ArticleLiterature Review

Endocannabinoids, exercise, pain, and a path to health with aging

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Abstract

Physical activity is an important lifestyle factor for growth, development, and sustained health throughout life. In recent years, the benefits of physical activity have drawn more attention to its physiological effects on the body, including well-being. The endocannabinoid system (ECS) has emerged as a focal point to ascertain the mechanisms for how exercise benefits the body and how it reduces or controls pain. The ECS, its ligands [the endocannabinoids (eCB)], receptors (CB1 and CB2), enzymes for the synthesis and degradation of eCB, and the polyunsaturated fatty acids (PUFA) that serve as substrates, comprise a powerful biological organization of multiple controls that affects mood, inflammation, pain, and other neurological aspects of the central nervous system and peripheral nervous system. Recently, investigators have reported increases in circulating levels of eCB after exercise, with some eCB exerting analgesic effects from exercise. The focus of this review is to discuss evidence for the role of eCB and the complexities of the ECS in exercise and pain. Some aspects presented herein are production of eCB and activation of the cannabinoid receptors in the brain following exercise; eCB, pain, and physical activity; oxylipins; and joint pain. Future research on the ECS must include mechanistic approaches to endocannabinoid signaling and explain the role of dietary PUFA in altering signaling of the receptors that affects pain. Additionally, how other types of exercise, such as Tai Chi, which is reported to improve well-being, should be investigated to ascertain if changes in eCB mediate the mind and body benefits of Tai Chi. As we age, exercise in the form of play has evolved with the exploration of our body from walking to running, recreational, and competitive sports, to midlife physical activity focusing on maintaining fitness and a healthy body weight. Furthermore, exercise has been a target of investigation to explore various hypotheses to explain the mechanisms for cognitive benefits in the young and in older adults. The science of exercise has matured to a level of importance in the life cycle to reduce pain with aging and include new investigations on the ECS to explain its role in well-being and improved quality of life in later years.

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... According to the literature, two key factors seem to participate in the increase of the prevalence of mental diseases: (i) The decline of mortality rates and, (ii) The [15][16][17][18]. Exercise influences multiple neurobiological networks, including the endocannabinoid system [19][20][21][22], therefore, it is likely that this endogenous signaling arrangement might influence the effectiveness of exercise as a treatment for managing mental disorders. ...
... Amongst the neurobiological networks that respond to exercise, the endocannabinoid system is included [203]. Remarkably, the research on the field has situated the endocannabinoid system as one of the possible moderators through which exercise may cause benefits on mental disturbances [19,20,204]. Following this idea, current findings have demonstrated an increase in the levels of the endocannabinoids after acute sessions of exercise. ...
... As reviewed, exercise influences several neurobiological elements, including the endocannabinoid system, suggesting a putative modulatory role of the endocannabinoid system on the effectiveness of physical activity and exercise as treatments for managing mental disorders [19][20][21][22]. Despite the Fig. (2). ...
Article
According to the World Health Organization (WHO), 47 million of people display mental health disorders Worldwide. In addition, epidemiological studies have shown that the extension of life expectancy and the increase in aged population will significantly impact in the prevalence of several mental impairments. Although there are strategies for preventing and alleviate mental illnesses such as pharmacological and psychological approaches, limited results have been observed. Thus, the search for new therapeutics for managing psychiatric disorders has explored multiple roads. In recent years, it has been demonstrated that physical activity and exercise promote health benefits. On the other hand, among the neurobiological systems that participate in the genesis and development of mental disruptions, the endocannabinoid system has been suggested as an active player. Supporting this hypothesis, data suggest that the elements comprising the endocannabinoid system, such as the CB1/CB2 cannabinoid receptors, endogenous ligands (N-arachidonoylethanolamine [anandamide, AEA] and 2-arachidonoylglycerol [2- AG]), transporters and the enzymes involved in the biosynthesis and degradation of the AEA and 2-AG, modulate mental diseases. In this review, we discuss that the endocannabinoid system might be considered as a modulator for the positive outcomes of exercise in the management of mental disorders. Clinically, this promising field might be exploited by targeting the elements of the endocannabinoid system aimed to increase the exercise benefits applied to patients with mental illnesses.
... Evidence of hypoalgesia that is insensitive to opioid antagonists suggests that EIH must be mediated in part by non-opioid mechanisms [6]. One such mechanism may involve the endocannabinoid system [68]. This system consists of the endogenous ligand agonists N-arachidonylethanolamide (AEA) and 2-arachidonoylglycerol (2-AG), Gprotein-coupled cannabinoid (CB) receptors CB1 and CB2 (type 1 and 2, respectively) and metabolising enzymes. ...
... This system consists of the endogenous ligand agonists N-arachidonylethanolamide (AEA) and 2-arachidonoylglycerol (2-AG), Gprotein-coupled cannabinoid (CB) receptors CB1 and CB2 (type 1 and 2, respectively) and metabolising enzymes. Endocannabinoids have been shown to have antinociceptive effects in models of acute pain in animals and humans [69,70] by binding to CB1 and CB2 receptors found in the PNS and at spinal and supraspinal pain processing sites [68,69]. Endocannabinoids are synthesised from arachidonic acid and can be released from cells immediately after their synthesis [71] in response to stress of a physical nature [49]. ...
... This would be supported by the dense expression of CB receptors on A-delta and C-delta primary afferents [74] which are activated during muscle contractions to produce alterations in circulating concentrations of endocannabinoids [6]. Similarly to opioid-mediated mechanisms, the mechanisms of analgesia driven by endocannabinoids likely include inhibition of presynaptic neurotransmitter and neuropeptide release and activation of the descending pain inhibitory pathway [68]. ...
Article
Exercise-induced hypoalgesia is characterised by a reduction in pain sensitivity following exercise. Recently, low intensity exercise performed with blood flow restriction has been shown to induce hypoalgesia. The purpose of this manuscript is to discuss the mechanisms of exercise-induced hypoalgesia and provide rationale as to why low intensity exercise performed with blood flow restriction may induce hypoalgesia. Research into exercise-induced hypoalgesia has identified several potential mechanisms, including opioid and endocannabinoid-mediated pain inhibition, conditioned pain modulation, recruitment of high threshold motor units, exercise-induced metabolite production and an interaction between cardiovascular and pain regulatory systems. We hypothesise that several mechanisms consistent with prolonged high intensity exercise may drive the hypoalgesia effect observed with blood flow restriction exercise. These are likely triggered by the high level of intramuscular stress in the exercising muscle generated by blood flow restriction including hypoxia, accumulation of metabolites, accelerated fatigue onset and ischemic pain. Therefore, blood flow restriction exercise may induce hypoalgesia through similar mechanisms to prolonged higher intensity exercise, but at lower intensities, by changing local tissue physiology, highlighting the importance of the blood flow restriction stimulus. The potential to use blood flow restriction exercise as a pain modulation tool has important implications following acute injury and surgery, and for several load compromised populations with chronic pain.
... Recently, Stensson et al. conducted a study on women with fibromyalgia; they indicated that a 15-week person-centered resistance exercise program led to a significant increase in AEA and 2-AG concentration, and therefore might increase muscle strength and provide some neurological alterations, such as analgesia or antidepressant effects [42]. On the contrary, some studies report the constant levels of 2-AG concentration in response to moderate or acute exercises performed by humans [43,44]. Moreover, lower circulating levels of 2-AG after both moderate and preferred physical activity were also demonstrated in some recent research conducted on women with major depressive disorders [11]. ...
... Furthermore, the activation of cannabinoid receptor type 1 in GABAergic neurons of the human ventral tegmental area (VTA) in the midbrain may result in disinhibition of VTA dopamine release, involved in reward-directed processes that occur during physical activity (mainly voluntary). Thus, this demonstrated a significant and promising correlation between the expression of CB1R, GABA, and dopamine [44,49]. Interestingly, Merill et al. using an animal model indicated that ventral tegmental area GABAergic and DAergic cells are able to produce various eCBs, and therefore might be involved in the alterations in the neuronal activity or plasticity in adaptive reward processing or addiction [50]. ...
... The molecular alterations in the endocannabinoid signaling triggered by physical activity mentioned above may directly correlate with systemic effects. Starting with the influence on mood, various types of exercise, both acute and chronic, and ending with resistant and aerobic training, all activate the endocannabinoid signaling and result in significant mood improvements, antidepressant effect, reduced anger, and tension, as well as increased vigor and motivation [35,40,44,52]. Euphoric and analgesic phenomena widely described by athletes that occur during a forced and prolonged physical activity called "runner's high" are the result of the activity of endorphins, monoamines, and endocannabinoids and their influence on the reward system in the brain [36,53]. ...
Article
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The worldwide prevalence of neurological and neurodegenerative disorders, such as depression or Alzheimer’s disease, has spread extensively throughout the last decades, becoming an enormous health issue. Numerous data indicate a distinct correlation between the altered endocannabinoid signaling and different aspects of brain physiology, such as memory or neurogenesis. Moreover, the endocannabinoid system is widely regarded as a crucial factor in the development of neuropathologies. Thus, targeting those disorders via synthetic cannabinoids, as well as phytocannabinoids, becomes a widespread research issue. Over the last decade, the endocannabinoid system has been extensively studied for its correlation with physical activity. Recent data showed that physical activity correlates with elevated endocannabinoid serum concentrations and increased cannabinoid receptor type 1 (CB1R) expression in the brain, which results in positive neurological effects including antidepressant effect, ameliorated memory, neuroplasticity development, and reduced neuroinflammation. However, none of the prior reviews presented a comprehensive correlation between physical activity, the endocannabinoid system, and neuropathologies. Thus, our review provides a current state of knowledge of the endocannabinoid system, its action in physical activity, as well as neuropathologies and a possible correlation between all those fields. We believe that this might contribute to finding a new preventive and therapeutic approach to both neurological and neurodegenerative disorders.
