Hormone replacement therapy did not alleviate temporomandibular joint inflammatory pain in ovariectomized rats.

This study had the aim of examining the relationships between variations in estrogen levels resulting from ovariectomy, and estrogen hormone replacement therapy (HRT) in rats subjected to an orofacial inflammatory pain model. Eighty adult female Wistar rats were initially divided into 2 groups: Sham or ovariectomy (OVX-D1). Seven days later (D7), the rats were subjected to an unilateral infiltration of Freund's Complete Adjuvant (CFA) or saline solution into the right temporomandibular joint (TMJ). Then, rats received 17ß-estradiol (28 µg/kg/day) or placebo for 21 days (D10-D31). Nociception was evaluated by the von Frey (VF) and the Hot Plate (HP) tests, and depressive-like behavior by the Forced Swimming (FS) test. On D32 all rats were euthanized and serum, hippocampus and brainstem were collected. The CFA groups presented a mechanical hyperalgesia until day 21 (p ≤ 0.05). No differences were observed among groups in the HP (p = 0.735), and in the immobility and swimming time of the FS (p = 0.800; p = 0.998, respectively). In the brainstem, there was a significant difference in the TNF-ɑ levels (p = 0.043), and a marginal significant difference in BDNF levels (p = 0.054), without differences among groups in the hippocampal BDNF and TNF-ɑ levels (p = 0.232; p = 0.081, respectively). In conclusion, the hormone replacement therapy did not alleviate orofacial pain in ovariectomized rats. However, there is a decrease in brainstem TNF-ɑ levels in the animals submitted to both models, which was partially reverted by HRT.

Evidence of Anti-Inflammatory Effect of Transcranial Direct Current Stimulation in a CFA-Induced Chronic Inflammatory Pain Model in Wistar Rats.

INTRODUCTION: Given that chronic inflammatory pain is highly prevalent worldwide, it is important to study new techniques to treat or relieve this type of pain. The present study evaluated the effect of transcranial direct current stimulation (tDCS) in rats submitted to a chronic inflammatory model by nociceptive response, biomarker levels (brain-derived neurotrophic factor [BDNF] and interleukin [IL]-6 and IL-10), and by histological parameters. METHODS: Sixty-day-old male Wistar rats were used in this study and randomized by weight into 6 major groups: total control, control + sham-tDCS, control + active tDCS, total CFA, CFA + sham-tDCS, and CFA + active tDCS. After inflammatory pain was established, the animals were submitted to the treatment protocol for 8 consecutive days, according to the experimental group. The nociceptive tests (von Frey and hot plate) were assessed, and euthanasia by decapitation occurred at day 8 after the end of tDCS treatment, and the blood serum and central nervous structures were collected for BDNF and IL measurements. All experiments and procedures were approved by the Institutional Committee for Animal Care and Use (UFPel #4538). RESULTS: The tDCS treatment showed a complete reversal of the mechanical allodynia induced by the pain model 24 h and 8 days after the last tDCS session, and there was partial reversal of the thermal hyperalgesia at all time points. Serum BDNF levels were decreased in CFA + sham-tDCS and CFA + tDCS groups compared to the control + tDCS group. The control group submitted to tDCS exhibited an increase in serum IL-6 levels in relation to the other groups. In addition, there was a significant decrease in IL-10 striatum levels in control + tDCS, CFA, and CFA + sham-tDCS groups in relation to the control group, with a partial tDCS effect on the CFA pain model. Local histology demonstrated tDCS effects in decreasing lymphocytic infiltration and neovascularization and tissue regeneration in animals exposed to CFA. CONCLUSION: tDCS was able to reverse the mechanical allodynia and decrease thermal hyperalgesia and local inflammation in a chronic inflammatory pain model, with a modest effect on striatum IL-10 levels. As such, we suggest that analgesic tDCS mechanisms may be related to tissue repair by modulating the local inflammatory process.

Transcranial Direct Current Stimulation (tDCS) Induces Analgesia in Rats with Neuropathic Pain and Alcohol Abstinence.

