Endogenous Cholinergic System Involved in Peripheral Analgesic Control in Mice Is Activated by TNF-α, CXCL-1, and IL-1ß.

INTRODUCTION: Tissue injury results in the release of inflammatory mediators, including a cascade of algogenic substances, which contribute to the development of hyperalgesia. During this process, endogenous analgesic substances are peripherally released to counterbalance hyperalgesia. The present study aimed to investigate whether inflammatory mediators TNF-α, IL-1ß, CXCL1, norepinephrine (NE), and prostaglandin E2 (PGE2) may be involved in the deflagration of peripheral endogenous modulation of inflammatory pain by activation of the cholinergic system. METHODS: Male Swiss mice were subjected to paw withdrawal test. All the substances were injected via the intraplantar route. RESULTS: The main findings of this study were as follows: (1) carrageenan (Cg), TNF-α, CXCL-1, IL1-ß, NE, and PGE2 induced hyperalgesia; (2) the acetylcholinesterase enzyme inhibitor, neostigmine, reversed the hyperalgesia observed after Cg, TNF-α, CXCL-1, and IL1-ß injection; (3) the non-selective muscarinic receptor antagonist, atropine, and the selective muscarinic type 1 receptor (m1AChr) antagonist, telenzepine, potentiated the hyperalgesia induced by Cg and CXCL-1; (4) mecamylamine, a non-selective nicotinic receptor antagonist, potentiated the hyperalgesia induced by Cg, TNF-α, CXCL-1, and IL1-ß; (5) Cg, CXCL-1, and PGE2 increased the expression of the m1AChr and nicotinic receptor subunit α4protein. CONCLUSION: These results suggest that the cholinergic system may modulate the inflammatory pain induced by Cg, PGE2, TNF-α, CXCL-1, and IL1-ß.

Investigation of the involvement of platelet-activating factor in the control of hypertension by aerobic training. A randomized controlled trial.

Although studies have demonstrated the effectiveness of exercise in controlling systemic arterial hypertension (SAH), the mechanisms involved in this effect are still poorly understood. Thus, this study investigated the impact of aerobic training on the relationship between platelet-activating factor (PAF) circulating levels and blood pressure in hypertensives. Seventy-seven hypertensive subjects were enrolled in this randomized controlled trial (age 66.51 ± 7.53 years, body mass 76.17 ± 14.19 kg). Participants were randomized to two groups: the intervention group (IG, n = 36), composed of hypertensive individuals submitted to an aerobic training protocol, and the control group (CG, n = 41), composed of non-exercised hypertensives. Body mass index, arterial blood pressure, quality of life, respiratory muscle strength, and functional capacity were assessed before and after 12 weeks. PAF and plasma cytokine levels were also evaluated respectively by liquid chromatography coupled with mass spectrometry and enzyme-linked immunosorbent assay. Aerobic training promoted a significant reduction in blood pressure while functional capacity, expiratory muscle strength, and quality of life, PAFC16:0 and PAFC18:1 plasma levels were increased in comparison to the CG (p < 0.05). In addition, multiple correlation analysis indicated a positive correlation [F (3.19) = 6.322; p = 0.001; R2adjusted = 0.499] between PAFC16:0 levels and expiratory muscle strength after aerobic training. Taken together, our findings indicate that PAF may be involved in the indirect mechanisms that control SAH, being mainly associated with increased respiratory muscle strength in hypertensive subjects undergoing aerobic training.

Photobiomodulation Reduces the Cytokine Storm Syndrome Associated with COVID-19 in the Zebrafish Model.