... Their discovery led to the so-called endocannabinoid hypothesis of the runner's high. In comparison to endorphins, eCBs are lipophilic molecules and can penetrate the blood-brain barrier easily, making them better candidates to explain the runner's high (Dietrich and McDaniel 2004;Fuss and others 2015;Siebers and others 2021;Watkins 2018). The eCB system is a potent endogenous system involved in various physiological functions in the nervous system. ...
... The eCB system is a potent endogenous system involved in various physiological functions in the nervous system. Some involved physiological processes are synaptic transmission, mood, reward, anxiety, appetite, memory processing, neuroprotection, and neuroinflammation (Hillard 2018;Watkins 2018;Fig. 1). ...
Article
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The runner’s high is an ephemeral feeling some humans experience during and after endurance exercise. Recent evidence in mice suggests that a runner’s high depends on the release of endocannabinoids (eCBs) during exercise. However, little is known under what circumstances eCBs are released during exercise in humans. This systematic review sampled all data from clinical trials in humans on eCB levels following exercise from the discovery of eCBs until April 20, 2021. PubMed/NCBI, Ovid MEDLINE, and Cochrane library were searched systematically and reviewed following the PRISMA guidelines. From 278 records, 21 met the inclusion criteria. After acute exercise, 14 of 17 studies detected an increase in eCBs. In contrast, after a period of long-term endurance exercise, four articles described a decrease in eCBs. Even though several studies demonstrated an association between eCB levels and features of the runner’s high, reliable proof of the involvement of eCBs in the runner’s high in humans has not yet been achieved due to methodological hurdles. In this review, we suggest how to advance the study of the influence of eCBs on the beneficial effects of exercise and provide recommendations on how endocannabinoid release is most likely to occur under laboratory conditions.
... Thus, it is conceivable that both changes in eCB level and types as well as reduced inflammatory mediators such as cytokines and oxylipins could be responsible for controlling pain and improving mood after exercise. However, the extent that EPEA and DHEA affect the nervous system and eCB signaling is not yet known (Watkins, 2018). ...
... Previous studies support that the ECS at least in part explain exercise effects on functions of the brain and peripheral tissues related to mood, reward, pain, appetite, immune functions, and energy metabolism (Tantimonaco et al., 2014;Watkins, 2018). Increased hippocampal neurogenesis correlates with both high AEA levels and increases of CB1 activity, which positively regulates BDNF activity (Butovsky et al., 2005;Hill, Titterness, et al., 2010). ...
Chapter
Aging is associated with changes in hormones, slowing of metabolism, diminished physiological processes, chronic inflammation and high exposure to oxidative stress factors, generally described as the biological cost of living. Lifestyle interventions of diet and exercise can improve the quality of life during aging and lower diet-related chronic disease. The endocannabinoid system (ECS) has important effects on systemic metabolism and physiological systems, including the central and peripheral nervous systems. Exercise can reduce the loss of muscle mass and improve strength, and increase the levels of endocannabinoids (eCB) in brain and blood. Although the ECS exerts controls on multiple systems throughout life it affords benefits to natural aging. The eCB are synthesized from polyunsaturated fatty acids (PUFA) and the primary ones are produced from arachidonic acid (n-6 PUFA) and others from the n-3 PUFA, namely eicosapentaenoic and docosahexaenoic acids. The eCB ligands bind to their receptors, CB1 and CB2, with effects on appetite stimulation, metabolism, immune functions, and brain physiology and neuroplasticity. Dietary families of PUFA are a primary factor that can influence the types and levels of eCB and as a consequence, the downstream actions when the ligands bind to their receptors. Furthermore, the association of eCB with the synthesis of oxylipins (OxL) is a connection between the physiological actions of eCB and the lipid derived immunological OxL mediators of inflammation. OxL are ubiquitous and influence neuroinflammation and inflammatory processes. The emerging actions of eCB on neuroplasticity, well-being and pain are important to aging. Herein, we present information about the ECS and its components, how exercise and diet affects specific eCB, their role in neuroplasticity, neuroinflammation, pain, mood, and relationship to OxL. Poor nutrition status and low nutrient intakes observed with many elderly are reasons to examine the role of dietary PUFA actions on the ECS to improve health.
... Hypoalgesia that is insensitive to opioid antagonists suggests nonopioid mechanisms contribute to EIH (39,71). One such mechanism is the endocannabinoid (ECB) system, which consists of cannabinoid receptors found at peripheral, spinal, and supraspinal pain processing sites (63,71) and endogenous ligand agonists, including anandamide and 2-arachidonoylglycerol (2AG). ...
... Hypoalgesia that is insensitive to opioid antagonists suggests nonopioid mechanisms contribute to EIH (39,71). One such mechanism is the endocannabinoid (ECB) system, which consists of cannabinoid receptors found at peripheral, spinal, and supraspinal pain processing sites (63,71) and endogenous ligand agonists, including anandamide and 2-arachidonoylglycerol (2AG). Endocannabinoids are synthesized and rapidly released from cells in response to stressful conditions such as exercise (10). ...
Article
Aim: This study aimed to investigate and compare the magnitude of exercise-induced hypoalgesia (EIH) with low intensity blood flow restriction (BFR) resistance exercise (RE) at varying pressures to other intensities of resistance exercise and examine endogenous mechanisms of pain reduction. Methodology: Twelve individuals performed four experimental trials involving unilateral leg press exercise in a randomised crossover design: low load RE at 30% of one repetition maximum (1RM), high load RE (70% 1RM) and BFR-RE (30% 1RM) at a low and high pressure. BFR pressure was prescribed relative to limb occlusion pressure at 40% and 80% for the low- and high-pressure trials. Pressure pain thresholds (PPT) were assessed before, 5-min and 24-h following exercise in exercising and non-exercising muscles. Venous blood samples were collected at the same timepoints to determine plasma concentrations of beta-endorphin and 2-arachidonoylglycerol. Results: High pressure BFR-RE increased PPTs in the exercising limb to a greater extent than all other trials. Comparable systemic EIH effects were observed with HLRE and both BFR-RE trials. PPTs in the exercising limb remained elevated above baseline at 24-h post-exercise following both BFR-RE trials. Post-exercise plasma beta-endorphin concentration was elevated during the BFR-RE trials. No changes to 2-arachidonoylglycerol concentration were observed. Conclusion: High pressure BFR-RE causes a greater EIH response in the exercising limb that persists for up to 24-h following exercise. The reduction in pain sensitivity with BFR-RE is partly driven by endogenous opioid production of beta-endorphin. BFR-RE should be introduced as a possible pain-modulation tool in individuals with acute and chronic pain.
... Anandamide or n-arachidonoylethanolamide (AEA) and 2-arachidonylglycerol (2-AG) are endogenous cannabinoids for the G-protein-coupled cannabinoid CB1 (type 1) and CB2 (type 2) receptors [1]. The endocannabinoid system plays a crucial role in the maintenance of homeostasis in thermoregulation and motor control [2], energy metabolism [3], skin function (barrier formation, regeneration) [4], appetite and digestion [5], learning and memory [6], chronic pain [7], and inflammation and other immune system responses [8]. ...
Article
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Background Increased circulating endocannabinoids levels are typically associated with aerobic exercise. This phenomenon is associated with a “runner’s high,” a state of euphoria and well-being experienced after a long exercise. We will provide in this review a transparent and standardized methodology following the PRISMA-P and Cochrane Handbook for Systematic Reviews of Interventions for conducting a systematic review and meta-analysis for synthesizing the available evidence about the effects of physical activity on the circulating levels of AEA and 2-AG endocannabinoids in healthy subjects. Methods A multi-disciplinary team with basic and clinical expertise in exercise science developed this protocol. PubMed, EMBASE, Web of Science, CINAHL, SPORTDiscus, and Scopus will be the databases. A health sciences librarian was consulted in the development of the research. Search strategies will combine MeSH terms and free text words, including “exercise,” “exercise, physical,” “exercise training,” “physical activity,” “endocannabinoids,” “2-arachidonoyl-glycerol,” “glyceryl 2-arachidonate,” “2-AG,” “anandamide,” “AEA,” “n-arachidonoylethanolamide,” “adult,” “young adult,” and “middle-aged.” We will select experimental or quasi-experimental studies published through December 2021. The selection of studies, data extraction, assessment of the risk of bias, and the quality of evidence will be carried out in a paired and independent manner, and the consistency will be assessed using the statistics of Cohen Kappa. Methodological quality will be assessed using the Revised Cochrane risk of bias tool for randomized trials (RoB 2) and the Risk Of Bias In Nonrandomized Studies of Interventions (ROBINS-I) risk tool. We will use the Grading of Recommendations Assessment, Development, and Evaluation to assess the quality of the evidence, χ ² and I ² tests for heterogeneity, funnel plots, and the Egger test for publication bias. A meta-analysis for each data comparison will be performed whenever possible to determine the effect of physical activity on endocannabinoids’ circulating levels. Discussion This systematic review and meta-analysis will provide an overview of the evidence about physical activity over AEA and 2-AG endocannabinoids, including comparability of variables between studies, critical interpretation of results, and use of accurate statistical techniques. The endocannabinoid is molecules by which muscles communicate with other tissues and organs, mediating the beneficial effects of exercise on health and performance, including increased glucose uptake, improved insulin action, and mitochondrial biogenesis. They are essential to exercise. Thus, this study will review the acute effect of physical exercise on circulating levels of endocannabinoids in healthy individuals. The results of this study will potentially be transferred to doctors, health professionals, and legislators to guide their decision making, as well as will improve future research. Systematic review registration PROSPERO CRD42020202886 .
... PE might induce its mitigating effect on premature aging and on chronic pain by directly affecting the pain system. PE has been known to increase the production and release of endocannabinoids [82] and endogenous opioids [45], which mediate endogenous pain inhibition. The enhanced pain modulation capacity of athletes may support this notion [30]. ...
