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Abstract

Central opioidergic mechanisms may modulate the positive effects of physical exercise such as mood elevation and stress reduction. How exercise intensity and concomitant affective changes affect central opioidergic responses is unknown. We studied the effects of acute physical exercise on the cerebral μ-opioid receptors (MOR) of 22 healthy recreationally active males using positron emission tomography (PET) and the MOR-selective radioligand [¹¹C]carfentanil. MOR binding was measured in three conditions on separate days: after a 60-min aerobic moderate-intensity exercise session, after a high-intensity interval training (HIIT) session, and after rest. Mood was measured repeatedly throughout the experiment. HIIT significantly decreased MOR binding selectively in the frontolimbic regions involved in pain, reward, and emotional processing (thalamus, insula, orbitofrontal cortex, hippocampus, and anterior cingulate cortex). Decreased binding correlated with increased negative emotionality. Moderate-intensity exercise did not change MOR binding, although increased euphoria correlated with decreased receptor binding. These observations, consistent with endogenous opioid release, highlight the role of the μ-opioid system in mediating affective responses to high-intensity training as opposed to recreational moderate physical exercise.

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... Exercising rats also show decreased sensitivity to antinociceptive effects of exogenous opioid agonists such as morphine, which may indicate downregulation of MORs resulting from increased endogenous opioid concentrations elevated by regular exercise training [29,30]. Human neuroimaging studies have demonstrated that a single bout of moderate-to-vigorous exercise stimulates endogenous opioid release in the brain, which is associated with affective responses induced by exercise [31][32][33]. ...
... We measured MOR availability with the agonist radioligand [ 11 C]carfentanil that has high affinity for MORs. Radioligand synthesis for the EXEBRAIN trial has been described previously [32]. For the scans from the PROSPECT trial, [ 11 C]carfentanil was synthesized using [ 11 C]methyl triflate, where cyclotronproduced [ 11 C]methane was halogenated by gas phase reaction into [ 11 C]methyl iodide [34] and converted online into [ 11 C]methyl triflate [35]. ...
... A subset of participants (n = 23) underwent an additional PET scan after a one-hour session of moderateintensity cycling exercise on a separate day; the protocol and opioid release data have been reported previously [32]. The order of the exercise / rest PET studies was randomized and counterbalanced for these participants. ...
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Central μ-opioid receptors (MORs) modulate affective responses to physical exercise. Individuals with higher aerobic fitness report greater exercise-induced mood improvements than those with lower fitness, but the link between cardiorespiratory fitness and the MOR system remains unresolved. Here we tested whether maximal oxygen uptake (VO 2peak ) and physical activity level are associated with cerebral MOR availability, and whether these phenotypes predict endogenous opioid release following aerobic exercise. We studied 64 healthy lean men who performed a maximal incremental cycling test for VO 2peak determination, completed a questionnaire assessing moderate-to-vigorous physical activity (MVPA, min/week), and underwent positron emission tomography with [ ¹¹ C]carfentanil, a specific radioligand for MOR. A subset of 24 subjects underwent additional PET scan also after a one-hour session of moderate-intensity exercise. Higher VO 2peak and self-reported MVPA level was associated with larger decrease in cerebral MOR binding after aerobic exercise in ventral striatum, orbitofrontal cortex and insula. That is, higher fit and more trained individuals showed greater opioid release acutely following exercise in brain regions especially relevant for reward and cognitive processing. Higher VO 2peak also associated with lower baseline BP ND in the reward and pain circuits, i.e., in frontal and cingulate cortices as well as in temporal lobes and subcortically in thalamus and putamen. We conclude that higher aerobic fitness and regular exercise training may induce neuroadaptation within the MOR system which might contribute to improved emotional and behavioural responses associated with long-term exercise.
... Specifically, compared to A-delta fibers, C-fibers are more susceptible to opioid inhibition and mediate heat pain sensations that are therefore preferentially inhibited following exercise. Human studies using positron emission tomography ligand activation with unselective (18F Diprenorphin;Boecker et al., 2008) and mu-opioid selective (11C-Carfentanil; Saanijoki et al., 2018) ligands were able to identify exerciseinduced endogenous opioid release in brain areas partially overlapping with areas belonging to the human pain matrix. Notably, exercise intensity-dependent effects on endogenous opioid release have been demonstrated with this method recently (Saanijoki et al., 2018), indicating that opioid-antinociception could also be a mechanism underlying the exercise dose dependency in the current study. ...