Neuromodulatory techniques have been studied to treat drug addiction or compulsive eating as well as different chronic pain conditions, such as neuropathic and inflammatory pain in the clinical and preclinical settings. In this study, we aimed to investigate the effect of transcranial direct current stimulation (tDCS) on the association of alcohol withdrawal with neuropathic pain based on nociceptive and neurochemical parameters in rats. Thirty-six adult male Wistar rats were randomized into five groups: control, neuropathic pain, neuropathic pain + tDCS, neuropathic pain + alcohol, and neuropathic pain + alcohol + tDCS. The neuropathic pain model was induced by chronic constriction injury (CCI) to the sciatic nerve. Rats were then exposed to alcohol (20%) by oral gavage administration for 15 days (beginning 24 h after CCI). tDCS was started on the 17th day after surgery and lasted for 8 consecutive days. The nociceptive test (hot plate) was performed at baseline, 16 days after CCI, and immediately and 24 h after the last session of tDCS. Rats were killed by decapitation, and structures were removed and frozen for biochemical analysis (nerve growth factor and interleukin (IL-1α, IL-1ß, and IL-10 measurements). Neuropathy-induced thermal hyperalgesia was reversed by tDCS, an effect that was delayed by alcohol abstinence. In addition, tDCS treatment induced modulation of central levels of IL-1α, IL-1ß, and IL-10 and neurotrophic growth factor. We cannot rule out that the antinociceptive effect of tDCS could be related to increased central levels of IL-1α and IL-10. Therefore, tDCS may be a promising non-pharmacological therapeutic approach for chronic pain treatment.

Antinociceptive and neurochemical effects of a single dose of IB-MECA in chronic pain rat models.

This study aimed to evaluate the effect of a single administration of IB-MECA, an A3 adenosine receptor agonist, upon the nociceptive response and central biomarkers of rats submitted to chronic pain models. A total of 136 adult male Wistar rats were divided into two protocols: (1) chronic inflammatory pain (CIP) using complete Freund's adjuvant and (2) neuropathic pain (NP) by chronic constriction injury of the sciatic nerve. Thermal and mechanical hyperalgesia was measured using von Frey (VF), Randal-Selitto (RS), and hot plate (HP) tests. Rats were treated with a single dose of IB-MECA (0.5 µmol/kg i.p.), a vehicle (dimethyl sulfoxide-DMSO), or positive control (morphine, 5 mg/kg i.p.). Interleukin 1ß (IL-1ß), brain-derived neurotrophic factor (BDNF), and nerve growth factor (NGF) levels were measured in the brainstem and spinal cord using enzyme-linked immunosorbent assay (ELISA). The establishment of the chronic pain (CIP or NP) model was observed 14 days after induction by a decreased nociceptive threshold in all three tests (GEE, P < 0.05). The antinociceptive effect of a single dose of IB-MECA was observed in both chronic pain models, but this was more effective in NP model. There was an increase in IL-1ß levels promoted by CIP. NP model promoted increase in the brainstem BDNF levels, which was reversed by IB-MECA.

Exogenously induced brain activation regulates neuronal activity by top-down modulation: conceptualized model for electrical brain stimulation.

Physiological and exogenous factors are able to adjust sensory processing by modulating activity at different levels of the nervous system hierarchy. Accordingly, transcranial direct current stimulation (tDCS) may use top-down mechanisms to control the access for incoming information along the neuroaxis. To test the hypothesis that brain activation induced by tCDS is able to initiate top-down modulation and that chronic stress disrupts this effect, 60-day-old male Wistar rats (n = 78) were divided into control; control + tDCS; control + sham-tDCS; stress; stress + tDCS; and stress + sham-tDCS. Chronic stress was induced using a restraint stress model for 11 weeks, and then, the treatment was applied over 8 days. BDNF levels were used to assess neuronal activity at spinal cord, brainstem, and hippocampus. Mechanical pain threshold was assessed by von Frey test immediately and 24 h after the last tDCS-intervention. tDCS was able to decrease BDNF levels in the structures involved in the descending systems (spinal cord and brainstem) only in unstressed animals. The treatment was able to reverse the stress-induced allodynia and to increase the pain threshold in unstressed animals. Furthermore, there was an inverse relation between pain sensitivity and spinal cord BDNF levels. Accordingly, we propose the addition of descending systems in the current brain electrical modulation model.

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.

Transcranial direct current stimulation is more effective than pregabalin in controlling nociceptive and anxiety-like behaviors in a rat fibromyalgia-like model.