Article
Chronic pain induces a multitude of harmful effects; recently it has been suggested that chronic pain is also associated with premature aging, manifested in shortened telomere length (TL). However, evidence for this hypothesis is scarce and inconsistent. The aim was twofold: 1) Investigate whether chronic pain is associated with premature aging, and 2) Determine whether physical exercise (PE) moderates this association if it exists. Participants were 116 male subjects, with (n=67) and without chronic pain (n=49). Blood samples for TL analysis were collected and participants were interviewed and completed questionnaires. As a part of the cohort, we included people with physical disability; this variable was controlled in the analysis. The TL of individuals with chronic pain was significantly shorter than that of pain-free individuals. Regression analysis revealed a significant moderating effect of PE on chronic pain and TL, above and beyond the effects of disability, age, and weight. Whereas chronic pain was associated with shorter telomeres in participants who did not exercise, this association was non-significant among participants who did exercise. The results suggest that chronic pain is associated with premature ageing; however, PE may mitigate this association and may protect individuals against the harmful effects of chronic pain. Perspective The study suggest that it is important to monitor signs of premature ageing among chronic pain patients as they are at risk. However, chronic pain patients may benefit from regular physical exercise in this respect as it may moderate premature ageing.
... The endocannabinoid system (ECS) includes two G protein-coupled cannabinoid receptors (CB1 and CB2), widely expressed all over the body, and their endogenous ligands, the most well-studied of which are two derivatives of the arachidonic acid: N-arachidonoylethanolamine (AEA, also known as anandamide) and 2-arachidonoylglycerol (2-AG). ECS also includes the enzymes necessary for synthesizing and degrading the ligands [291]. In addition to CB1 and CB2 receptors, 2-AG and AEA can bind to the vanilloid receptor (TRPV1); moreover, AEA also functions as an agonist of some subtypes of the peroxisome proliferator-activated receptor (PPAR) family of nuclear receptors [292]. ...
Article
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Physical activity (PA) has been central in the life of our species for most of its history, and thus shaped our physiology during evolution. However, only recently the health consequences of a sedentary lifestyle, and of highly energetic diets, are becoming clear. It has been also acknowledged that lifestyle and diet can induce epigenetic modifications which modify chromatin structure and gene expression, thus causing even heritable metabolic outcomes. Many studies have shown that PA can reverse at least some of the unwanted effects of sedentary lifestyle, and can also contribute in delaying brain aging and degenerative pathologies such as Alzheimer's Disease, diabetes, and multiple sclerosis. Most importantly, PA improves cognitive processes and memory, has analgesic and antidepressant effects, and even induces a sense of wellbeing, giving strength to the ancient principle of "menssanain corporesano" (i.e., a sound mind in a sound body). In this review we will discuss the potential mechanisms underlying the effects of PA on brain health, focusing on hormones, neurotrophins, and neurotransmitters, the release of which is modulated by PA, as well as on the intra- and extra-cellular pathways that regulate the expression of some of the genes involved.
... Nicht vollständig geklärt ist hingegen, welche Mechanismen bei chronischen Schmerzpatienten ursächlich für diese Störung sind [27]. Als mögliche Störfaktoren gelten u. a. Dysfunktionen des Immun- [28], des Endocannabinoid- [29,30] sowie des vegetativen Nervensystems [31]. Geschlechtsspezifische und psychologische Faktoren korrelieren dagegen offenbar nicht zu stark mit Störungen der EIH-Reaktion [32,33]. ...
... In recent years, public demand for medical cannabinoids favoured studies concerning the possible applications of Cannabis sativa L. extracts for various pathological conditions, which include inflammation control and its inhibition. Furthermore, the emerging role of the endocannabinoid system (ECS) in tissue homeostasis and its maintenance is highlighted in recent studies [7,21,37,41]. ECS is comprised of socalled endocannabinoids (e.g. anandamide and 2-arachidonoylglycerol), their receptors (e.g. ...
Article
Herbal extracts are promising immunomodulating compounds. Their standardization may improve clinical outcome in various conditions related to inflammatory state. The aim of this study was to assess the utility of Cannabis sativa L. and Humulus lupulus extracts obtained by supercritical carbon dioxide (scCO2) in the reduction of pro-inflammatory cytokines release after LPS stimulation in the in vitro model. After scCO2 extraction, the cytotoxic potential of the obtained compounds was determined. The highest non-cytotoxic concentrations were selected for further inflammatory testing. PMA-differentiated U937 cells were used as an LPS induced model of the inflammation to assess the extracts potential to decrease the level of the pro-inflammatory cytokines IL-1β, IL-6 and TNF-α. Either individually tested or in combination scCO2 extracts markedly reduced the level of released pro-inflammatory cytokines in comparison to LPS stimulated positive control. Our results show that the usage of standardized Cannabis sativa L. and Humulus lupulus extracts might be beneficial in reducing the inflammatory state. Application of the mixed extracts not only reduces the need for a high concentration of pure compounds, but also broadens the possible therapeutic effect. Moreover, scCO2 extraction may serve as the efficient method of obtaining functional anti-inflammatory extracts from either hop cones or cannabis.
... Previous literature has shown mixed findings in acute AE increasing cannabinoid metabolites (i.e., THCCOOH) [118,119]. Further, AE releases endocannabinoids [120][121][122], which may help mitigate the negative impact of repeated exogenous cannabis exposure. Notable for future studies, it is hypothesized this relationship may be gender-specific; thus, research examining the potential use of aerobic interventions in cannabis users should prioritize investigation of potential gender differences. ...
Article
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Cannabis use in adolescents and young adults is linked with aberrant brain structure, although findings to date are inconsistent. We examined whether aerobic fitness moderated the effects of cannabis on cortical surface structure and whether gender may play a moderating role. Seventy-four adolescents and young adults completed three-weeks of monitored abstinence, aerobic fitness testing, and structural magnetic resonance imaging (sMRI). Whole-sample linear regressions examined the effects of gender, VO 2 max, cannabis use, and their interactions on the surface area (SA) and local gyrification index (LGI). Cannabis use was associated with greater cuneus SA. Gender-by-cannabis predicted precuneus and frontal SA, and precentral, supramarginal, and frontal LGI; female cannabis users demonstrated greater LGI, whereas male cannabis users demonstrated decreased LGI compared to non-users. Aerobic fitness was positively associated with various SA and LGI regions. Cannabis-by-aerobic fitness predicted cuneus SA and occipital LGI. These findings demonstrate that aerobic fitness moderates the impact of cannabis on cortical surface structure, and gender differences are evident. These moderating factors may help explain inconsistencies in the literature and warrant further investigation. Present findings and aerobic fitness literature jointly suggest aerobic intervention may be a low-cost avenue for improving cortical surface structure, although the impact may be gender-specific.
... In recent years, the benefits of physical activity have drawn more attention to its physiological effects on the body. 10 Considering the side effect of pharmacological treatment for osteoporosis, there is an increasing demand for nonpharmacologic therapy, such as physiotherapy and physical activity that are used appropriately and for long periods. 11 Previous experiments and/or clinical trials based on different types of physical activity such as aerobic exercise and/or resistance exercise have provided fundamental knowledge on this topic. ...
Article
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Purpose The aim of this meta-analysis was to evaluate the efficacy of Tai chi (TC) as an adjuvant treatment for osteopenia and primary osteoporosis. Methods We went through eight databases to identify relevant randomized controlled trials that compared TC with a control group. The primary outcome was osteoporosis-related fractures (fracture incidence). Meta-analyses and trial sequential analyses (TSA) were conducted using RevMan 5.3 and TSA 0.9. Results Fifteen randomized controlled trials involving a total of 857 patients were included in the analyses. No trials reported primary outcome; however, bone mineral density (BMD) values differed significantly in subgroup 1 (TC vs no treatment; weighted mean difference [WMD] =0.05 g/cm², 95% CI 0.03 to 0.07; P<0.00001; P for heterogeneity =0.22, I²=22%) and subgroup 2 (TC vs conventional treatments; WMD =0.16 g/cm², 95% CI 0.11 to 0.21; P<0.00001; P for heterogeneity =0.008, I²=75%). In addition, two trials compared TC with conventional treatments, which found a significant difference in bone gla protein (standardized mean difference =−1.18, 95% CI −1.66 to −0.70; P<0.00001; P for heterogeneity =0.58, I²=75%). The results of the BMD were confirmed by TSA. Also, TC may have a certain effect on the relief of osteoporotic pain (WMD = −2.61, 95% CI −3.51 to −1.71; WMD = −1.39, 95% CI −2.01 to −0.77). However, it did not promote the quality of life, level of serum calcium, serum phosphorus, and also had no effect on bone turnover markers. Conclusion Although there is no study monitoring fracture incidence, TC may be beneficial for patients in improving BMD values, level of bone gla protein, and relieving osteoporotic pain. However, due to the low methodological quality, current evidence for treating osteopenia and primary osteoporosis through TC is insufficient.
... Además de provocar un efecto analgésico, el sistema endocannabinoide mejora el desempeño en actividades aeróbicas. La administración de antagonistas del receptor CB1 disminuye la velocidad en corredores[22].Algunos estudios sugieren que la forma más efectiva de estimulación del sistema endocannabinoide es a través de la realización de ejercicio moderado[23] ya que observaron niveles elevados de anandamidas en esa modalidad e inferiores cuando el ejercicio es intenso o suave. La analgesia provocada por la activación del sistema endocannabinoide puede verse ...
Article
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Physical inactivity and sedentary lifestyle are currently a global health problem that concerns because of its systematic growth, the health consequences it causes for adults and, in alarming escalation, also for the younger population. On the contrary, regular physical activity has shown benefits to physical, neurological and mental health. Despite the incontrovertible information about its positive effects, less than half of the world's population excercises regularly. This work's objective is to make a brief description of the neurocognitive mechanisms that are involved in the motivational processes, especially those linked to physical activity, in order to present pragmatic recommendations that increase adherence to physical training programs, based on techniques of cognitive psychology and analyzed from a neurocognitive perspective.
... In this context, it is interesting to mention the role of the cannabinoid system, and its ligands, on reducing oxidative stress parameters [51]. In fact, the direct effect of physical exercise on the endocannabinoid system can also explain the exercise-induced analgesia observed in the present study, once the endocannabinoid system has emerged as the main mechanisms for how exercise benefits the whole organism and how it reduces and controls pain [52]. ...