... Human studies using positron emission tomography ligand activation with unselective (18F Diprenorphin;Boecker et al., 2008) and mu-opioid selective (11C-Carfentanil; Saanijoki et al., 2018) ligands were able to identify exerciseinduced endogenous opioid release in brain areas partially overlapping with areas belonging to the human pain matrix. Notably, exercise intensity-dependent effects on endogenous opioid release have been demonstrated with this method recently (Saanijoki et al., 2018), indicating that opioid-antinociception could also be a mechanism underlying the exercise dose dependency in the current study. Endogenous opioid release has been shown to influence the perception of pain administered experimentally, potentially via effects on descending antinociceptive pain pathways (Sprenger et al., 2006), supporting this as a mechanism relevant for EIH triggered by exercise, presumably in a dose-dependent fashion. ...
... Whereas mutual connections between affect and pain processing are well established in the literature (Wiech & Tracey, 2009), current results found no indications for exercise-intensity related affective responses: The PANAS positive scale was elevated directly post exercise, independent of the tested intensities (i.e. without significant differences between high and low), generally corroborating previous findings reporting similar mood scores after exercise regardless of intensity (Bixby et al., 2001), although not unambiguously (Saanijoki et al., 2018). ...
Article
Background: The phenomenon of exercise-induced hypoalgesia and concomitant mood changes is well established. How exercise-induced hypoalgesia and affective responses are shaped by the intensity of an acute exercise bout and individual fitness levels is as yet not well understood. This study investigates whether heat pain threshold (PTh), pain tolerance (PTol), and affective parameters are modulated by the intensity of an acute exercise bout and/or individuals' fitness level. Stronger analgesic responses are hypothesized after high-intensity exercise in physically fitter subjects, possibly in sync with concomitant mood changes. Methods: Thirty-three healthy men were recruited (sedentary: N=17 or recreational: N=14; mean age: 25.3±4.4 years). After a fitness assessment on a cycle ergometer, subjects underwent three experimental conditions on separate days: high (20 minutes exercise 20% above lactate threshold), low (20 minutes exercise 20% below lactate threshold) and control (seated rest). Before and after each intervention Positive and Negative Affect Schedule, PTh and PTol (cold water emersion test) were assessed. Results: Results indicate an increase of the Positive Affect Scale (high: 26.7±9.0 vs. 32.9±7.1, p<0.001; low: 26.3±7.2 vs. 32.0±7.0, p<0.001) and PTh (high: 45.1±3.1 °C vs. 46.0±2.6 °C, p=0.003; low: 45.4±2.7 °C vs. 45.9±2.6 °C, p=0.012) after both exercise conditions. In an exploratory analysis, PTol significantly increased only after the high exercise condition (51.2±33.7 sec. vs. 72.4±64.0 sec., p=0.045). Fitness level was positively correlated with the increase in PTol from pre to post high-intensity exercise (r=0.59, p(one-tailed)=0.002). Conclusion: Exercise-induced hypoalgesia depends on exercise intensity and appears to be influenced by individual fitness status, independent of mood responses.
... In contrast to research implying that recalling an episode of physical activity can bring about improvements subjective vitality, there is evidence that enhancements in psychological well-being result from alterations in biological pathways, particularly those related to the brain opioid system (Daniel et al., 1992;Saanijoki et al., 2018). According to this perspective, active participation in physical activity would be necessary to achieve psychological benefits. ...
... Furthermore, the benefits of physical activity appear to be tied to active engagement in the activity rather than recalling a session. This finding is consistent with the literature on the biological pathways affected by physical activity showing that some of the positive effects of engagement in activity may be due to the brain opioid system (Daniel et al., 1992;Saanijoki et al., 2018) and implies physiological arousal is needed for the physical activity-subjective vitality relationship. These results are inconsistent with the literature that has reported imagining different scenarios can lead to improvements in well-being (Ko et al., 2021). ...