OBJECTIVES: Despite the fact that fibromyalgia, a widespread disease of the musculoskeletal system, has no specific treatment, patients have shown improvement after pharmacological intervention. Pregabalin has demonstrated efficacy; however, its adverse effects may reduce treatment adherence. In this context, neuromodulatory techniques such as transcranial direct current stimulation (tDCS) may be employed as a complementary pain-relieving method. Consequently, the purpose of this study was to evaluate the effect of pregabalin and tDCS treatments on the behavioral and biomarker parameters of rats submitted to a fibromyalgia-like model. METHODS: Forty adult male Wistar rats were divided into two groups: control and reserpine. Five days after the end of the administration of reserpine (1 mg/kg/3 days) to induce a fibromyalgia-like model, rats were randomly assigned to receive either vehicle or pregabalin (30 mg/kg) along with sham or active- tDCS treatments. The evaluated behavioral parameters included mechanical allodynia by von Frey test and anxiety-like behaviors by elevated plus-maze test (time spent in opened and closed arms, number of entries in opened and closed arms, protected head-dipping, unprotected head-dipping [NPHD], grooming, rearing, fecal boluses). The biomarker analysis (brain-derived neurotrophic factor [BDNF] and tumor necrosis factor-α [TNF-α]) was performed in brainstem and cerebral cortex and in serum. RESULTS: tDCS reversed the reduction in the mechanical nociceptive threshold and the decrease in the serum BDNF levels induced by the model of fibromyalgia; however, there was no effect of pregabalin in the mechanical threshold. There were no effects of pregabalin or tDCS found in TNF-α levels. The pain model induced an increase in grooming time and a decrease in NPHD and rearing; while tDCS reversed the increase in grooming, pregabalin reversed the decrease in NPHD. CONCLUSIONS: tDCS was more effective than pregabalin in controlling nociception and anxiety-like behavior in a rat model-like fibromyalgia. Considering the translational aspect, our findings suggest that tDCS could be a potential non-pharmacological treatment for fibromyalgia.

Involvement of GABAergic, glutamatergic, opioidergic, and brain-derived neurotrophic factor systems in the trigeminal neuropathic pain process.

Trigeminal neuropathic pain (TNP) is an intense pain condition characterized by hyperalgesia and allodynia; however, its neural mechanisms are not completely understood. Its management is complex, and studies that investigate its biochemical mechanisms are important for improving clinical approaches. This study aimed to evaluate the involvement of GABAergic, glutamatergic, and opioidergic systems and brain-derived neurotrophic factor (BDNF) levels in the TNP process in rats. TNP is induced by chronic constriction injury of the infraorbital nerve (CCI-ION). Nociceptive responses were evaluated using the facial von Frey test before and after the administration of GABAergic and opioidergic agonists and glutamatergic antagonists. The rats were divided into vehicle-treated control (C), sham-surgery (SS), and CCI-ION groups, and then subdivided into the vehicle (V)-treated SS-V and CCI-ION-V groups, SS-MK801 and CCI-ION-MK801, treated with the N-methyl-d-aspartate receptor selective antagonist MK801; SS-PB and CCI-ION-PB, treated with phenobarbital; SS-BZD and CCI-ION-BZD, treated with diazepam; SS-MOR and CCI-ION-MOR, treated with morphine. BDNF levels were evaluated in the cerebral cortex, brainstem, trigeminal ganglion, infraorbital branch of the trigeminal nerve, and serum. CCI-ION induced facial mechanical hyperalgesia. Phenobarbital and morphine reversed the hyperalgesia induced by CCI-ION, and the CCI-BZD group had an increased nociceptive threshold until 60 min. CCI-ION-GLU increased the nociceptive threshold at 60 min. Cerebral cortex and brainstem BDNF levels increased in the CCI-ION and SS groups. Only the CCI group presented high levels of BDNF in the trigeminal ganglion. Our data suggest the involvement of GABAergic, glutamatergic, and opioidergic systems and peripheral BDNF in the TNP process.

Association of low-dose naltrexone and transcranial direct current stimulation in fibromyalgia: a randomized, double-blinded, parallel clinical trial.