Article
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Chronic pain affects significant portion of the world's population and physical exercise has been extensively indicated as non-pharmacological clinical intervention to relieve symptoms in chronic pain conditions. In general, studies on pain chronification and physical exercise intervention have focused on neuropathic pain, although chronic pain commonly results from an original inflammatory episode. Based on this, the objective of the present study was to investigate the therapeutic and preventive effect of the running wheel exercise on the persistent hyperalgesia induced by repetitive inflammatory stimulus, a rodent model that simulates clinical conditions of chronic pain that persist even with no more inflammatory stimulus present. To evaluate the therapeutic effect of physical exercise, we first induced persistent hyperalgesia through 14 days of PGE2 hind paw injections and, after that, mice have access to the regular voluntary running wheel. To evaluate the preventive effect of physical exercise , we first left the mice with access to the regular voluntary running wheel and, after that, we performed 14 days of PGE2 hind paw injection. Our results showed that voluntary running wheel exercise reduced persistent mechanical and chemical hyperalgesia intensity induced by repetitive inflammatory stimulus. In addition, we showed that this therapeutic effect is long-lasting and is observed even if started belatedly, i.e. two weeks after the development of hyperalgesia. Also, our results showed that voluntary running wheel exercise absolutely prevented persistent mechanical and chemical hyperalgesia induction. We can conclude that physical exercise has therapeutic and preventive effect on inflammatory stimulus induced persistent hyperalgesia. Our data from animal experiments bypass placebo effects bias of the human studies and reinforce physical exercise clinical recommendations to treat and prevent chronic pain.
... 30 Genel olarak CB1 reseptör aktivasyonu ağrı, anksiyete, depresyon, travma sonrası stres bozukluğu, postmenopozal osteoporoz, kanser ve nörodejeneratif hastalıkların tedavisinde kullanılabilir. Reseptörün inhibisyonu ise obezite, diyabet, karaciğer hastalıkları, kardiyometa-bolik komplikasyonlar, alkol-ilaç bağımlılığı ve postmenopozal osteoporoz tedavisinde terapötik amaçlı kullanılabilmektedir. 31 Avrupa uyuşturucu raporlarından elde edilen sonuçlar, esrarın en çok kullanılan yasa dışı uyuşturucu olduğunu göstermiştir. WADA, 2004'te yayımladığı yasaklı maddeler listesinde kannabinoidleri de içermekte olup, esrarın bazı sporlarda performansı artırabileceğini ve çoğu ülkede yasa dışı bir ilaç olduğunu iddia etmiştir. ...
... The endocannabinoid system, including AEA and 2-AG, is located in both the central and peripheral nervous systems [33]. This system is responsible for numerous physiological tasks including sensations of pain [34] and mood disorders [35]. ...
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... This represents a novel finding in the aerobic fitness literature. One possible mechanism underlying these findings is that recent studies have revealed that aerobic exercise releases endocannabinoids (Heyman et al., 2012;Hillard, 2018;Meyer, Crombie, Cook, Hillard, & Koltyn, 2019;Watkins, 2018). This may lessen the negative impact of repeated and regular exogenous CAN exposure in youth. ...
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Context: With increased use of cannabis-based products by the public for both recreational and medical use, sports medicine clinicians should be informed of historical context, current legal considerations, and existing evidence with regard to efficacy, safety, and risks in the athletic community. Evidence acquisition: A review of ClinicalTrials.gov, MEDLINE, and CINAHL from 2015 to present was conducted with emphasis on the most recent literature using search terms, cannabis, nabiximols, cannabinoids, pain management, THC, CBD, and marijuana. Bibliographies based on original search were utilized to pursue further literature search. Study design: Clinical review. Level of evidence: Level 3. Results: At present, limited high-quality studies exist for use of cannabinoids for acute pain, chronic pain, or concussion. None of the trials involving cannabinoids included the athletic population. Thus, results from this clinical review are extrapolated to conditions of the sports medicine population. For acute pain, 2 small-randomized double-blinded crossover trials concluded no immediate effect of cannabinoid therapy. More robust evidence exists for treatment of chronic pain conditions through meta-analysis and systemic reviews. Cannabinoid therapy exhibits moderate efficacy as a treatment for some chronic pain conditions. Investigations included a broad spectrum of chronic pain conditions, including neuropathic, musculoskeletal, inflammatory, and central pain conditions, and reveal reduction in pain and improvement of quality of life with limited adverse effects. For concussion, evidence is based on preclinical in vitro and animal models revealing possible neuroprotective effects as well as 2 clinical studies involving the presence of cannabinoids for concussion (some sports-related), but there are no high-quality trials evaluating efficacy for treatment with cannabinoids at this time. Conclusion: Although various biochemical explanations exist on the use of cannabinoid therapy through modulation of the endocannabinoid system for several medical issues affecting athletes, recommendations from clinicians must be extrapolated from a majority of research done in the nonathletic population. Lack of strong-quality clinical evidence, coupled with inconsistent federal and state law as well as purity issues with cannabis-based products, make it difficult for the sports medicine clinician to widely recommend cannabinoid therapeutics at present. Future larger, higher quality clinical research studies with standardized pure extracts will better guide appropriate medical use going forward. At present, evidence for a multitude of therapeutic applications is emerging for cannabinoid treatment approaches. With emphasis placed on patient-centered clinical decisions, cannabinoids hold promise of treatment for athletes with chronic pain conditions. Clinicians who treat the athletic community must consider legal and ethical issues when discussing and recommending the use of cannabinoids, with acknowledgment of inconsistencies in purity of various formulations and concerns of drug testing.
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Agnieszka Pajak, Magdalena Kostrzewa, Natalia Malek, Michal Korostynski, Katarzyna Starowicz Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland Abstract: Matrix metalloproteinases (MMPs) are considered important in articular cartilage breakdown during osteoarthritis (OA). Similarly, the endocannabinoid system (ECS) is implicated in joint function and modulation of nociceptive processing. Functional interplay between ECS and MMPs has been recently indicated. Here, we tested if changes in the expression of selected MMPs and major ECS elements temporally correlate with the intensity of OA-related pain. Knee OA was induced in male Wistar rats by intra-articular sodium monoiodoacetate injection. OA-like pain behavior was tested using the dynamic weight bearing. Joint tissue samples at different time points after OA induction were subjected to gene (quantitative polymerase chain reaction) and protein (Western blot) expression analyses. Monoiodoacetate-induced nocifensive responses in rats showed a biphasic progression pattern. The alterations in expression of selected MMPs elegantly corresponded to the two-stage development of OA pain. The most substantial changes in the expression of the ECS system were revealed at a later stage of OA progression. Alterations within ECS are involved in the process of adaptation to persistent painful stimuli. The accumulation of MMPs in osteoarthritic cartilage may have a role in the biphasic progression of OA-related pain. Temporal association of changes in ECS and MMPs expression shows a potential therapeutic approach that utilizes the concept of combining indirect ECS-mediated MMP inhibition and ECS modulation of pain transduction. Keywords: osteoarthritis, monoiodoacetate, pain, matrix metalloproteinases, endocannabinoid system
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Several studies reported that Tai Chi showed potential effects for chronic pain, but its role remains controversial. This review assessed the evidence regarding the effects of Tai Chi for chronic pain conditions. 18 randomized controlled trials were included in our review. The aggregated results have indicated that Tai Chi showed positive evidence on immediate relief of chronic pain from osteoarthritis (standardized mean difference [SMD], −0.54; 95% confidence intervals [CI], −0.77 to −0.30; P < 0.05). The valid duration of Tai Chi practice for osteoarthritis may be more than 5 weeks. And there were some beneficial evidences regarding the effects of Tai Chi on immediate relief of chronic pain from low back pain (SMD, −0.81; 95% CI, −1.11 to −0.52; P < 0.05) and osteoporosis (SMD, −0.83; 95% CI, −1.37 to −0.28; P = 0.003). Therefore, clinicians may consider Tai Chi as a viable complementary and alternative medicine for chronic pain conditions.
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Endocannabinoid system (ECS) overactivation is associated with increased adiposity and likely contributes to type II diabetes risk. Elevated tissue cannabinoid receptor 1 (CB1) and circulating endocannabinoids derived from the n-6 polyunsaturated acid (PUFA) arachidonic acid occur in obese and diabetic patients. Here we investigate whether the n-3 PUFA docosahexaenoic acid (DHA) in the diet can reduce ECS overactivation (i.e. action of ligands, receptors, and enzymes of EC synthesis and degradation) to influence glycemic control. This study targets the ECS tonal regulation of circulating glucose uptake by skeletal muscle as its primary endpoint. Male C57BL/6J mice were fed a semi-purified diet containing DHA or the control lipid. Serum, skeletal muscle, epididymal fat pads, and liver were collected after 62 and 118 d of feeding. Metabolites, genes and gene-products associated with the ECS, glucose uptake and metabolism, and inflammatory status were measured. Dietary DHA enrichment reduced epididymal fat pad mass and increased ECS-related genes, while reducing downstream ECS activation markers, indicating that ECS activation was diminished. The mRNA of glucose-related genes and proteins elevated in mice fed the DHA diet with increases in DHA- and reductions in AA-derived EC and EC-like compounds. In addition, DHA feeding reduced plasma levels of various inflammatory cytokines, 5-lipoxygenase-dependent inflammatory mediators, and the vasoconstrictive 20-HETE. This study provides evidence that DHA feeding altered ECS gene expression to reduce CB1 activation and reduce fat accretion. Further the DHA diet led to higher expression of genes associated with glucose use by muscle in mice, and reduced those associated with systemic inflammatory status.International Journal of Obesity accepted article preview online, 29 July 2015. doi:10.1038/ijo.2015.135.