... Although SDT is the framework most used to study subjective vitality (Lavrusheva, 2020), it is important to recognize that results of the present study do not discount the possibility that the differences in subjective vitality found in these studies were due to increases in physiological arousal associated with physical activity. Biological pathways, particularly those related to the brain opioid system (Daniel et al., 1992;Saanijoki et al., 2018), are affected by physical activity and may be responsible for improvements in psychological well-being, including subjective vitality. This implies that the intensity of a physical activity episode is central to the experience of subjective vitality and is consistent with research documenting physical activity intensity influences both the arousal and valence dimensions of core affect (Ekkekakis et al., 2008). ...
Article
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Subjective vitality is a form of eudemonic well-being and signifies the availability of energy that an individual can use to adaptively engage with their environment. Subjective vitality is a positive predictor of physical health outcomes and overall well-being. Prior work with older adults has shown that individuals who follow prescribed or structured physical activity programs experience increases in subjective vitality. There is limited research testing whether self-directed, leisure time physical activity is associated with similar improvements in subjective vitality. Three studies tested whether self-directed, leisure time physical activity leads to higher subjective vitality among a population of emerging adults. All three studies supported the hypothesis that subjective vitality is higher following a session of self-directed, leisure time physical activity than before. Study 2 further showed that the influence of self-directed, leisure time physical activity was tied to active participation and was not triggered through simple recall of a recent episode of self-directed, leisure time physical activity. Study 3 suggested the influence of self-directed, leisure time physical activity on subjective vitality dissipates quickly. Taken together, these findings demonstrate that self-directed, leisure time physical activity could serve as an effective means of providing individuals with immediate boosts in subjective vitality. Such boosts may facilitate adaptive behaviors that, in turn, support future health and well-being. Implications for theory and research are discussed.
... In highly trained runners, pharmacological opioid receptor blockade with naloxone eliminates the hypoalgesic effects of running [31,47], indicating involvement of EO mechanisms. In addition, Positron Emission Tomography (PET) studies confirm that aerobic exercise releases EOs in the brain [28,49,50]. In contrast, Droste et al. [18] reported no effect of opioid blockade on aerobic exercise-induced hypoalgesia. ...
... Existing studies focusing almost exclusively on pain-free individuals suggested that aerobic exercise might enhance endogenous pain inhibitory capacity, as reflected in reduced evoked pain responsiveness, or more specifically, increased EO analgesia. This latter finding, while intriguing and consistent with the popular idea of the "runner's high," is to date based entirely on studies regarding effects of acute exercise in non-pain populations [15,28,31,47,49,50]. The current work sought to test for the first time whether aerobic exercise A C C E P T E D Copyright Ó 8 8 by the International Association for the Study of Pain. ...
Article
Aerobic exercise is believed to be an effective chronic low back pain (CLBP) intervention, although its mechanisms remain largely untested. This study evaluated whether endogenous opioid (EO) mechanisms contributed to the analgesic effects of an aerobic exercise intervention for CLBP. Individuals with CLBP were randomized to a 6-week, 18-session aerobic exercise intervention (n = 38) or usual activity control (n = 44). Before and after the intervention, participants underwent separate laboratory sessions to assess responses to evoked heat pain after receiving saline placebo or i.v. naloxone (opioid antagonist) in double-blinded, crossover fashion. Chronic pain intensity and interference were assessed before and after the intervention. EO analgesia was indexed by naloxone-placebo condition differences in evoked pain responses (blockade effects). Relative to controls, exercise participants reported significantly greater pre-post intervention decreases in chronic pain intensity and interference (p's < .04) and larger reductions in placebo condition evoked pain responsiveness (McGill Pain Questionnaire-Short Form [MPQ]-Total). At the group level, EO analgesia (MPQ-Total blockade effects) increased significantly pre-post intervention only among female exercisers (p = .03). Dose-response effects were suggested by a significant positive association in the exercise group between exercise intensity (based on meeting heart rate targets) and EO increases (MPQ-Present Pain Intensity; p = .04). Enhanced EO analgesia (MPQ-Total) was associated with significantly greater improvement in average chronic pain intensity (p = .009). Aerobic exercise training in the absence of other interventions appears effective for CLBP management. Aerobic exercise-related enhancements in endogenous pain inhibition, in part EO-related, likely contribute to these benefits.