Although the exact mechanism of the pathogenesis of coronavirus SARS-CoV-2 (COVID-19) is not fully understood, oxidative stress and the release of pro-inflammatory cytokines have been highlighted as playing a vital role in the pathogenesis of the disease. In this sense, alternative treatments are needed to reduce the level of inflammation caused by COVID-19. Therefore, this study aimed to investigate the potential effect of red photobiomodulation (PBM) as an attractive therapy to downregulate the cytokine storm caused by COVID-19 in a zebrafish model. RT-qPCR analyses and protein-protein interaction prediction among SARS-CoV-2 and Danio rerio proteins showed that recombinant Spike protein (rSpike) was responsible for generating systemic inflammatory processes with significantly increased levels of pro-inflammatory (il1b, il6, tnfa, and nfkbiab), oxidative stress (romo1) and energy metabolism (slc2a1a and coa1) mRNA markers, with a pattern similar to those observed in COVID-19 cases in humans. On the other hand, PBM treatment was able to decrease the mRNA levels of these pro-inflammatory and oxidative stress markers compared with rSpike in various tissues, promoting an anti-inflammatory response. Conversely, PBM promotes cellular and tissue repair of injured tissues and significantly increases the survival rate of rSpike-inoculated individuals. Additionally, metabolomics analysis showed that the most-impacted metabolic pathways between PBM and the rSpike treated groups were related to steroid metabolism, immune system, and lipid metabolism. Together, our findings suggest that the inflammatory process is an incisive feature of COVID-19 and red PBM can be used as a novel therapeutic agent for COVID-19 by regulating the inflammatory response. Nevertheless, the need for more clinical trials remains, and there is a significant gap to overcome before clinical trials can commence.

Investigation of the effects of therapeutic ultrasound or photobiomodulation and the role of spinal glial cells in osteoarthritis-induced nociception in mice.

Pain is the most common symptom of osteoarthritis, and spinal glia is known to contribute to this symptom. Therapeutic ultrasound and laser therapy have been used to effectively treat osteoarthritis, with few adverse effects. Thus, this study aimed to investigate the effects of ultrasound and photobiomodulation on the symptoms and evaluate the participation of spinal glia in osteoarthritis-induced nociception in mice. Male Swiss mice were subjected to osteoarthritis induction with a 0.1-mg intra-articular injection of monosodium iodoacetate. Additionally, the mice received chronic ultrasound or photobiomodulation treatment for 21 days or a single treatment at day 14. Nociception was evaluated using von Frey filaments, and osteoarthritis symptoms were assessed by analysis of gait, joint temperature, and knee joint diameter. The role of spinal microglia and astrocytes on nociception was evaluated via an intrathecal injection of minocycline or fluorocitrate, and the spinal release of IL-1ß and TNF-α was assessed by ELISA after chronic treatment with ultrasound or photobiomodulation. Our data showed that both single and chronic treatment with ultrasound or photobiomodulation attenuated the osteoarthritis-induced nociception. No differences in gait, knee joint temperature, or knee joint diameter were found. The intrathecal injection of minocycline and fluorocitrate decreased the osteoarthritis-induced nociception. There was an increase in the spinal levels of TNF-α, which was reverted by chronic ultrasound and laser treatments. These results suggest that osteoarthritis induces nociception and glial activation via spinal release of TNF-α and that the chronic treatment with ultrasound or photobiomodulation decreased nociception and TNF-α release.

Evaluation of respiratory and peripheral muscle training in individuals undergoing myocardial revascularization.

OBJECTIVES: To investigate the effect of peripheral muscle strength training (PMT) and respiratory muscle strength training (RMT) muscle strength training associated with conventional physical therapy on the respiratory muscle strength, functional capacity, and quality of life in the immediate postoperative period of patients undergoing coronary artery bypass graft (CABG). METHODS: This was a randomized controlled trial. Eighty-three patients undergoing CABG were divided into two groups: Intervention group, patients that received PMT and RMT associated with conventional physical therapy, one session a day for 5 days; control group, patients that received conventional physical therapy, one session a day for 5 days. All patients had respiratory muscle strength, peripheral muscle strength, functional capacity, and quality of life evaluated by manovacuometry, dynamometry, 6-min walking test, and 36-item Short-Form Health Survey Questionnaire, respectively, before and 5 days after CABG. RESULTS: Both groups showed a significantly reduced respiratory muscle strength after CABG; however, in the intervention group, the inspiratory muscle strength reduction was lower (confidence interval [CI] 95%: 2.29 [1.9; 27.54]). The quality of live domains for pain (CI 95%: 3.08 [5.21; 24.97]) and vitality perception (CI 95%: 2.51 [2.12; 19.53]) worsened in the control and improved in the intervention group (pain: CI 95%: 1.19 [-3.38; 13.09]; vitality CI 95%: 0.07 [-6.55; 7.04]). Both groups showed reduced functional capacity and expiratory muscle strength after CABG. CONCLUSION: Conventional physical therapy combined with PMT and RMT may reduce inspiratory muscle strength loss and improve pain and vitality perception in the immediate postoperative period after CABG.