INTRODUCTION: Fibromyalgia is a complex, generalized, and diffuse chronic musculoskeletal pain. Pharmacological approaches are widely used to relieve pain and increase quality of life. Low-Dose Naltrexone (LDN) was shown to increase the nociceptive threshold in patients with fibromyalgia. Transcranial Direct Current Stimulation (tDCS) is effective for pain management. OBJECTIVE: The purpose of this study was to evaluate the analgesic and neuromodulatory effects of a combination of LDN and tDCS in patients with fibromyalgia. METHODS: This was a randomized, double-blinded, parallel, placebo/sham-controlled trial (NCT04502251; RBR-7HK8N) in which 86 women with fibromyalgia were included, and written informed consent was obtained from them. The patients were allocated into four groups: LDN + tDCS (n = 21), LDN + tDCS Sham (n = 22), placebo + tDCS (n = 22), and placebo+tDCS Sham (n = 21). The LDN or placebo (p.o.) intervention lasted 26 days; in the last five sessions, tDCS was applied (sham or active, 20 min, 2 mA). The following categories were assessed: sociodemographic, Visual Analog Pain Scale (VAS), Pain Catastrophizing Scale (PCS), State-Trait Anxiety Inventory (STAI), Fibromyalgia Impact Questionnaire (FIQ), Beck Depression Inventory (BDI-II), Profile of Chronic Pain Scale (PCP:S), Pain Pressure Threshold (PPT), and Conditioned Pain Modulation (CPM). Blood samples were collected to analyze BDNF serum levels. RESULTS: At baseline, no significant difference was found regarding all measurements. VAS pain was significantly reduced in the LDN + tDCS (p = 0.010), LDN + tDCS Sham (p = 0.001), and placebo+tDCS Sham (p = 0.009) groups. In the PCP:S, the LDN+tDCS group showed reduced pain frequency and intensity (p = 0.001), effect of pain on activities (p = 0.014) and emotions (p = 0.008). Depressive symptoms reduced after all active interventions (p > 0.001). CONCLUSION: Combined LDN+tDCS has possible benefits in reducing pain frequency and intensity; however, a placebo effect was observed in pain using VAS, and further studies should be performed to analyze the possible association.

Short-term effectiveness of transcranial direct current stimulation in the nociceptive behavior of neuropathic pain rats in development.

Neuropathic pain (NP) is caused by a lesion that triggers pain chronification and central sensitization and it can develop in a different manner, dependent of age. Recent studies have demonstrated the efficacy of transcranial direct current stimulation (tDCS) for treating NP. Then, we aimed to investigate the effects of tDCS and BDNF levels in neuropathic pain rats in development, with 30 days old in the beginning of experiments. Eight-five male Wistar rats were subjected to chronic constriction injury. After establishment of NP, bimodal tDCS was applied to the rats for eight consecutive days, for 20 minutes each session. Subsequently, nociceptive behavior was assessed at baseline, 14 days after surgery, 1 day and 7 days after the end of tDCS. The rats were sacrificed 8 days after the last session of tDCS. An increase in the nociceptive threshold was observed in rats in development 1 day after the end of tDCS (short-term effect), but this effect was not maintained 7 days after the end of tDCS (long-term effect). Furthermore, brain derived neurotrophic factor (BDNF) levels were analyzed in the frontal cortex, spinal cord and serum using ELISA assays. The neuropathic pain model showed an effect of BDNF in the spinal cord of rats in development. There were no effects of BNDF levels of pain or tDCS in the frontal cortex or serum. In conclusion, tDCS is an effective technique to relieve nociceptive behavior at a short-term effect in neuropathic pain rats in development, and BDNF levels were not altered at long-term effect.

Nociceptive Profile and Analgesic use of Patients Submitted to Rotator Cuff Repair Surgery: A Prospective Cohort.

Objective This study aimed to evaluate the nociceptive profile and the intake of analgesic drugs of patients submitted to rotator cuff repair surgery. Also, to evaluate the nociceptive thresholds and the integrity of the descending inhibitory system, pain catastrophism and prevalence of nociceptive or neuropathic pain. Methods Approved by the Ethics Committee of La Salle University (1.325.433/2015). 40 patients (>18 years old) who underwent rotator cuff repair surgery (divided in small and large injuries) were recruited. The used instruments were: Sociodemographic Questionnaire, Functional Pain Scale, Visual Analogue Scale (VAS), Quantitative Sensory Test (QST) and Conditioned Pain Modulation Task (CPM). Results Patients had a significant difference in pain thresholds QST heat (independent samples t test) and quality of sleep, mood and anxiety (paired t test) in groups preoperative. There was a significant correlation between preoperative CPM and postoperative VAS (Pearson Correlation). It was observed that, in preoperative, 38 patients used analgesics continuously. Besides that, in postoperative, use of opioid drugs was higher in patients with small injury (13 patients) than in those with large injury (9 patients). Conclusion Therefore, patients with rotator cuff injuries did not present alterations in the descending inhibitory system, but showed alterations in pain thresholds, which may interfere in the postoperative period and still be related to the consumption of analgesics.

Bimodal transcranial direct current stimulation reduces alcohol consumption and induces long-term neurochemical changes in rats with neuropathic pain.