... While antagonist ligands at tracer doses are without pharmacological effect, the safe use of carfentanil PET calls for attention in maintaining ultra-high specific activity. These PET tracers have found use in investigating a wide range of topics including chronic pain syndromes [30], monitoring of methadone occupancy in patients treated for heroin addiction [31], the physiological basis of obesity [32,33], compulsive behaviors such as gambling and binge eating [34] and alcohol addiction [35], opioid modulation of cognitive dysfunction in the contexts of depression [36], and physiological correlates of high-intensity exercise [37]. While impressive in its scope and implications for human disease, this body of research is outperformed at least ten-fold by corresponding studies of brain dopamine; this might be remedied in part by the development of useful SPECT ligands for opioid receptor imaging, which would increase the accessibility of this line of medical research. ...
... Reactions of 5βmethylthebaine (12a, Figure 13) with various dienophiles (ethyl acrylate, methyl vinyl ketone, and p-benzoquinone) were investigated. Products from the β-face approach to the diene system were exclusively obtained in all cases (36,37,38). Ergo, the 5-methyl-substitution did not alter the course or orientation of the Diels-Alder reaction. ...
Article
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6,14-ethenomorphinans are semisynthetic opiate derivatives containing an ethylene bridge between positions 6 and 14 in ring-C of the morphine skeleton that imparts a rigid molecular structure. These compounds represent an important family of opioid receptor ligands in which the 6,14-etheno bridged structural motif originates from a [4 + 2] cycloaddition of morphinan-6,8-dienes with dienophiles. Certain 6,14-ethenomorphinans having extremely high affinity for opioid receptors are often non-selective for opioid receptor subtypes, but this view is now undergoing some revision. The agonist 20R-etorphine and 20R-dihydroetorphine are several thousand times more potent analgesics than morphine, whereas diprenorphine is a high-affinity non-selective antagonist. The partial agonist buprenorphine is used as an analgesic in the management of post-operative pain or in substitution therapy for opiate addiction, sometimes in combination with the non-selective antagonist naloxone. In the context of the current opioid crisis, we communicated a summary of several decades of work toward generating opioid analgesics with lesser side effects or abuse potential. Our summary placed a focus on Diels–Alder reactions of morphinan-6,8-dienes and subsequent transformations of the cycloadducts. We also summarized the pharmacological aspects of radiolabeled 6,14-ethenomorphinans used in molecular imaging of opioid receptors.
... No estudo de Boecker et al. [11] utilizou-se neuroimagem (PET) para analisar a liberação de endorfina em algumas áreas do cérebro (pré frontal e regiões límbicas) de 10 atletas antes e depois de duas horas de corrida. A intensidade afeta a liberação da endorfina e o sistema opióide cerebral está envolvido em sentimentos positivos e negativos causados pelo exercício físico realizado em diferentes intensidades [12]. ...
... Outra possível explicação é pela liberação de monoaminas, ou seja, o exercício aumenta o nível de neurotransmissores (dopamina, serotonina e noradrenalina) [25] e endorfinas ocasionando um estado de euforia [11], embora esse último mecanismo esteja relacionado com exercício de alta intensidade e longa duração [12]. A harmonia entre os aspectos psicológicos e sociais que o exercício proporciona também é um importante fator a ser considerado neste estudo de acordo com Szabo [26] que investigou a relação de exercício e afeto, considerando a carga preferida dos participantes, 32 mulheres correram/caminharam por 20 minutos em velocidade autoselecionada e a PHT diminuiu significativamente 89%, não foram encontradas correlações com a intensidade do exercício. ...
Article
Introdução: Pilates é um método de condicionamento que integra o corpo e a mente proporcionando bem-estar geral aos indivíduos. Objetivo: Avaliar o efeito do Pilates sobre o estado de humor de mulheres no climatério. Métodos: Participaram do estudo 10 mulheres sedentárias entre 41 e 64 anos, na fase do climatério. As participantes foram submetidas a um programa de treinamento de Pilates, composto por 10 sessões, uma vez por semana com duração de 50 minutos utilizando 7 exercícios. O estado de humor foi avaliado através do POMS (Profile of Mood States), composto por 42 adjetivos subdivididos em 6 estados de humor. Para avaliação dos sintomas do climatério foi aplicado o Índice de Kupperman e Blatt. O teste de Shapiro-Wilk foi realizado para confirmar a normalidade dos dados e teste t de Student pareado para analisar as diferenças entre as médias pré e pós-sessão. A significância de 5% foi utilizada para os testes estatísticos através do software SPSS. Resultados: Aumento significativo do Vigor (p< 0,01), diminuição da Fadiga (p<0,02) e redução da Perturbação Total de Humor (p<0,04). Conclusão: Pilates com frequência de uma vez por semana foi capaz de melhorar significativamente o estado de humor de mulheres sedentárias na fase do climatério.Palavras-chave: Pilates, climatério, humor.