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Background: The aim of this study was to evaluate the role of interleukin-17 (IL-17) level in synovia and its relationship with the severity of knee osteoarthritis (OA). Material and methods: We enrolled 226 OA patients and 106 controls in this study. The symptomatic/radiation severity of OA was assessed by the Western Ontario McMaster University Osteoarthritis Index (WOMAC) pain score/Kellgren-Lawrence (KL) grading system. Serum IL-17 levels were measured by enzyme-linked immunosorbent assay (ELISA). Results: Synovia IL-17 levels were significantly higher in OA patients compared with controls (P<0.01), and were negatively correlated with OA severity. IL-17 level gradually decreased among different phases but lacked statistical significance. Conclusions: IL-17 might play a crucial role in the pathogenesis of OA and is closely related to pain. Blocking the IL-17 signaling pathway may delay pain related to OA.
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The levels of the endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol In this study, we investigated the role of the endocannabinoid system (ECS) in the emotional and cognitive alterations associated with osteoarthritis pain. The monosodium iodoacetate model was used to evaluate the affective and cognitive manifestations of osteoarthritis pain in type 1 (CB1R) and type 2 (CB2R) cannabinoid receptor knockout and wild-type mice, and the ability of CB1R (ACEA) and CB2R (JWH133) selective agonists to improve these manifestations during a three week time period.(2-AG) were measured in plasma and brain areas involved in the control of these manifestations. Knee osteoarthritis patients and healthy controls were recruited to evaluate pain, affective and cognitive symptoms, as well as plasma endocannabinoid levels and cannabinoid receptor gene expression in peripheral blood lymphocytes. The affective manifestations of osteoarthritis were enhanced in CB1R knockout mice and absent in CB2R knockouts. Interestingly, both ACEA and JWH133 ameliorated the nociceptive and affective alterations, whereas ACEA also improved the associated memory impairment. An increase of 2-AG levels in prefrontal cortex and plasma was observed in this mouse model of osteoarthritis. In agreement, an increase of 2-AG plasmatic levels and an up-regulation of CB1R and CB2R gene expression in peripheral blood lymphocytes were observed in osteoarthritis patients compared to healthy subjects. Changes found in these biomarkers of the ECS correlated with pain, affective and cognitive symptoms in these patients. The ECS plays a crucial role in osteoarthritis and represents an interesting pharmacological target and biomarker of this disease.
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For many years, the brain has been the primary focus for research on eating behavior. More recently, the discovery of the endocannabinoids (EC) and the endocannabinoid system (ECS), as well as the characterization of its actions on appetite and metabolism, has provided greater insight on the brain and food intake. The purpose of this review is to explain the actions of EC in the brain and other organs as well as their precursor polyunsaturated fatty acids (PUFA) that are converted to these endogenous ligands. The binding of the EC to the cannabinoid receptors in the brain stimulates food intake, and the ECS participates in systemic macronutrient metabolism where the gastrointestinal system, liver, muscle, and adipose are involved. The EC are biosynthesized from two distinct families of dietary PUFA, namely the n-6 and n-3. Based on their biochemistry, these PUFA are well known to exert considerable physiological and health-promoting actions. However, little is known about how these different families of PUFA compete as precursor ligands of cannabinoid receptors to stimulate appetite or perhaps down-regulate the ECS to amend food intake and prevent or control obesity. The goal of this review is to assess the current available research on ECS and food intake, suggest research that may improve the complications associated with obesity and diabetes by dietary PUFA intervention, and further reveal mechanisms to elucidate the relationships between substrate for EC synthesis, ligand actions on receptors, and the physiological consequences of the ECS. Dietary PUFA are lifestyle factors that could potentially curb eating behavior, which may translate to changes in macronutrient metabolism, systemically and in muscle, benefiting health overall.
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Context: The endocannabinoid (eCB) system is involved in the regulation of food intake and of peripheral metabolism. Although the cross talk between energy metabolism and the circadian system is well documented, little is known about a potential circadian modulation of human eCB activity. Objective: The objective of the study was to define the 24-hour profile of circulating levels of the most abundant endogenous ligand of the CB1 receptor, 2-arachidonoylglycerol (2-AG), in healthy young nonobese adults studied under controlled bedtime, dietary, and activity conditions. Methods: Fourteen subjects participated in this 4-day laboratory study with fixed light-dark cycles, standardized meals, and bedtimes. Sleep was recorded each night. On the third day, blood sampling at 15- to 30-minute intervals began at 9:30 pm and continued for 24 hours. Cortisol, leptin, and ghrelin were assayed on all samples, whereas the levels of 2-AG and its structural analog, 2-oleoylglycerol (2-OG), were measured at 60-minute intervals. Results: All participants exhibited a large circadian variation of 2-AG serum concentrations with a nadir around midsleep, coincident with the middle of the overnight fast. Levels of 2-AG increased continually across the morning, peaking in the early to midafternoon. Peak values represented, on average, a nearly 3-fold increase above nocturnal nadir levels. Concentrations of 2-OG followed a similar pattern, although with a shorter morning increase and lower amplitude. Conclusions: The findings demonstrate that activity of the eCB system is profoundly modulated by circadian rhythmicity and suggest that its impact on the regulation of food intake is suppressed during sleep and is maximal during early to midafternoon.
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Background Endocannabinoids and temperament traits have been linked to both physical activity and body mass index (BMI) however no study has explored how these factors interact in females. The aims of this cross-sectional study were to 1) examine differences among distinct BMI groups on daytime physical activity and time spent in moderate-vigorous physical activity (MVPA), temperament traits and plasma endocannabinoid concentrations; and 2) explore the association and interaction between MVPA, temperament, endocannabinoids and BMI. Methods Physical activity was measured with the wrist-worn accelerometer Actiwatch AW7, in a sample of 189 female participants (43 morbid obese, 30 obese, and 116 healthy-weight controls). The Temperament and Character Inventory-Revised questionnaire was used to assess personality traits. BMI was calculated by bioelectrical impedance analysis via the TANITA digital scale. Blood analyses were conducted to measure levels of endocannabinoids and endocannabinoid-related compounds. Path-analysis was performed to examine the association between predictive variables and MVPA. Results Obese groups showed lower MVPA and dysfunctional temperament traits compared to healthy-weight controls. Plasma concentrations of 2-arachidonoylglyceryl (2-AG) were greater in obese groups. Path-analysis identified a direct effect between greater MVPA and low BMI (b = −0.13, p = .039) and high MVPA levels were associated with elevated anandamide (AEA) levels (b = 0.16, p = .049) and N-oleylethanolamide (OEA) levels (b = 0.22, p = .004), as well as high Novelty seeking (b = 0.18, p<.001) and low Harm avoidance (b = −0.16, p<.001). Conclusions Obese individuals showed a distinct temperament profile and circulating endocannabinoids compared to controls. Temperament and endocannabinoids may act as moderators of the low MVPA in obesity.
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We describe a novel liquid chromatography method for the simultaneous and quantitative profiling of forty-three oxylipins including eicosanoids, endocannabinoids and structurally-related bioactive lipids with modified acyl groups. The LC-MS/MS method uses switching at a defined time between negative and positive electrospray ionisation modes to achieve optimal detection sensitivity for all the lipids. The validated method is linear over a range 0.01 - 5 nmol/g (0.1 to 50 nmol/g for 2-arachidonoyl glycerol) with intra- and inter-day precision and accuracy was between 1.38 and 26.76% and 85.22 and 114.3% respectively. The method successfully quantified bioactive lipids in different tissue types in the rat, including spinal cord, dorsal root ganglia), knee joint, brain and plasma. Distinct regional differences in the pattern of lipid measured between tissue types were observed using principle component analysis (PCA). The method was applied to analyse tissue samples from an established pre-clinical rat model of osteoarthritis (OA) pain and showed that levels of 12-hydroxyeicosatetraenoic acid were significantly increased in the OA rat knee joint, compared to controls and that 15- hydroxyeicosatetraenoic acids was significantly increased in the dorsal root ganglia in model of osteoarthritis, compared to controls. The developed LC-MS/MS method has potential to provide detailed pathway profiling in tissues and biofluids where the disruption of bioactive oxylipins may be involved in disease states.
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Skeletal muscle is a major storage site for glycogen and a focus for understanding insulin resistance and type-2-diabetes. New evidence indicates that overactivation of the peripheral endocannabinoid system (ECS) in skeletal muscle diminishes insulin sensitivity. Specific n-6 and n-3 polyunsaturated fatty acids (PUFA) are precursors for the biosynthesis of ligands that bind to and activate the cannabinoid receptors. The function of the ECS and action of PUFA in skeletal muscle glucose uptake was investigated in proliferating and differentiated C2C12 myoblasts treated with either 25 μM of arachidonate (AA) or docosahexaenoate (DHA), 25 μM of EC [anandamide (AEA), 2-arachidonoylglycerol (2-AG), docosahexaenoylethanolamide (DHEA)], 1 μM of CB1 antagonist NESS0327, and CB2 inverse agonist AM630. Compared to the BSA vehicle control cell cultures in both proliferating and differentiated myoblasts those treated with DHEA, the EC derived from the n-3 PUFA DHA, had higher 24 h glucose uptake, while AEA and 2-AG, the EC derived from the n-6 PUFA AA, had lower basal glucose uptake. Adenylyl cyclase mRNA was higher in myoblasts treated with DHA in both proliferating and differentiated states while those treated with AEA or 2-AG were lower compared to the control cell cultures. Western blot and qPCR analysis showed higher expression of the cannabinoid receptors in differentiated myoblasts treated with DHA while the opposite was observed with AA. These findings indicate a compensatory effect of DHA and DHEA compared to AA-derived ligands on the ECS and associated ECS gene expression and higher glucose uptake in myoblasts.
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Recognized as a "disease modifier", physical activity (PA) is increasingly viewed as a more holistic, cost-saving method for prevention, treatment and management of human disease conditions. The traditional view that PA engages the monoaminergic and endorphinergic systems has been challenged by the discovery of the endocannabinoid system (ECS), composed of endogenous lipids, their target receptors, and metabolic enzymes. Indeed, direct and indirect evidence suggests that the ECS might mediate some of the PA-triggered effects throughout the body. Moreover, it is now emerging that PA itself is able to modulate ECS in different ways. Against this background, in the present review we shall discuss evidence of the cross-talk between PA and the ECS, ranging from brain to peripheral districts and highlighting how ECS must be tightly regulated during PA, in order to maintain its beneficial effects on cognition, mood, and nociception, while avoiding impaired energy metabolism, oxidative stress, and inflammatory processes.