Involvement of the Hsp70/TLR4/IL-6 and TNF-α pathways in delayed-onset muscle soreness.

Delayed-onset muscle soreness (DOMS) is a very common condition in athletes and individuals not accustomed to physical activity that occurs after moderate/high-intensity exercise sessions. The activation of microglial Toll-like receptor 4 (TLR4) in the spinal cord has been described to be important for the induction and maintenance of persistent pain. Based on that, we hypothesize that 70 kilodalton heat-shock protein (Hsp70), a mediator released by exercise, could activate microglial TLR4 in the spinal cord, releasing proinflammatory cytokines and contributing to the start of DOMS. In fact, we found that the knockout of TLR4, myeloid differentiation primary response 88 (MyD88), interleukin-6 (IL-6), or both tumor necrosis factor-α (TNF-α) receptor 1 and TNF-α receptor 2 in mice prevented the development of DOMS following acute aerobic exercise in contrast to the findings in male C57BL/6 wild-type mice. Furthermore, DOMS in exercised wild-type mice was also prevented after pre-treatment with microglia inhibitor, TLR4 antagonist, and anti-Hsp70 antibody. During exercise-induced DOMS, Hsp70 mRNA, TLR4 mRNA, and protein levels, as well as Iba-1 (a microglial marker), IL-6, and TNF-α protein levels, were increased in the muscle and/or spinal cord. Together, these findings suggest that Hsp70 released during exercise-induced DOMS activates the microglial TLR4/IL-6/TNF-α pathway in the spinal cord. Thus, the blockade of TLR4 activation may be a new strategy to prevent the development of DOMS before intense exercise.

Association between respiratory muscle strength and reduction of arterial blood pressure levels after aerobic training in hypertensive subjects.

[Purpose] The purpose of present study was associate the increase of respiratory muscle strength with blood pressure levels in hypertensive subjects who underwent an aerobic exercise program. [Subjects and Methods] 90 hypertensive subjects were divided in two groups: intervention and control. All participants had an interview with a physiotherapist and were evaluated by 6-minute walk test, maximal inspiratory pressure, maximal expiratory pressure, heart rate, systolic blood pressure and diastolic blood pressure, before and after the 8 weeks. In the intervention group, the subjects underwent aerobic exercise program, 2 times a week for 8 weeks [Results] After the program, the levels of blood pressure were significantly reduced and the distance walked in the 6-minute walk test and the respiratory muscle strength were increased, compared to pre intervention and control group values. However, there was no correlation between the results provided by 6-minute walk test, maximal inspiratory pressure and maximal expiratory pressure with systolic arterial blood pressure levels. Nonetheless, the distance walked correlated with respiratory muscle strength values, in the intervention group. [Conclusion] The present study demonstrated that the aerobic training was effective in reducing the arterial blood pressure in hypertensive subjects associated with an improvement of physical conditioning and respiratory muscle strength.

The Nitric oxide/CGMP/KATP pathway mediates systemic and central antinociception induced by resistance exercise in rats.