... This was the first time any central evidence had ever been shown. A full ten years later, two studies 31,32 provided additional evidence of opioid receptor activation changes (using PET) that were also associated with changes in affect and influenced by exercise intensity. Hiura et al. 31 had males cycle for 20 min at two different intensities: (a) Heavy, corresponding to the anaerobic threshold (AT); (b) Severe, approximately 50% of the distance between the AT and maximal aerobic capacity (VO 2peak ). ...
... For the Severe condition, binding potential was increased in the pituitary gland and this corresponded to an increase in fatigue. The work by Saanijoki et al. 32 examined moderate-intensity continuous exercise (~55% of max) compared to a bout of high-intensity interval exercise, again using PET imaging with [ 11 C]carfentanil and assessing affective responses. Binding potential was reduced following highintensity interval exercise in brain regions associated with the frontolimbic system (e.g., PFC, ACC, hippocampus, amygdala); this was related to increased negative affect. ...
... The latter also changed the respondents' attitude and motivation for exercise and made them start taking charge of their health by challenging the disease. 7 With regard to neurophysiological mechanisms, exercise intensity can influence the inflammatory response 19 and the response of stress-related biomarkers such as brain-derived neurotrophic factor, opioids, and cortisol, 65,66 which in turn affect pain experience and affective response. 55,66 Therefore, this systematic review investigated the effects of different modes of exercise intensity on psychosocial outcomes in adult persons with CMSDs. ...
... 7 With regard to neurophysiological mechanisms, exercise intensity can influence the inflammatory response 19 and the response of stress-related biomarkers such as brain-derived neurotrophic factor, opioids, and cortisol, 65,66 which in turn affect pain experience and affective response. 55,66 Therefore, this systematic review investigated the effects of different modes of exercise intensity on psychosocial outcomes in adult persons with CMSDs. ...
Article
Context Psychosocial parameters play an important role in the onset and persistence of chronic musculoskeletal disorders (CMSDs). Exercise therapy is a valuable therapeutic modality as part of CMSD rehabilitation. Hereby, exercise intensity is an important factor regarding changes in pain and disability in multiple CMSDs. However, the impact of exercise intensity on psychosocial outcomes remains poorly explored. Objective To identify the effects of different modes of exercise intensity on psychosocial outcomes in persons with CMSDs. Data Sources A systematic search was conducted up to November 2020 using the following databases: PubMed/MEDline, PEDro, Cochrane Library, and Web of Science. Study Selection Studies reporting exercise therapy in CMSDs with a predefined display of exercise intensity and an evaluation of at least 1 psychosocial outcome were included. Study Design Systematic review. Level of Evidence Level 2a. Data Extraction Data regarding demographics, exercise intensity, and psychosocial outcomes were included in a descriptive analysis. Methodological quality was assessed using the PEDro scale and Critical Appraisal Skills Programme (CASP) checklist. Results A total of 22 studies, involving 985 participants (with fibromyalgia, chronic low back pain, knee osteoarthritis, psoriatic arthritis, and axial spondyloarthritis) were included (mean PEDro score = 5.77/10). The most common psychosocial outcomes were quality of life (QoL) (n = 15), depression (n = 10), and anxiety (n = 9). QoL improved at any exercise intensity in persons with fibromyalgia. However, persons with fibromyalgia benefit more from exercising at low to moderate intensity regarding anxiety and depression. In contrast, persons with chronic low back pain benefit more from exercising at a higher intensity regarding QoL, anxiety, and depression. Other CMSDs only showed limited or conflicting results regarding the value of certain exercise intensities. Conclusion Psychosocial outcomes are influenced by the intensity of exercise therapy in fibromyalgia and chronic low back pain, but effects differ across other CMSDs. Future research is necessary to determine the exercise intensity that yields optimal exercise therapy outcomes in specific CMSDs.