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Osteoarthritis (OA) of the joint is a prevalent disease accompanied by chronic, debilitating pain. Recent clinical evidence has demonstrated that central sensitization contributes to OA pain. An improved understanding of how OA joint pathology impacts upon the central processing of pain is crucial for the identification of novel analgesic targets/new therapeutic strategies. Inhibitory cannabinoid 2 (CB2) receptors attenuate peripheral immune cell function and modulate central neuro-immune responses in models of neurodegeneration. Systemic administration of the CB2 receptor agonist JWH133 attenuated OA-induced pain behaviour, and the changes in circulating pro- and anti-inflammatory cytokines exhibited in this model. Electrophysiological studies revealed that spinal administration of JWH133 inhibited noxious-evoked responses of spinal neurones in the model of OA pain, but not in control rats, indicating a novel spinal role of this target. We further demonstrate dynamic changes in spinal CB2 receptor mRNA and protein expression in an OA pain model. The expression of CB2 receptor protein by both neurones and microglia in the spinal cord was significantly increased in the model of OA. Hallmarks of central sensitization, significant spinal astrogliosis and increases in activity of metalloproteases MMP-2 and MMP-9 in the spinal cord were evident in the model of OA pain. Systemic administration of JWH133 attenuated these markers of central sensitization, providing a neurobiological basis for analgesic effects of the CB2 receptor in this model of OA pain. Analysis of human spinal cord revealed a negative correlation between spinal cord CB2 receptor mRNA and macroscopic knee chondropathy. These data provide new clinically relevant evidence that joint damage and spinal CB2 receptor expression are correlated combined with converging pre-clinical evidence that activation of CB2 receptors inhibits central sensitization and its contribution to the manifestation of chronic OA pain. These findings suggest that targeting CB2 receptors may have therapeutic potential for treating OA pain.
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The hunting and gathering lifestyle adopted by human ancestors around 2 Ma required a large increase in aerobic activity. High levels of physical activity altered the shape of the human body, enabling access to new food resources (e.g. animal protein) in a changing environment. Recent experimental work provides strong evidence that both acute bouts of exercise and long-term exercise training increase the size of brain components and improve cognitive performance in humans and other taxa. However, to date, researchers have not explored the possibility that the increases in aerobic capacity and physical activity that occurred during human evolution directly influenced the human brain. Here, we hypothesize that proximate mechanisms linking physical activity and neurobiology in living species may help to explain changes in brain size and cognitive function during human evolution. We review evidence that selection acting on endurance increased baseline neurotrophin and growth factor signalling (compounds responsible for both brain growth and for metabolic regulation during exercise) in some mammals, which in turn led to increased overall brain growth and development. This hypothesis suggests that a significant portion of human neurobiology evolved due to selection acting on features unrelated to cognitive performance.
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Endocannabinoids (eCB) are endogenous ligands for cannabinoid receptors that are densely expressed in brain networks responsible for reward. Recent work shows that exercise activates the eCB system in humans and other mammals, suggesting eCBs are partly responsible for the reported improvements in mood and affect following aerobic exercise in humans. However, exercise-induced psychological changes reported by runners are known to be dependent on exercise intensity, suggesting that any underlying molecular mechanism should also change with varying levels of exercise intensity. Here, we examine circulating levels of eCBs following aerobic exercise (treadmill running) in recreationally fit human runners at four different intensities. We show that eCB signaling is indeed intensity dependent, with significant changes in circulating eCBs observed following moderate intensities only (very high and very low intensity exercises do not significantly alter circulating eCB levels). Our results are consistent with intensity-dependent psychological state changes with exercise and therefore support the hypothesis that eCB activity is related to neurobiological effects of exercise. Thus, future studies examining the role of exercise-induced eCB signaling on neurobiology or physiology must take exercise intensity into account.
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The immediate early gene Arc is emerging as a versatile, finely tuned system capable of coupling changes in neuronal activity patterns to synaptic plasticity, thereby optimizing information storage in the nervous system. Here, we attempt to overview the Arc system spanning from transcriptional regulation of the Arc gene, to dendritic transport, metabolism, and translation of Arc mRNA, to post-translational modification, localization, and degradation of Arc protein. Within this framework we discuss the function of Arc in regulation of actin cytoskeletal dynamics underlying consolidation of long-term potentiation (LTP) and regulation of AMPA-type glutamate receptor endocytosis underlying long-term depression (LTD) and homeostatic plasticity. Behaviorally, Arc has a key role in consolidation of explicit and implicit forms of memory, with recent work implicating Arc in adaptation to stress as well as maladaptive plasticity connected to drug addiction. Arc holds considerable promise as a “master regulator” of protein synthesis-dependent forms of synaptic plasticity, but the mechanisms that modulate and switch Arc function are only beginning to be elucidated. KeywordsSynaptic plasticity–LTP/LTD–Gene expression–Memory–Stress–Drug addiction–Neurogenesis–RNA decay
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The goal of this review is to summarize studies in which concentrations of circulating endocannabinoids in humans have been examined in relationship to physiological measurements and pathological status. The roles of endocannabinoids in the regulation of energy intake and storage have been well studied and the data obtained consistently support the hypothesis that endocannabinoid signaling is associated with increased consumption and storage of energy. Physical exercise mobilizes endocannabinoids, which could contribute to refilling of energy stores and also to the analgesic and mood-elevating effects of exercise. Circulating concentrations of 2-arachidonoylglycerol are very significantly circadian and dysregulated when sleep is disrupted. Other conditions under which circulating endocannabinoids are altered include inflammation and pain. A second important role for endocannabinoid signaling is to restore homeostasis following stress. Circulating endocannabinoids are stress-responsive and there is evidence that their concentrations are altered in disorders associated with excessive stress, including post-traumatic stress disorder. Although determination of circulating endocannabinoids can provide important information about the state of endocannabinoid signaling and thus allow for hypotheses to be defined and tested, the large number of physiological factors that contribute to their circulating concentrations makes it difficult to use them in isolation as a biomarker for a specific disorder.
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The cannabinoid system is composed of Gi/o protein-coupled cannabinoid type 1 receptor (CB1) and cannabinoid type 2 (CB2) receptor and endogenous compounds. The CB1 receptor is widely distributed in the central nervous system (CNS) and it is involved in the regulation of common physiological functions. At the neuronal level, the CB1 receptor is mainly placed at GABAergic and glutamatergic axon terminals, where it modulates excitatory and inhibitory synapses. To date, the involvement of CB2 receptor in the regulation of neurotransmission in the CNS has not been clearly shown. The majority of noradrenergic (NA) cells in mammalian tissues are located in the locus coeruleus (LC) while serotonergic (5-HT) cells are mainly distributed in the raphe nuclei including the dorsal raphe nucleus (DRN). In the CNS, NA and 5-HT systems play a crucial role in the control of pain, mood, arousal, sleep-wake cycle, learning/memory, anxiety, and rewarding behaviour. This review summarizes the electrophysiological, neurochemical and behavioural evidences for modulation of the NA/5-HT systems by cannabinoids and the CB1 receptor. Cannabinoids regulate the neuronal activity of NA and 5-HT cells and the release of NA and 5-HT by direct and indirect mechanisms. The interaction between cannabinoid and NA/5-HT systems may underlie several behavioural changes induced by cannabis such as anxiolytic and antidepressant effects or side effects (e.g. disruption of attention). Further research is needed to better understand different aspects of NA and 5-HT systems regulation by cannabinoids, which would be relevant for their use in therapeutics.
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Chronic pain states are highly prevalent and yet poorly controlled by currently available analgesics, representing an enormous clinical, societal, and economic burden. Existing pain medications have significant limitations and adverse effects including tolerance, dependence, gastrointestinal dysfunction, cognitive impairment, and a narrow therapeutic window, making the search for novel analgesics ever more important. In this article, we review the role of an important endogenous pain control system, the endocannabinoid (EC) system, in the sensory, emotional, and cognitive aspects of pain. Herein, we briefly cover the discovery of the EC system and its role in pain processing pathways, before concentrating on three areas of current major interest in EC pain research; 1. Pharmacological enhancement of endocannabinoid activity (via blockade of EC metabolism or allosteric modulation of CB1receptors); 2. The EC System and stress-induced modulation of pain; and 3. The EC system & medial prefrontal cortex (mPFC) dysfunction in pain states. Whilst we focus predominantly on the preclinical data, we also include extensive discussion of recent clinical failures of endocannabinoid-related therapies, the future potential of these approaches, and important directions for future research on the EC system and pain.
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Background Physical exercise is seen as a promising intervention to prevent or delay cognitive decline in individuals aged 50 years and older, yet the evidence from reviews is not conclusive. Objectives To determine if physical exercise is effective in improving cognitive function in this population. Design Systematic review with multilevel meta-analysis. Data sources Electronic databases Medline (PubMed), EMBASE (Scopus), PsychINFO and CENTRAL (Cochrane) from inception to November 2016. Eligibility criteria Randomised controlled trials of physical exercise interventions in community-dwelling adults older than 50 years, with an outcome measure of cognitive function. Results The search returned 12 820 records, of which 39 studies were included in the systematic review. Analysis of 333 dependent effect sizes from 36 studies showed that physical exercise improved cognitive function (0.29; 95% CI 0.17 to 0.41; p<0.01). Interventions of aerobic exercise, resistance training, multicomponent training and tai chi, all had significant point estimates. When exercise prescription was examined, a duration of 45–60 min per session and at least moderate intensity, were associated with benefits to cognition. The results of the meta-analysis were consistent and independent of the cognitive domain tested or the cognitive status of the participants. Conclusions Physical exercise improved cognitive function in the over 50s, regardless of the cognitive status of participants. To improve cognitive function, this meta-analysis provides clinicians with evidence to recommend that patients obtain both aerobic and resistance exercise of at least moderate intensity on as many days of the week as feasible, in line with current exercise guidelines.