Resistance exercise (RE) is characterized to increase strength, tone, mass, and/or muscular endurance and also for produces many beneficial effects, such as blood pressure and osteoporosis reduction, diabetes mellitus control, and analgesia. However, few studies have investigated endogenous mechanisms involved in the RE-induced analgesia. Thus, the aim of this study was evaluate the role of the NO/CGMP/KATP pathway in the antinociception induced by RE. Wistar rats were submitted to acute RE in a weight-lifting model. The nociceptive threshold was measured by mechanical nociceptive test (paw-withdrawal). To investigate the involvement of the NO/CGMP/KATP pathway the following nitric oxide synthase (NOS) non-specific and specific inhibitors were used: N-nitro-l-arginine (NOArg), Aminoguanidine, N5-(1-Iminoethyl)-l-ornithine dihydrocloride (l-NIO), Nω-Propyl-l-arginine (l-NPA); guanylyl cyclase inhibitor, 1H-[1,2,4]oxidiazolo[4,3-a]quinoxalin-1-one (ODQ); and KATP channel blocker, Glybenclamide; all administered subcutaneously, intrathecally and intracerebroventricularly. Plasma and cerebrospinal fluid (CSF) nitrite levels were determined by spectrophotometry. The RE protocol produced antinociception, which was significantly reversed by NOS specific and unspecific inhibitors, guanylyl cyclase inhibitor (ODQ) and KATP channel blocker (Glybenclamide). RE was also responsible for increasing nitrite levels in both plasma and CSF. These finding suggest that the NO/CGMP/KATP pathway participates in antinociception induced by RE.

Ang-(1-7) activates the NO/cGMP and ATP-sensitive K+ channels pathway to induce peripheral antinociception in rats.

Angiotensin-(1-7) is a bioactive component of the renin-angiotensin system that is formed endogenously and induces nitric oxide release in several tissues. The L-arginine/NO/cyclic GMP pathway and ATP-sensitive K+ channels have been proposed as the mechanism of action for the peripheral antinociception of several groups of drug and endogenous substances, including opioids, non-steroidal analgesics, acetylcholine and others. The aim of the present study was to investigate the involvement of the L-arginine/NO/cGMP and KATP+ pathway on antinociception induced by angiotensin-(1-7). Paw pressure in rats was used to induce hyperalgesia via an intraplantar injection of prostaglandin E2 (2 µg/paw). Ang-(1-7) (2, 3 and 4 µg/paw) elicited a local peripheral antinociceptive effect that was antagonized by the nonselective NO synthase (NOS) inhibitor L-NOarg and the selective neuronal NOS (nNOS) inhibitor L-NPA. The selective inhibition of endothelial (eNOS) and inducible (iNOS) NOS by L-NIO and L-NIL, respectively, was ineffective at blocking the effects of a local Ang-(1-7) injection. In addition, the level of nitrite in the homogenized paw tissue, as determined by a colorimetric assay, indicated that exogenous Ang-(1-7) is able to induce NO release. The soluble guanylyl cyclase inhibitor ODQ and the specific blocker of ATP-sensitive K+ channels glibenclamide (40, 80 and 160 µg/paw) antagonized the Ang-(1-7) response. The results provide evidence that Ang-(1-7) most likely induces peripheral antinociceptive effects via the L-arginine/NO/cGMP pathway and KATP+ pathway activation.

Acute resistance exercise induces antinociception by activation of the endocannabinoid system in rats.