This study aimed to evaluate the effects of repeated bimodal transcranial direct current stimulation (tDCS) on alcohol consumption and immunohistological and neurochemical parameters in nerve-injured rats. Forty-eight adult male Wistar rats were distributed into six groups: control, neuropathic pain (NP) + sham-tDCS, NP + alcohol + sham-tDCS, alcohol + sham-tDCS, alcohol + tDCS, and NP + alcohol + tDCS. NP is induced by chronic sciatic nerve constriction (CCI). The rats were exposed to a 10% alcohol solution by voluntary consumption for 14 days. From the 16th day after surgery, bimodal tDCS was applied for 20 min/day for 8 days. Brain structures were collected to evaluate the number of neuropeptide Y (NPY)-positive neurons, neurites, and argyrophilic grains by immunohistochemistry, and brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), interleukin (IL)-6, and IL-10 by ELISA. Nerve-injured rats showed a progressive increase in alcohol consumption compared to the non-injured rats. In addition, there was a reduction in voluntary alcohol consumption over time induced by tDCS. Alcohol exposure, chronic pain, and tDCS treatment modulated the central NPY immunoreactivity. tDCS increased the cerebellar levels of IL-6 and IL-10, and CCI and/or tDCS reduced striatal BDNF levels. The current data suggest that tDCS could be a promising non-pharmacological adjuvant to treat patients with chronic pain who use alcohol to relieve their symptoms.

tDCS and exercise improve anxiety-like behavior and locomotion in chronic pain rats via modulation of neurotrophins and inflammatory mediators.

Anxiety disorders cause distress and are commonly found to be comorbid with chronic pain. Both are difficult-to-treat conditions for which alternative treatment options are being pursued. This study aimed to evaluate the effects of transcranial direct current stimulation (tDCS), treadmill exercise, or both, on anxiety-like behavior and associated growth factors and inflammatory markers in the hippocampus and sciatic nerve of rats with neuropathic pain. Male Wistar rats (n = 216) were subjected to sham-surgery or sciatic nerve constriction for pain induction. Fourteen days following neuropathic pain establishment, either bimodal tDCS, treadmill exercise, or a combination of both was used for 20 min a day for 8 consecutive days. The elevated plus-maze test was used to assess anxiety-like behavior and locomotor activity during the early (24 h) or late (7 days) phase after the end of treatment. BDNF, TNF-ɑ, and IL-10 levels in the hippocampus, and BDNF, NGF, and IL-10 levels in the sciatic nerve were assessed 48 h or 7 days after the end of treatment. Rats from the pain groups developed an anxiety-like state. Both tDCS and treadmill exercise provided ethological and neurochemical alterations induced by pain in the early and/or late phase, and a modest synergic effect between tDCS and exercise was observed. These results indicate that non-invasive neuromodulatory approaches can attenuate both anxiety-like status and locomotor activity and alter the biochemical profile in the hippocampus and sciatic nerve of rats with neuropathic pain and that combined interventions may be considered as a treatment option.

LOW-DOSE NALTREXONE REVERSES FACIAL MECHANICAL ALLODYNIA IN A RAT MODEL OF TRIGEMINAL NEURALGIA.

Trigeminal neuralgia (TN) is a type of neuropathic pain characterized by intense pain; although anticonvulsants are used as an option to relieve pain, adverse side effects can decrease patient adherence. In this context, a low dose of naltrexone is effective in relieving pain in other pain conditions. Thus, the objective of the present study was to evaluate the analgesic effect of low-dose naltrexone on facial mechanical allodynia in a rat model of TN, as well as its effect(s) on biomarkers in the central nervous system (tumor necrosis factor-alpha, brain-derived neurotrophic factor [BDNF], interleukin [IL]-10, and toll-like receptor-4). Fifty-nine adult male Wistar rats (CEUA-HCPA#2017-0575) were allocated to following groups: control; sham-pain + vehicle; sham-pain + carbamazepine (100 mg/kg); sham-pain + naltrexone (0.5 mg/kg); pain + vehicle; pain + carbamazepine; and pain + naltrexone. TN was induced using chronic constriction of the infraorbital nerve. Facial allodynia was assessed using von Frey test. Drugs were administered by gavage 14 days after surgery for 10 days. At baseline, the mechanical threshold was similar between groups (P > 0.05; generalized estimating equation). Seven days after surgery, facial allodynia was observed in sham-TN and pain-TN groups (P < 0.05). Fourteen days after surgery, only pain-TN groups exhibited facial allodynia. The first dose of low-dose naltrexone or carbamazepine partially reversed facial allodynia. After 10 days of treatment, both drugs completely reversed it. Spinal cord levels of BDNF and IL-10 were modulated by low-dose naltrexone. Thus, low-dose naltrexone may be suitable to relieve TN; however, the exact mechanisms need to be clarified.