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The cannabinoid CB2 receptor (CB2R) represents a promising therapeutic target for various forms of tissue injury and inflammatory diseases. Although numerous compounds have been developed and widely used to target CB2R, their selectivity, molecular mode of action and pharmacokinetic properties have been poorly characterized. Here we report the most extensive characterization of the molecular pharmacology of the most widely used CB2R ligands to date. In a collaborative effort between multiple academic and industry laboratories, we identify marked differences in the ability of certain agonists to activate distinct signalling pathways and to cause off-target effects. We reach a consensus that HU910, HU308 and JWH133 are the recommended selective CB2R agonists to study the role of CB2R in biological and disease processes. We believe that our unique approach would be highly suitable for the characterization of other therapeutic targets in drug discovery research.
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Postmenopausal women (PMW) report marginal n-3 PUFA intakes and are at risk of chronic diseases associated with the skeletal, muscular, neuroendocrine, and cardiovascular systems. How n-3 PUFA affect the amounts of endocannabinoids (EC) and oxylipins (OL) of metabolic and physiologic importance in PMW is not clear. Based on our recent findings that dietary n-3 PUFA alter gene targets of the EC system and lower pro-inflammatory OL we proceeded to characterize these actions in blood of PMW. Our aim was to determine levels of the EC, OL, and global metabolites (GM) in white PMW (75 ± 7 y), randomized in a double-masked manner, from baseline to 6 mo after receiving a fish oil supplement of n-3 PUFA (720 mg 20:5n3 + 480 mg 22:6n3/d, n = 20) or placebo (1.8 g oleic acid/d, n = 20). EC and OL in serum were determined by UPLC-MS/MS and GM by GC-MS and LC-MS/MS. Plasma 20:5n3 and 22:6n3 levels increased in PMW given fish oil. EC n-6 acyl-ethanolamides, arachidonate-derived diols were decreased and 20:5n3 and 22:6n3 diols, epoxides, and alcohols were increased in PMW given fish oil. GM analysis revealed that n-3 PUFA supplementation increased renal steroid hormone and proteolytic metabolite levels in PMW. Herein, we confirm that gene targets of the EC system, previously found as modifiable by n-3 PUFA result in changes in the levels of EC and OL in PMW. This study shows phenotypic responses (in levels) to n-3 PUFA supplementation in PMW and increases of n-3 acyl-ethanolamide and n-3-derived OL of clinical considerations in aging.
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Rheumatoid arthritis (RA) and osteoarthritis (OA) are inflammatory joint diseases, characterized by pain and structural damage. Besides prostaglandins, usually targeted by non-steroidal anti-inflammatory drugs, other lipids, including fatty acids, phospholipids and other bioactive lipid mediators derived from fatty acids could also contribute to RA and OA. In this review, we present evidence for the role of fatty acids and derivatives in RA and OA by summarizing findings related to their presence in serum and synovial fluid, as well as their association with clinical characteristics and effects on RA and OA tissues in vitro. Finally, a more direct evidence for their role in RA and OA derived from intervention studies in humans or mouse models of disease is summarized. Based on the presented data, we present a research agenda, in which some key unresolved questions regarding the role of lipids in RA and OA are formulated.
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Within the last 15 years, the endocannabinoid system (ECS) has emerged as a lipid signaling system critically involved in the regulation of energy balance, since it exerts a regulatory control on every aspect related to the search, the intake, the metabolism and the storage of calories. An overactive endocannabinoid-cannabinoid type 1 (CB1) receptor signaling promotes the development of obesity, insulin resistance and dyslipidemia, representing a valuable pharmacotherapeutic target for obesity and metabolic disorders. However, due to psychiatric side effects, the first generation of brain-penetrant CB1 receptor blockers developed as anti-obesity treatment was removed from the European market in late 2008. Since then, recent studies have identified new mechanisms of action of the ECS in energy balance and metabolism, as well as novel ways of targeting the system that may be efficacious for the treatment of obesity and metabolic disorders. These aspects will be especially highlighted in the present review.International Journal of Obesity accepted article preview online, 16 September 2015. doi:10.1038/ijo.2015.179.
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To investigate the regulation of cannabinoid receptors CB1 and CB2 on immune cells by proinflammatory cytokines and its potential relevance to the inflammatory neurological disease, multiple sclerosis (MS). CB1 and CB2 signalling may be anti-inflammatory and neuroprotective in neuroinflammatory diseases. Cannabinoids can suppress inflammatory cytokines but the effects of these cytokines on CB1 and CB2 expression and function are unknown. Immune cells from peripheral blood were obtained from healthy volunteers and patients with MS. Expression of CB1 and CB2 mRNA in whole blood cells, peripheral blood mononuclear cells (PBMC) and T cells was determined by quantitative real time-polymerase chain reaction (qRT-PCR). Expression of CB1 and CB2 protein was determined by flow cytometry. CB1 and CB2 signaling in PBMC was determined by Western blotting for Erk1/2. Proinflammatory cytokines IL-1β, IL-6 and TNF-α (the latter likely NFκB-dependently) can up-regulate CB1 and CB2 on human whole blood and peripheral blood mononuclear cells (PBMC). We also demonstrate up-regulation of CB1 and CB2 and increased IL-1β, IL-6 and TNF-α mRNA in blood of MS patients compared with controls. The levels of CB1 and CB2 can be up-regulated by inflammatory cytokines, which can explain their increase in inflammatory conditions including MS. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
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The aim of this study was to analyze the effects of therapeutic Tai Chi on balance, gait, and quality of life in chronic stroke patients. Twenty-two inpatients diagnosed with stroke were divided randomly into two groups: one treated with both general physical therapy and Tai Chi exercise (11 patients) and one treated with only general physical therapy (11 patients). Therapeutic Tai Chi included 10 different movements and was performed for 60 min, twice per week, for 6 weeks. Pretest and post-test measurements were recorded for sway length and sway velocity using Gaitview, the functional reach test, the dynamic gait index, the 10-m walking test, the timed up-and-go test, and SF-36 survey. Both the Tai Chi group and the control group showed a significant improvement in sway length and sway velocity, and the Tai Chi group showed greater improvement than the control group in degree of variation. In addition, only the Tai Chi group showed a significant result for functional reach test, the dynamic gait index, the 10-m walking test, the timed up-and-go test, and the Tai Chi group improved. In the quality of life, the therapeutic Tai Chi group showed a significant improvement in five items (physical function, pain, vitality, general health, mental health) among eight items in SF-36. This study confirmed that therapeutic Tai Chi influences the balance, gait, and life quality of stroke patients. Therefore, therapeutic Tai Chi can be used as an effective exercise in combination with general physical therapy to improve the balance, gait, and quality of life in stroke patients.
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Since the first reports in 2001, great advances have been made towards the understanding of endocannabinoid-mediated synaptic modulation. Electrophysiological studies have revealed that one of the two major endocannabinoids, 2-arachidonoylglycerol (2-AG), is produced from membrane lipids upon postsynaptic Ca(2+) elevation and/or activation of Gq/11-coupled receptors, and released from postsynaptic neurons. The released 2-AG then acts retrogradely onto presynaptic cannabinoid CB1 receptors and induces suppression of neurotransmitter release either transiently or persistently. These forms of 2-AG-mediated retrograde synaptic modulation are functional throughout the brain. The other major endocannabinoid, anandamide, mediates a certain form of endocannabinoid-mediated long-term depression (LTD). Anandamide also functions as an agonist for transient receptor potential vanilloid receptor type 1 (TRPV1) and mediates endocannabinoid-independent and TRPV1-dependent forms of LTD. It has also been demonstrated that the endocannabinoid system itself is plastic, which can be either up- or down-regulated by experimental or environmental conditions. In this review, I will make an overview of the mechanisms underlying endocannabinoid-mediated synaptic modulation.
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Osteoarthritis is a degenerative joint disease associated with articular cartilage degradation. The major clinical outcome of osteoarthritis is a complex pain state that includes both nociceptive and neuropathic mechanisms. Currently, the therapeutic approaches for osteoarthritis are limited as no drugs are available to control the disease progression and the analgesic treatment has restricted efficacy. Increasing evidence from preclinical studies supports the interest of the endocannabinoid system as an emerging therapeutic target for osteoarthritis pain. Indeed, pharmacological studies have shown the anti-nociceptive effects of cannabinoids in different rodent models of osteoarthritis, and compelling evidence suggests an active participation of the endocannabinoid system in the pathophysiology of this disease. The ubiquitous distribution of cannabinoid receptors, together with the physiological role of the endocannabinoid system in the regulation of pain, inflammation and even joint function further support the therapeutic interest of cannabinoids for osteoarthritis. However, limited clinical evidence has been provided to support this therapeutic use of cannabinoids, despite the promising preclinical data. This review summarizes the promising results that have been recently obtained in support of the therapeutic value of cannabinoids for osteoarthritis management.
Article
Objective The infrapatellar fat pad (IPFP) in the knee joint is hypothesized to contribute to osteoarthritis (OA) development by the IFPF possibly by influencing inflammatory processes. Oxylipins are essential mediators in the inflammatory process. We undertook this study to investigate secretion by the IFPF of fatty acids and oxylipins derived from those fatty acids. MethodsIPFP explants from 13 OA donors undergoing joint replacement surgery and from 10 normal donors postmortem were cultured for 24 hours, and supernatants (fat-conditioned medium [FCM]) were collected. Liquid chromatography tandem mass spectrometry detected fatty acids and oxylipins in FCM samples. Univariate and multivariate (partial least-squares discriminant analysis [PLS-DA]) analyses were performed, followed by pathway analysis. To validate these outcomes, a second set of OA FCM samples was measured (n = 23). ResultsTwenty-nine oxylipins and fatty acids could be detected in FCM. Univariate analysis showed no differences between normal donor and OA donor FCM; however, PLS-DA revealed an oxylipin/fatty acid profile consisting of 14 mediators associated with OA (accuracy rate 72%). The most important contributors to the model were lipoxin A(4) (decreased), thromboxane B-2 (increased), and arachidonic acid (increased). The statistical model predicted 64% of the second set of OA FCM samples correctly. Pathway analysis indicated differences in individual mediators rather than in complete pathways. Conclusion The IPFP secretes multiple and different oxylipins, and a subset of these oxylipins provides a distinctive profile for OA donors. It is likely that the observed changes are regulated by the OA process rather than being a consequence of basal metabolism changes, as an increase in fatty acid levels was not necessarily associated with an increase in oxylipins derived from that fatty acid.