BACKGROUND: Resistance exercise (RE) is also known as strength training, and it is performed to increase the strength and mass of muscles, bone strength, and metabolism. RE has been increasingly prescribed for pain relief. However, the endogenous mechanisms underlying this antinociceptive effect are still largely unexplored. Thus, we investigated the involvement of the endocannabinoid system in RE-induced antinociception. METHODS: Male Wistar rats were submitted to acute RE in a weight-lifting model. The nociceptive threshold was measured by a mechanical nociceptive test (paw pressure) before and after exercise. To investigate the involvement of cannabinoid receptors and endocannabinoids in RE-induced antinociception, cannabinoid receptor inverse agonists, endocannabinoid metabolizing enzyme inhibitors, and an anandamide reuptake inhibitor were injected before RE. After RE, CB1 cannabinoid receptors were quantified in rat brain tissue by Western blot and immunofluorescence. In addition, endocannabinoid plasma levels were measured by isotope dilution-liquid chromatography mass spectrometry. RESULTS: RE-induced antinociception was prevented by preinjection with CB1 and CB2 cannabinoid receptor inverse agonists. By contrast, preadministration of metabolizing enzyme inhibitors and the anandamide reuptake inhibitor prolonged and enhanced this effect. RE also produced an increase in the expression and activation of CB1 cannabinoid receptors in rat brain tissue and in the dorsolateral and ventrolateral periaqueductal regions and an increase in endocannabinoid plasma levels. CONCLUSIONS: The present study suggests that a single session of RE activates the endocannabinoid system to induce antinociception.

Effect of dietary caloric restriction on the nociceptive threshold of rats that underwent aerobic and resistance exercise training.

The purpose of this study was to evaluate the effect that exercise and caloric restriction have on the nociceptive threshold of rats. Male Wistar rats were divided into two groups: one group that was fed ad libitum (FED) and another group that was subjected to dietary caloric restriction (CR). The CR group received 50% of the food the FED group received, for 4 weeks. Both groups were submitted to aerobic (AE) and resistance (RE) exercise training protocols performed in a rodent treadmill and in a weight-lifting exercise model, respectively. Mechanical and thermal nociceptive thresholds were measured by tail-flick and paw-withdrawal tests, respectively. Both exercise protocols produced antinociception, but there was no difference found between the FED and CR groups after either 1 or 4 weeks. Additionally, although dietary caloric restriction alone did not result in antinociception, it did increase the running time of animals during aerobic exercise and increased the load lifted in resistance exercise after 4 weeks. These results indicate that caloric restriction for 1 or 4 weeks did not alter the nociceptive threshold, but could play an important role in improvement of physical performance.

Opioid receptors are not involved in the increase of the nociceptive threshold induced by aerobic exercise.

OBJECTIVE: To investigate the involvement of opioid receptors in antinociception induced by different aerobic exercise protocols in rats. METHODS: This experimental study, conducted in the Federal University of Minas Gerais, Belo Horizonte, Brazil from November 2011 to May 2012, included 60 female Wistar rats, divided into 10 groups of 6 animals per group. The rats were subjected to different aerobic exercise protocols: acute, cardiac stress, eccentric, and training. The nociceptive threshold was measured by the paw-withdrawal test. To investigate the involvement of the endogenous opioids system, the non-selective opioid receptor antagonist naloxone (5 mg/kg) was administered subcutaneously before the beginning of the exercise. RESULTS: All exercise protocols increased the nociceptive threshold for 15 minutes. The naloxone pre-treatment did not alter the antinociception induced by aerobic exercise protocols. CONCLUSION: The endogenous opioids system did not participate in the antinociceptive effect produced by the aerobic exercise protocols.

Spinal HMGB1 participates in the early stages of paclitaxel-induced neuropathic pain via microglial TLR4 and RAGE activation.