Transcranial direct current stimulation combined with exercise modulates the inflammatory profile and hyperalgesic response in rats subjected to a neuropathic pain model: Long-term effects.

BACKGROUND: Behavioral alterations, like mechanical and thermal hyperalgesia, and modulation of biomarkers in the peripheral and central nervous systems (CNS) are markers of chronic pain. Transcranial direct current stimulation (tDCS) with exercise is a promising therapy for pain due to its neuromodulatory capacity. OBJECTIVE: To assess the individual effects of tDCS, exercise, and the two combined on the nociceptive response and BDNF, IL-1ß, and IL-4 levels in the CNS structures of rats in a chronic pain model. METHODS: For 8 consecutive days after the establishment of chronic neuropathic pain by inducing a constriction injury to the sciatic nerve (CCI), the rats received tDCS, exercise, or both treatments combined (20 min/day). The hyperalgesic response was assessed by von Frey and hot plate tests at baseline, 7, and 14 days after CCI surgery and immediately, 24 h, and 7 days after the end of treatment. The BDNF, IL-1ß, and IL-4 levels were assessed in the cerebral cortex, brainstem, and spinal cord by enzyme-linked immunosorbent assay at 48 h and 7 days after the end of treatment. RESULTS: The CCI model triggered marked mechanical and thermal hyperalgesia. However, bimodal tDCS, aerobic exercise, and the two combined relieved nociceptive behavior for up to 7 days following treatment completion. CONCLUSIONS: Bimodal tDCS, aerobic exercise, or both treatments combined promoted analgesic effects for neuropathic pain. Such effects were reflected by cytokine modulation throughout the spinal cord-brainstem-cerebral cortex axis.

Single exercise stress reduces central neurotrophins levels and adenosine A1 and A2 receptors expression, but does not revert opioid-induced hyperalgesia in rats.

BACKGROUND: This study assessed the effects of an acute stress model upon the long-term hyperalgesia induced by repeated morphine administration in neonatal rats. We also evaluated neurotrophins and cytokines levels; expressions of adenosine and acetylcholine receptors, and acetylcholinesterase enzyme at the spinal cord. MATERIAL AND METHODS: Male Wistar rats were subjected to morphine or saline administration from P8 to P14. Thermal hyperalgesia and mechanical hyperesthesia were assessed using the hot plate (HP) and von Frey (vF) tests, respectively, at postnatal day P30 and P60. After baseline measurements, rats were subjected to a single exercise session, as an acute stress model, at P30 or P60. We measured the levels of BDNF and NGF, interleukin-6, and IL-10 in the cerebral cortex and the brainstem; and the expression levels of adenosine and muscarinic receptors, as well as acetylcholinesterase (AChE) enzyme at the spinal cord. RESULTS: A stress exercise session was not able to revert the morphine-induced hyperalgesia. The morphine and exercise association in rats induced a decrease in the neurotrophins brainstem levels, and A1 , A2A , A2B receptors expression in the spinal cord, and an increase in the IL-6 cortical levels. The exercise reduced M2 receptors expression in the spinal cord of naive rats, while morphine prevented this effect. CONCLUSIONS: Single session of exercise does not revert hyperalgesia induced by morphine in rats; however, morphine plus exercise modulate neurotrophins, IL-6 central levels, and expression of adenosine receptors.

Multidisciplinary treatment program for improvement in pain and disability associated with nonspecific chronic low back pain / Programa de tratamento multidisciplinar para melhora da dor e incapacidade associada a dor crônica lombar inespecífica

ABSTRACT BACKGROUND AND OBJECTIVES: Lumbar disorders, which contribute to significant workplace absenteeism and chronic disability, are associated with a considerable financial and social burden. Although a conservative approach provides satisfactory pain relief, biomechanical improvement and is associated with a low risk of adverse effects, there is lack of consensus in the literature regarding the best therapeutic strategy in such cases. METHODS: This retrospective longitudinal study used secondary data from the institutional medical records of patients who completed a multidisciplinary program for the treatment of low back pain between 2019 and 2021. Data regarding pain levels and motor skills were obtained from patients who completed the care program at a private hospital in Bento Gonçalves, RS. The following step-wise treatment algorithm was used: evaluation by a specialist physician for the etiological diagnosis of pain, pharmacological management and dry needling, followed by standard rehabilitation intervention performed by the physiotherapy team and exercises by the physical education team. The visual analogue scale (VAS) was used to measure pain at the start and at the completion of the intervention, and the Oswestry Disability Index (ODI) was used to measure motor skills at the start and at 6 and 12 months following the multiprofessional intervention for rehabilitation. RESULTS: A reduction in pain and motor disability in patients who completed all stages of the treatment program was observed. Pain by the VAS presented the following scores: baseline 7 [5-8] and after treatment 2 [0-4]; and the scores of the ODI were: at baseline 0.34 [0.26 - 0.40], at 6 months 0.16 [0.08 - 0.26] and after treatment 0.12 [0.04 - 0.21]. CONCLUSION: The treatment program reduced the pain and disability associated with low back pain and can serve as the basis for further studies carried out to confirm the effectiveness of this intervention.

