The neuropathic pain model was induced by partial sciatic nerve compression at 14 days after surgery; the tDCS treatment was initiated. The animals of treated groups were subjected to a 20 minute session of tDCS, for eight days. The Open Field and Elevated Pluz Maze tests were applied 24 h (phase I) and 7 days (phase II) after the end of tDCS treatment. The serum, spinal cord, brainstem and cerebral cortex BDNF levels were determined 48 h (phase I) and 8 days (phase II) after tDCS treatment by ELISA. RESULTS The chronic constriction injury (CCI) induces decrease in locomotor and exploratory activities, increases in the behavior-like anxiety, and increases in the brainstem BDNF levels, the last, in phase II (one-way ANOVA/SNK, P<0.05 for all). The tDCS treatment already reverted all these effects induced by CCI (one-way ANOVA/SNK, P<0.05 for all). Furthermore, the tDCS treatment decreased serum and cerebral cortex BDNF levels and it increased these levels in the spinal cord in phase II (one-way ANOVA/SNK, P<0.05). CONCLUSION tDCS reverts behavioral alterations associated to neuropathic pain, indicating possible analgesic and anxiolytic tDCS effects. tDCS treatment induces changes in the BDNF levels in different regions of the central nervous system (CNS), and this effect can be attributed to different cellular signaling activations.

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 (β = .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 (β = .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.

Melatonin administration reduces inflammatory pain in rats

In view of the broad range of effects attributed to melatonin, this study evaluated its analgesic effect on inflammatory pain induced by complete Freund’s adjuvant (CFA) in Wistar rats. Inflammation was induced by intradermal CFA injection in the hind paw of all animals, which were then divided into two groups that received either 60 mg/kg of melatonin or vehicle (1% alcohol in saline), intraperitoneally, for three days. The analgesic effect of melatonin was assessed by the hot-plate test, immediately and thereafter at 30, 60, 90, and 120 minutes after the first administration and 24 hours after once-daily administration for 2 more days. After CFA injection, melatonin administration increased withdrawal latency at 60 minutes after the first dose. After the end of treatment, melatonin showed a significant analgesic effect on inflammatory pain. This study paves the way for exploration of how brief courses of treatment could improve this analgesic effect in the late phases of inflammatory pain.

BDNF as an effect modifier for gender effects on pain thresholds in healthy subjects

BDNF is an important marker of neuronal plasticity. It has also been associated with pain processing. Increased BDNF levels are observed in chronic pain syndromes. In order to understand the role of BDNF associated with other factors such as gender on experimental pain we aimed to determine whether experimental heat or pressure pain threshold is correlated with brain derived neurotrophic factor (BDNF) level, gender and age. Heat pain threshold and pressure pain threshold were measured in 49 healthy volunteers (27 females). The multivariate linear regression models (on heat and pressure pain thresholds) revealed a significant effect of gender (p=0.001 for both models), serum BDNF (p<0.004 for both models) and interaction between BDNF and gender (<0.001 for both models). In fact, when adjusting for BDNF levels and age, heat and pressure pain thresholds were significantly reduced in women as compared to men (p<0.001 for both models). These effects were not observed when gender was analyzed alone. These finding suggests that experimental heat and pressure pain threshold is gender-related and BDNF dependent. In fact BDNF has a facilitatory effect on pain threshold in females but has an opposite effect in males; supporting the notion that BDNF is an effect modifier of the gender effects on pain threshold in healthy subjects.

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

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.

Lifetime behavioural changes after exposure to anaesthetics in infant rats.

The aim of this study was to assess the effect of acute use of general anaesthetic with or without a surgical procedure, at post-natal day 14 (P14), on behavioural responses in the short-, medium- and long-term, evaluated in open field (OF) and elevated plus-maze (EPM) tests. Fourteen-day-old male Wistar rats were divided into two experimental designs (ED): inhalation and intravenous anaesthetic, and these groups were subdivided into: 1st ED - control (C), isoflurane (ISO), isoflurane/surgery (ISO-SUR); 2nd ED - control (C), fentanyl/S(+)-ketamine (FK) and fentanyl+ketamine-s/surgery (FK-SUR). In the OF the following were found: (a) in the 1st ED: an increase in the locomotor activity in the ISO group at P14, and ISO and ISO-SUR groups at P30; the ISO-SUR group showed a reduced latency to leave the first quadrant at P30 and P60; (b) in the 2nd ED: FK and FK-SUR groups presented increased locomotor activity at P30, and the FK group showed a reduction in the number of faecal boluses. In the EPM the following were found: FK and FK-SUR groups presented an increase in the number of non-protected head-dipping (NPHD) movements and in the number of entries and time spent in open arms at P30; the FK group showed an increased number of protected head-dipping movements, NPHD and entries and time spent in the open arms at P60. The behavioural changes observed may be related to locomotor activity (1st ED) and anxiety level (2nd ED) and they may result from changes in neurotransmitters/hormones (DA, 5HT, CRH) and glutamate/NMDA receptors, respectively.