Introduction: Chemotherapy-induced neuropathic pain (CINP) is one of the main adverse effects of chemotherapy treatment. At the spinal level, CINP modulation involves glial cells that upregulate Toll-like receptor 4 (TLR4) and signaling pathways, which can be activated by pro-inflammatory mediators as the high mobility group box-1 (HMGB1). Objective: To evaluate the spinal role of HMGB1 in the paclitaxel-induced neuropathic pain via receptor for advanced glycation end products (RAGE) and TLR4 activation expressed in glial cells. Methods: Male C57BL/6 Wild type and TLR4 deficient mice were used in the paclitaxel-induced neuropathic pain model. The nociceptive threshold was measured using the von Frey filament test. In addition, recombinant HMGB1 was intrathecally (i.t.) injected to confirm its nociceptive potential. To evaluate the spinal participation of RAGE, TLR4, NF-kB, microglia, astrocytes, and MAPK p38 in HMGB1-mediated nociceptive effect during neuropathic pain and recombinant HMGB1-induced nociception, the drugs FPS-ZM1, LPS-RS, PDTC, minocycline, fluorocitrate, and SML0543 were respectively administrated by i.t. rout. Microglia, astrocytes, glial cells, RAGE, and TLR4 protein expression were analyzed by Western blot. ELISA immunoassay was also used to assess HMGB1, IL-1ß, and TNF-α spinal levels. Results: The pharmacological experiments demonstrated that spinal RAGE, TLR4, microglia, astrocytes, as well as MAPK p38 and NF-kB signaling are involved with HMGB1-induced nociception and paclitaxel-induced neuropathic pain. Furthermore, HMGB1 spinal levels were increased during the early stages of neuropathic pain and associated with RAGE, TLR4 and microglial activation. RAGE and TLR4 blockade decreased spinal levels of pro-inflammatory cytokines during neuropathic pain. Conclusion: Taken together, our findings indicate that HMGB1 may be released during the early stages of paclitaxel-induced neuropathic pain. This molecule activates RAGE and TLR4 receptors in spinal microglia, upregulating pro-inflammatory cytokines that may contribute to neuropathic pain.

Efficacy of Respiratory Muscle Training in the Immediate Postoperative Period of Cardiac Surgery: A Systematic Review and Meta-Analysis.

INTRODUCTION: This study aimed to evaluate the efficacy of respiratory muscle training during the immediate postoperative period of cardiac surgery on respiratory muscle strength, pulmonary function, functional capacity, and length of hospital stay. METHODS: This is a systematic review and meta-analysis. A comprehensive search on PubMed®, Excerpta Medica Database (or Embase), Cumulative Index of Nursing and Allied Health Literature (or CINAHL), Latin American and Caribbean Health Sciences Literature (or LILACS), Scientific Electronic Library Online (or SciELO), Physiotherapy Evidence Database (or PEDro), and Cochrane Central Register of Controlled Trials databases was performed. A combination of free-text words and indexed terms referring to cardiac surgery, coronary artery bypass grafting, respiratory muscle training, and clinical trials was used. A total of 792 studies were identified; after careful selection, six studies were evaluated. RESULTS: The studies found significant improvement after inspiratory muscle training (IMT) (n = 165, 95% confidence interval [CI] 9.68, 21.99) and expiratory muscle training (EMT) (n = 135, 95% CI 8.59, 27.07) of maximal inspiratory pressure and maximal expiratory pressure, respectively. Also, IMT increased significantly (95% CI 19.59, 349.82, n = 85) the tidal volume. However, no differences were found in the peak expiratory flow, functional capacity, and length of hospital stay after EMT and IMT. CONCLUSION: IMT and EMT demonstrated efficacy in improving respiratory muscle strength during the immediate postoperative period of cardiac surgery. There was no evidence indicating the efficacy of IMT for pulmonary function and length of hospital stay and the efficacy of EMT for functional capacity.

Effects of Resistance Exercise with and without Blood Flow Restriction on Acute Hemodynamic Responses: A Systematic Review and Meta-Analysis.