RESUMO JUSTIFICATIVA E OBJETIVOS: As doenças lombares, que contribuem para um absenteísmo significativo no local de trabalho e para a incapacidade crônica, estão associadas a um encargo financeiro e social considerável. Embora a abordagem conservadora proporcione alívio satisfatório da dor, melhore a biomecânica e esteja associada a baixo risco de efeitos adversos, não há consenso na literatura sobre a melhor estratégia terapêutica nesses casos. MÉTODOS: Neste estudo longitudinal retrospectivo, foram utilizados dados secundários dos prontuários médicos institucionais de pacientes que completaram um programa multidisciplinar para tratamento de dor lombar entre 2019 e 2021. Dados sobre níveis de dor e habilidades motoras foram obtidos de pacientes que completaram o programa assistencial de um hospital privado de Bento Gonçalves, RS. Foi utilizado o seguinte tratamento passo a passo: avaliação por médico especialista para diagnóstico etiológico da dor, manejo farmacológico e agulhamento a seco, seguido de intervenção de reabilitação padrão realizada pela equipe de fisioterapia e exercícios pela equipe de educação física. A escala analógica visual (EAV) foi utilizada para medir a dor no início e após a conclusão da intervenção, e o Índice de Incapacidade de Oswestry (ODI) foi usado para medir as habilidades motoras no início e aos 6 e 12 meses após a intervenção multiprofissional para reabilitação. RESULTADOS: Observou-se redução na dor e na incapacidade motora em pacientes que completaram todas as etapas do programa de tratamento. A intensidade da dor medida pela EAV apresentou as seguintes pontuações: basal 7 [5-8] e após tratamento 2 [0-4]; enquanto o ODI apresentou as pontuações: basal 0,34 [0,26 - 0,40], até 6 meses 0,16 [0,08 - 0,26] e após o tratamento 0,12 [0,04 - 0,21]. CONCLUSÃO: O programa de tratamento reduziu a dor e a incapacidade associadas à dor lombar e pode servir de base para novos estudos realizados para confirmar a eficácia desta intervenção.

Neurobiological mechanisms of antiallodynic effect of transcranial direct current stimulation (tDCS) in a mice model of neuropathic pain.

BACKGROUND: Neuropathic pain is relatively common and occurs in approximately 6-8% of the population. It is associated with allodynia and hyperalgesia. Thus, non-pharmacological treatments, such as transcranial direct current stimulation (tDCS) may be useful for relieving pain. OBJECTIVES: This study aimed to investigate the antiallodynic effect of tDCS in a mice model of neuropathic pain, and the underlying neurotransmission systems that could drive these effects. METHODS: Male, Swiss mice, weighing 25-35 g, were subjected to partial sciatic nerve ligation (PSNL). Allodynia was assessed using a Von Frey filament (0.6 g). First, the behavioral time-course of these mice was assessed after 5, 10, 15 and 20 min of tDCS (0.5 mA). Second, the mice that underwent PSNL were assigned to either the tDCS (0.5 mA, 15 min) or tDCS sham group, and further assigned to receive either saline or a drug (i.e., naloxone, yohimbine, a-methyl-p-tyrosine, q-chlorophenylalanine methyl ester, caffeine, 1,3-dipropyl-8-cyclopentylxanthine, AM281, AM630, flumazenil, MK-801, or lidocaine). RESULTS: The antiallodynic effect of tDCS lasted 2 h and 4 h, after 10 min and 15 or 20 min of treatment, respectively (P < .001, P < .01, and P < .05, respectively). The antiallodynic effect of tDCS was associated with all the systems that were analyzed, i.e., the opioidergic (P < .01), adenosinergic (P < .001), serotonergic (P < .01), noradrenergic (P < .001), cannabinoid (P < .001), GABAergic, and glutamatergic (P < .001) systems. Lidocaine did not reverse the antiallodynic effect of tDCS (P > .05). CONCLUSION: The antiallodynic effect of tDCS was associated with different neurotransmitters systems; the duration of these after-effects depended on the time exposure to tDCS.