Article
In contrast to well-characterized PUFA levels in serum, little is known regarding their downstream metabolic products. However, many of these compounds are lipid mediators with prominent roles during pro- and antiinflammatory processes. In this double blind crossover study on asthmatics, shifts in serum levels of ω-3 and ω-6 PUFA-derived oxidized fatty acids (e.g. eicosanoids, oxylipins) were quantified following dietary fish oil supplementation. Serum was obtained from subjects following fasting at three occasions; (i) prior to supplementation, (ii) following a 3-week supplement intake of either placebo or fish oil, and (iii) following a 3-week washout period with a subsequent 3-week period of either fish oil or placebo supplement. A total of 87 oxylipins representing cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP) metabolic pathways were screened via LC-MS/MS. The primary alterations observed were in CYP- and 15-LOX-derived EPA- and CYP-derived DHA oxylipins. The results indicate that intake of an ω-3 rich diet alters not only the PUFA ratio, but also the ratio of downstream oxylipins. These data further support that dietary manipulation with ω-3 PUFAs affects not only PUFA levels, but importantly also the downstream metabolic profile.
Article
The mechanisms underlying the anti-inflammatory and anti-hypertensive effects of long chain ω-3 polyunsaturated fatty acids (PUFAs) are still unclear. The epoxides of an ω-6 fatty acid, arachidonic acid (epoxyeicosatrienoic acids; EETs) also exhibit anti-hypertensive and anti-inflammatory effects. Thus, we hypothesized that the major ω-3 PUFAs including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) may lower blood pressure and attenuate renal markers of inflammation through their epoxide metabolites. Here, we supplemented mice with an ω-3 rich diet for three weeks in a murine model of angiotensin-II dependent hypertension. Also, since EPA and DHA epoxides are metabolized by soluble epoxide hydrolase (sEH), we tested the combination of a sEH inhibitor and the ω-3 rich diet. Our results show that ω-3 rich diet in combination with the sEH inhibitor lowered Ang-II increased blood pressure, further increased renal levels of EPA and DHA epoxides, reduced renal markers of inflammation (i.e. prostaglandins and MCP-1), down-regulated an epithelial sodium channel and up-regulated Angiotensin converting enzyme-2 message (ACE-2) and significantly modulated cyclooxygenase and lipoxygenase metabolic pathways. Overall, our findings suggest that epoxides of the ω-3 PUFAs contribute to lowering SBP and attenuating inflammation in part by reduced prostaglandins and MCP-1 and by up-regulation of ACE-2 in angiotensin-II dependent hypertension.
Article
Obesity incidence continues to escalate as a global nutrition and health problem. Scientists and clinicians are engaged in numerous research approaches that include behavior, education, applied nutrition studies and clinical therapies to prevent, control and reverse obesity. The common goal is to identify areas of basic and clinical research to understand aspects of human biology that contribute to obesity. In these approaches recent discoveries in biology and advancing technologies are tools employed to prevent and reverse obesity. The purpose of this review article is to present the current knowledge of key components of the endocannabinoid system that contribute to eating, influence systemic energy metabolism, and dietary factors that alter the responses of ligand binding and activation of cannabinoid receptors. Herein the objectives are to 1) describe the relationship between dietary polyunsaturated fatty acids (PUFA) and obesity, 2) explain the role of this signaling system in obesity, and 3) present areas of consequential future research with dietary long chain PUFA. There are several gaps in the knowledge of the role dietary PUFA play in the tone of the endocannabinoid signaling system involving ligands and receptors. Elucidating the PUFA relationship to signaling tone may explain the presumed overstimulation of signaling believed to contribute to over eating, fat accretion and inflammation. Future research in this endeavor must be hypothesis driven utilizing appropriate models for investigations on dietary PUFA, endocannabinoids and obesity.
Article
Background: We have shown that the endogenous stimulation of cannabinoid type-1 (CB₁) receptors is a prerequisite for voluntary running in mice, but the precise mechanisms through which the endocannabinoid system exerts a tonic control on running performance remain unknown. Methods: We analyzed the respective impacts of constitutive/conditional CB₁ receptor mutations and of CB₁ receptor blockade on wheel-running performance. We then assessed the consequences of ventral tegmental area (VTA) CB₁ receptor blockade on the wheel-running performances of wildtype (gamma-aminobutyric acid [GABA]-CB₁⁺/⁺) and mutant (GABA-CB₁⁻/⁻) mice for CB₁ receptors in brain GABA neurons. Using in vivo electrophysiology, the consequences of wheel running on VTA dopamine (DA) neuronal activity were examined in GABA-CB₁⁺/⁺ and GABA-CB₁⁻/⁻ mice. Results: Conditional deletion of CB₁ receptors from brain GABA neurons, but not from several other neuronal populations or from astrocytes, decreased wheel-running performance in mice. The inhibitory consequences of either the systemic or the intra-VTA administration of CB1 receptor antagonists on running behavior were abolished in GABA-CB₁⁻/⁻ mice. The absence of CB1 receptors from GABAergic neurons led to a depression of VTA DA neuronal activity after acute/repeated wheel running. Conclusions: This study provides evidence that CB₁ receptors on VTA GABAergic terminals exert a permissive control on rodent voluntary running performance. Furthermore, it is shown that CB₁ receptors located on GABAergic neurons impede negative consequences of voluntary exercise on VTA DA neuronal activity. These results position the endocannabinoid control of inhibitory transmission as a prerequisite for wheel-running performance in mice.
Article
The endocannabinoid system was revealed following the understanding of the mechanism of action of marijuana's major psychotropic principle, Δ(9)-tetrahydrocannabinol, and includes two G-protein-coupled receptors (GPCRs; the cannabinoid CB1 and CB2 receptors), their endogenous ligands (the endocannabinoids, the best studied of which are anandamide and 2-arachidonoylglycerol (2-AG)), and the proteins that regulate the levels and activity of these receptors and ligands. However, other minor lipid metabolites different from, but chemically similar to, anandamide and 2-AG have also been suggested to act as endocannabinoids. Thus, unlike most other GPCRs, cannabinoid receptors appear to have more than one endogenous agonist, and it has been often wondered what could be the physiological meaning of this peculiarity. In 1999, it was proposed that anandamide might also activate other targets, and in particular the transient receptor potential of vanilloid type-1 (TRPV1) channels. Over the last decade, this interaction has been shown to occur both in peripheral tissues and brain, during both physiological and pathological conditions. TRPV1 channels can be activated also by another less abundant endocannabinoid, N-arachidonoyldopamine, but not by 2-AG, and have been proposed by some authors to act as ionotropic endocannabinoid receptors. This article will discuss the latest discoveries on this subject, and discuss, among others, how anandamide and 2-AG differential actions at TRPV1 and cannabinoid receptors contribute to making this signalling system a versatile tool available to organisms to fine-tune homeostasis.
Article
Abstract The endocannabinoid system (ECS) plays an important role in the regulation of physiological functions, from stress and memory regulation to vegetative control and immunity. The ECS is considered a central and peripheral stress response system to emotional or physical challenges and acts through endocannabinoids (ECs), which bind to their receptors inducing subsequent effecting mechanisms. In our studies, the ECS responses have been assessed through blood concentrations of the ECs anandamide and 2-arachidonoylglycerol. In parallel, saliva cortisol was determined and the degree of perceived stress was quantified by questionnaires. This report summarizes the reactivity of the ECS in humans subjected to brief periods of kinetic stress and weightlessness during parabolic flights and to prolonged stress exposure during life onboard the International Space Station (ISS). Both conditions resulted in a significant increase in circulating ECs. Under the acute stress during parabolic flights, individuals who showed no evidence of motion sickness were in low-stress conditions and had a significant increase of plasma ECs. In contrast, highly stressed individuals with severe motion sickness had an absent EC response and a massive increase in hypothalamic-pituitary-adrenal axis activity. Likewise, chronic but well-tolerated exposure to weightlessness and emotional and environmental stressors on the ISS for 6 months resulted in a sustained increase in EC blood concentrations, which returned to baseline values after the cosmonauts' return. These preliminary results suggest that complex environmental stressors result in an increase of circulating ECs and that enhanced EC signaling is probably required for adaptation and tolerance under stressful conditions.
Article
The results of recent studies add the endocannabinoid system, and more specifically CB1 receptor signalling, to the complex mechanisms that negatively modulate insulin sensitivity and substrate oxidation in skeletal muscle. CB1 receptors might become overactive in the skeletal muscle during obesity due to increased levels of endocannabinoids. However, quite surprisingly, one of the most studied endocannabinoids, anandamide, when administered in a sufficient dose, was shown to improve muscle glucose uptake and activate some key molecules of insulin signalling and mitochondrial biogenesis. This is probably because anandamide is only a partial agonist at CB1 receptors and interacts with other receptors (PPARγ, TRPV1), which may trigger positive metabolic effects. This putative beneficial role of anandamide is worth considering because increased plasma anandamide levels were recently reported after intense exercise. Whether the endocannabinoid system is involved in the positive exercise effects on mitochondrial biogenesis and glucose fatty acid oxidation remains to be confirmed. Noteworthy, when exercise becomes chronic, a decrease in CB1 receptor expression in obese metabolically deregulated tissues occurs. It is then tempting to hypothesize that physical activity would represent a complementary alternative approach for the clinical management of endocannabinoid system deregulation in obesity, without the side effects occurring with CB1 receptor antagonists.