Low-load intensity resistance exercise with blood flow restriction (BFR) is an alternative method for enhancing strength and muscle mass. However, acute cardiovascular responses to a complete training session remain uncertain compared to high-load intensity resistance exercise (HI). Therefore, the objective of this study to examine acute and post-exercise hemodynamic responses to low-load BFR and HI protocols. This systematic review and meta-analysis (RD42022308697) followed PRISMA guidelines to investigate whether the responses of heart rate (HR), blood systolic (SBP), blood diastolic pressure (DBP), and rate pressure product (RPP) immediately after and up to 60 min post-exercise from BFR were consistent with those reported after resistance exercises performed at HI in healthy individuals. Searches using PICO descriptors were conducted in databases from January 2011 to December 2023, and effect sizes were determined by Hedge's g. The selected studies involved 160 participants in nine articles, for which the responses immediately after BFR and HI exercises showed no differences in HR (p = 0.23) or SBP (p = 0.57), but significantly higher DBP (p < 0.01) and lower RPP (p < 0.01) responses were found when comparing BFR to HI. Furthermore, the BFR and HI protocols showed no differences regarding SBP (p = 0.21) or DBP (p = 0.68) responses during a 15 to 60 min post-exercise period. Thus, these results indicated that hemodynamic responses are similar between BFR and HI, with a similar hypotensive effect up to 60 min following exercise.

Effect of a cardiac telerehabilitation program during COVID-19 associated social isolation.

This study aimed to compare the impact of a cardiac telerehabilitation (CTR) protocol aimed at patients with cardiovascular diseases (CVDs) during the period of coronavirus disease 2019 (COVID-19) associated with social isolation. This retrospective cohort study included 58 participants diagnosed with stable cardiovascular diseases (CVDs), which were divided into three groups: conventional cardiac rehabilitation (CCR) group (n â€‹= â€‹20), composed of patients undergoing conventional cardiac rehabilitation; cardiac telerehabilitation (CTR) group (n â€‹= â€‹18), composed of patients undergoing cardiac telerehabilitation and control group (n â€‹= â€‹20), composed of patients admitted for cardiac rehabilitation who had not started training programs. The results showed that body mass index was reduced (p â€‹= â€‹0.019) and quality of life was improved (e.g., limitations due to physical aspects [p â€‹= â€‹0.021), vitality [p â€‹= â€‹0.045] and limitations due to emotional aspects [p â€‹= â€‹0.024]) by CCR compared to baseline. These outcomes were not improved by CTR (p â€‹> â€‹0.05). However, this strategy prevented clinical deterioration in the investigated patients. Although CCR achieved a superior effect on clinical improvement and quality of life, CTR was relevant to stabilize the blood pressure and quality of life of patients with cardiovascular diseases during the period of COVID-19-associated social isolation.

Synergistic effect of cannabidiol and transcutaneous electrical nerve stimulation on neuropathic and inflammatory pain in mice.

OBJECTIVES: Pain is the most common cause of seeking healthcare and the leading cause of disability worldwide. Although cannabidiol and transcutaneous electrical nerve stimulation (TENS) are effective and safe strategies for treating chronic pain, the combined effect of these interventions remains overlooked. To compare the isolated and combined effect of cannabidiol and TENS in the treatment of experimental neuropathic and inflammatory pain. METHODS: Swiss mice were subjected to chronic constriction injury (CCI)-induced neuropathic or carrageenan-induced inflammatory pain models. Cannabidiol or TENS alone and the combination of these therapies were administered once. The nociceptive threshold was measured by the von Frey test. IL-1ß, TNF-α and IL-10 cytokine levels were measured by ELISA from spinal cord samples. RESULTS: Combined, cannabidiol and TENS potentiate antinociception only in neuropathic pain. IL-1ß and TNF-α levels were similarly reduced when TENS or cannabidiol were administered alone or in combination. However, only cannabidiol and TENS combined increased IL-10 levels. CONCLUSIONS: Our findings indicated TENS and cannabidiol combined were effective in potentiating antinociception in a neuropathic pain model, an effect potentially associated with spinal IL-10 upregulation.

Cannabidiol prevents chemotherapy-induced neuropathic pain by modulating spinal TLR4 via endocannabinoid system activation.