... Cerebellar MOR expression was documented in humans by different methods (e.g., Peckys and Landwehrmeyer 1999, Schadrack et al. 1999, Platzer et al. 2000, Saanijoki et al. 2018, Valentino and Volkow 2018 that reaffirmed the expression of functional receptors. Since rodents' cerebellum is typically devoid of the mu-opioid receptors (Darcq and Kieffer 2018), we hypothesize an evolutionary shift of increase in cerebellar OPRM1 expression. ...
Article
The mu-opioid receptors (MOR, OPRM1) mediate the effects of beta-endorphin and modulate many biological functions including reward processing and addiction. The present study aimed to use bioinformatics to determine OPRM1 brain expression profiles in higher primates and to look for regulatory mechanisms. We used the same computational pipeline to analyze publicly available expression data from postmortem brain regions across humans, chimpanzees, and rhesus macaques. The most intriguing finding was high OPRM1 cerebellar expression in humans and chimpanzees and low expression in macaques. Together with previous reports of low cerebellar OPRM1 expression in mice, this suggests an evolutionary shift in the expression profiles. Bioinformatic analysis of the OPRM1 upstream region revealed a functional CTCF-binding region that evolved from tandem insertions of retrotransposons L1P1 and L1PA1 upstream (−60 kb) of OPRM1. The insertions arose in different time points after the split of small apes from great apes, and their combined sequence is unique. Furthermore, the derived G allele of SNP rs12191876, in the inserted region, is associated with an increased OPRM1 expression in the cerebellum of postmortem human brains (p = 4.7e–5). The derived G allele became the major allele (60–90%) in the populations represented in the 1000 Genomes Project and may be beneficial. This study provides a foundation for building new knowledge about evolutionary differences in OPRM1 brain expression. Further investigations are needed to elucidate the role of the inserted region and its SNPs in OPRM1 expression, and to assess the biological function and relevance of OPRM1 expression in the cerebellum.
... On the other hand, an [ 18 F]FE-DPN (16) PET study in athletes contrasting receptor availability at rest with the condition immediately after running a half marathon showed reduced binding in various paralimbic and prefontal cortical structures, to an extent correlation with post-running euphoria ("runner's high") [162]. Similarly, a [ 11 C]Caf (8) study in recreationally active men showed a relationship between post-exercising euphoria with decreased µOR binding in widespread cortical areas after high intensity exercise, although effects were less clear after moderate intensity exercise [163]. ...
Article
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The discovery of endogenous peptide ligands for morphine binding sites occurred in parallel with the identification of three subclasses of opioid receptor (OR), traditionally designated as µ, δ, and κ, along with the more recently defined opioid-receptor-like (ORL1) receptor. Early efforts in opioid receptor radiochemistry focused on the structure of the prototype agonist ligand, morphine, although N-[methyl-11 C]morphine, -codeine and -heroin did not show significant binding in vivo. [11C]Diprenorphine ([11C]DPN), an orvinol type, non-selective OR antagonist ligand, was among the first successful PET tracers for molecular brain imaging, but has been largely supplanted in research studies by the µ-preferring agonist [11C]carfentanil ([11C]Caf). These two tracers have the property of being displaceable by endogenous opioid peptides in living brain, thus potentially serving in a competition-binding model. Indeed, many clinical PET studies with [11C]DPN or [11C]Caf affirm the release of endogenous opioids in response to painful stimuli. Numerous other PET studies implicate µ-OR signaling in aspects of human personality and vulnerability to drug dependence, but there have been very few clinical PET studies of µ-ORs in neurological disorders. Tracers based on naltrindole, a non-peptide antagonist of the δ-preferring endogenous opioid enkephalin, have been used in PET studies of δORs, and [11C]GR103545 is validated for studies of κORs. Structures such as [11C]NOP-1A show selective binding at ORL-1 receptors in living brain. However, there is scant documentation of δ-, κ-, or ORL1 receptors in healthy human brain or in neurological and psychiatric disorders; here, clinical PET research must catch up with recent progress in radiopharmaceutical chemistry.