Association of low-dose naltrexone and transcranial direct current stimulation in fibromyalgia: a randomized, double-blinded, parallel clinical trial

Abstract Introduction Fibromyalgia is a complex, generalized, and diffuse chronic musculoskeletal pain. Pharmacological approaches are widely used to relieve pain and increase quality of life. Low-Dose Naltrexone (LDN) was shown to increase the nociceptive threshold in patients with fibromyalgia. Transcranial Direct Current Stimulation (tDCS) is effective for pain management. Objective The purpose of this study was to evaluate the analgesic and neuromodulatory effects of a combination of LDN and tDCS in patients with fibromyalgia. Methods This was a randomized, double-blinded, parallel, placebo/sham-controlled trial (NCT04502251; RBR-7HK8N) in which 86 women with fibromyalgia were included, and written informed consent was obtained from them. The patients were allocated into four groups: LDN + tDCS (n = 21), LDN + tDCS Sham (n = 22), placebo + tDCS (n = 22), and placebo+tDCS Sham (n = 21). The LDN or placebo (p.o.) intervention lasted 26 days; in the last five sessions, tDCS was applied (sham or active, 20 min, 2 mA). The following categories were assessed: sociodemographic, Visual Analog Pain Scale (VAS), Pain Catastrophizing Scale (PCS), State-Trait Anxiety Inventory (STAI), Fibromyalgia Impact Questionnaire (FIQ), Beck Depression Inventory (BDI-II), Profile of Chronic Pain Scale (PCP:S), Pain Pressure Threshold (PPT), and Conditioned Pain Modulation (CPM). Blood samples were collected to analyze BDNF serum levels. Results At baseline, no significant difference was found regarding all measurements. VAS pain was significantly reduced in the LDN + tDCS (p = 0.010), LDN + tDCS Sham (p= 0.001), and placebo+tDCS Sham (p= 0.009) groups. In the PCP:S, the LDN+tDCS group showed reduced pain frequency and intensity (p= 0.001), effect of pain on activities (p= 0.014) and emotions (p= 0.008). Depressive symptoms reduced after all active interventions (p > 0.001). Conclusion Combined LDN+tDCS has possible benefits in reducing pain frequency and intensity; however, a placebo effect was observed in pain using VAS, and further studies should be performed to analyze the possible association.

Morphine exposure during early life alters thermal and mechanical thresholds in rats.

BACKGROUND: Morphine is an opioid analgesic used to relieve moderate-to-severe pain, including pain in neonates at the intensive care unit. In our previous study, we showed that repeated morphine exposure during early life could trigger long-lasting implications on the developing nervous system, such as long-term neurochemical and behavioral alterations in adult rats. AIMS: The aim of our study was to determine the short-, intermediate-, and long-term effects of repeated morphine administration during early life on the thermal and mechanical thresholds and on the central levels (cerebral cortex and brainstem) of neurotrophins (brain-derived neurotrophic factor [BDNF] and nerve growth factor [NGF]) and cytokines (interleukin-6 [IL-6] and IL-10). METHODS: Male Wistar rats were administered morphine (5µg/day, s.c.) or saline for 7days from postnatal day 8 (P8) until P14. The nociceptive effect was assessed by evaluating the thermal response using the hot plate test (HPT) and the mechanical response by Von Frey (VFT) and Randall-Selitto (RST) tests at P16, P30, and P60. BDNF, NGF, IL-6, and IL-10 levels were measured in the cerebral cortex and brainstem. RESULTS: In HPT, no difference in latency was observed at P16; however, at P30 and P60, the morphine-treated group exhibited a less increase in the nociceptive threshold compared to the saline group. VFT and RST demonstrated an interaction between group and age, where the morphine group showed a less pronounced increase in latency with age, which is indicative of allodynia. In the cerebral cortex, an association between BDNF and NGF levels and age was observed, where neurotrophin level increased with age in the saline group, and decreased with age in the morphine group. In addition, IL-10 levels decreased with age in both groups; however, there was no significant difference in IL-6 levels. In the brainstem, BDNF, NGF, IL-6, and IL-10 levels increased with age. DISCUSSION: Repeated morphine exposure during neonatal life triggered alterations in the nociceptive behavior, including thermal hyperalgesia and mechanical allodynia, as well as decreased levels of BDNF and NGF in the cerebral cortex. Our study highlights the importance of extensive comprehension of the pharmacological interventions during CNS maturation.