OBJECTIVES: This study aimed to investigate the effect of cannabidiol (CBD) on type 4 Toll-like receptors (TLR4), glial cells and pro-inflammatory cytokines during the neuropathic pain induced by the chemotherapy agent paclitaxel (PTX), as well as the involvement of the endocannabinoid system in this process. METHODS: Male C57BL6 mice were subjected to PTX-induced neuropathic pain. To evaluate the involvement of the TLR4, glial cells and cannabinoid CB2 receptor, specific inhibitors or antagonists were intrathecally administered. The western blotting and immunofluorescence assay was performed to evaluate the spinal expression of TLR4, microglia, astrocytes and cannabinoid CB2 receptor. The levels of spinal pro-inflammatory cytokines and endocannabinoids were determined by enzyme-linked immunosorbent assay and liquid chromatography-mass spectrometry analysis, respectively. KEY FINDINGS: CBD prevented PTX-induced neuropathic pain, and the cannabinoid CB2 receptor antagonist AM630 reversed this effect. In addition, CBD treatment inhibited the spinal expression of TLR4 and Iba1 in mice with neuropathic pain. CBD also increased spinal levels of endocannabinoids anandamide and 2-arachidonoylglycerol, and reduced levels of cytokines in mice with neuropathic pain. CONCLUSIONS: CBD was efficient in preventing PTX-induced neuropathic pain, and this effect may involve inhibition of the TLR4 on microglia spinal with activation of the endocannabinoid system.

Involvement of the Endocannabinoid System in the Control of Pain and Obesity by Exercise in Rodents: A Systematic Review.

Studies in recent years have shown that the endocannabinoid (eCB) system is activated by exercise and modulates several physiological processes. Thus, the present review aimed to summarize the literature about the involvement of the eCB system in the control of pain, obesity, and metabolism by exercise. MEDLINE, EMBASE, and Web of Science were searched for experimental studies that investigated the presence of the eCB system in animal models of pain and obesity, in which the animals were subjected to different exercise modalities. The primary outcomes were pain, obesity, and metabolism. The databases were searched for articles from their inception up until March 2020. Two independent reviewers extracted the data and assessed the methodological quality of the included studies. Thirteen studies were considered eligible for this review. The results indicated that there was increased expression and levels of cannabinoid receptors and eCBs, respectively, after aerobic and resistance exercise, and that this effect was associated with antinociception. The eCB system was modulated by exercise in obese rats, confirming that it may also be involved in the control of obesity and metabolism when these are modulated by aerobic training. Exercise can be effective in controlling pain, partly through the involvement of the eCB system. In addition, exercise can modulate the imbalance of the eCB system in obesity and metabolic disorders, thus also controlling these pathologies through this signaling system.

Cannabidiol reduces lipopolysaccharide-induced nociception via endocannabinoid system activation.

Bacterial infections are often accompanied by fever and generalized muscle pain. However, the treatment of pain with an infectious aetiology has been overlooked. Thus, we investigated the impact of cannabidiol (CBD) in bacterial lipopolysaccharide (LPS)-induced nociception. Male Swiss mice received intrathecal (i.t.) LPS injection, and the nociceptive threshold was measured by the von Frey filaments test. Spinal involvement of the cannabinoid CB2 receptor, toll-like receptor 4 (TLR4), microglia and astrocytes were evaluated by i.t. administration of their respectively antagonists or inhibitors. Western blot, immunofluorescence, ELISA and liquid chromatography-mass spectrometry were used to assess Cannabinoid CB2 receptors and TLR4 spinal expression, proinflammatory cytokines and endocannabinoid levels. CBD was administered intraperitoneally at 10 mg/kg. The pharmacological assay demonstrated TLR4 participation in LPS-induced nociception. In addition, spinal TLR4 expression and proinflammatory cytokine levels were increased in this process. CBD treatment prevented LPS-induced nociception and TLR4 expression. AM630 reversed antinociception and reduced CBD-induced endocannabinoids up-regulation. Increased spinal expression of the cannabinoid CB2 receptor was also found in animals receiving LPS, which was accompanied by reduced TLR4 expression in CBD-treated mice. Taken together, our findings indicated that CBD is a potential treatment strategy to control LPS-induced pain by attenuating TLR4 activation via the endocannabinoid system.