... Best described are the mechanisms underlying mood changes. Potentially, these affective responses are mediated by levels of endogenous opioids, which are found to be elevated after acute bouts of exercise in both humans and animals in the peripheral blood; this effect seems to be intensity-dependent and has been linked to mood improvements [86][87][88][89][90]. Independent PET ligand activation studies from different groups were able to report local exercise-induced central opioid release and related opioid tracer binding changes in the anterior insula [91][92][93] after strenuous exercise, which fits well with brain areas found in the ARN in our study. ...
Article
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Acute exercise bouts alter resting state functional connectivity (rs-FC) within cognitive, sensorimotor, and affective networks, but it remains unknown how these effects are influenced by exercise intensity. Twenty-five male athletes underwent individual fitness assessments using an incremental treadmill test. On separate days, they performed 'low' (35% below lactate threshold) and 'high' (20% above lactate threshold) intensity exercise bouts of 30 min. Rs-fMRI and Positive and Negative Affect Scale (PANAS) were acquired before and after each exercise bout. Networks of interest were extracted from twenty-two participants (3 dropouts). Pre-to-post changes and between conditions effects were evaluated using FSL's randomise by applying repeated measures ANOVA. Results were reported at p < 0.05, corrected for multiple comparisons using threshold free cluster enhancement. PANAS revealed a significant increase in positive mood after both exercise conditions. Significant effects were observed between conditions in the right affective and reward network (ARN), the right fronto parietal network (FPN) and the sensorimotor network (SMN). Pre-to-post comparisons after 'low' exercise intensity revealed a significant increase in rs-FC in the left and right FPN, while after 'high'-intensity exercise rs-FC decreased in the SMN and the dorsal attention network (DAN) and increased in the left ARN. Supporting recent findings, this study is the first to report distinct rs-FC alterations driven by exercise intensity: (i) Increased rs-FC in FPN may indicate beneficial functional plasticity for cognitive/attentional processing, (ii) increased rs-FC in ARN may be linked to endogenous opioid-mediated internal affective states. Finally, (iii) decreased rs-FC in the SMN may signify persistent motor fatigue. The distinct effects on rs-FC fit with theories of transient persistent network alterations after acute exercise bouts that are mediated by different exercise intensities and impact differentially on cognitive/attentional or affective responses.
... (i) Runner's high is associated with the binding of endogenous opiates in frontolimbic circuitry, and the amount of bonding of endogenous opiates is positively related to euphoria [51]. Running per se is not essential-numerous kinds of highintensity effort suffice [52]. One alternative hypothesis has been raised for the popularity of dancing, characterized as a similar athletic experience, with associate experiments showing that dancing both increased pain thresholds and increased social bonding [53], though no direct argument was made for why such exercise should increase opiate bonding. ...
Article
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Research in the neuroscience of pain perception and visual perception has taken contrasting paths. The contextual and the social aspects of pain judgements predisposed pain researchers to develop computational and functional accounts early, while vision researchers tended to simple localizationist or descriptive approaches first. Evolutionary thought was applied to distinct domains, such as game-theoretic approaches to cheater detection in pain research, versus vision scientists' studies of comparative visual ecologies. Both fields now contemplate current motor or decision-based accounts of perception, particularly predictive coding. Vision researchers do so without the benefit of earlier attention to social and motivational aspects of vision, while pain researchers lack a comparative behavioural ecology of pain, the normal incidence and utility of responses to tissue damage. Hybrid hypotheses arising from predictive coding as used in both domains are applied to some perplexing phenomena in pain perception to suggest future directions. The contingent and predictive interpretation of complex sensations, in such domains as ‘runner's high’, multiple cosmetic procedures, self-harm and circadian rhythms in pain sensitivity is one example. The second, in an evolutionary time frame, considers enhancement of primary perception and expression of pain in social species, when expressions of pain might reliably elicit useful help. This article is part of the Theo Murphy meeting issue ‘Evolution of mechanisms and behaviour important for pain’.
... Physical exercise appears to strengthen amygdalar-insular rs-FC, leading to an improved mood and reduced fear, a concept that will have to be validated experimentally in dedicated patient populations in the future. Potentially, these effects are mediated by endogenous opioid release, given that positron emission tomography ligand activation studies were able to report local exercise-induced opioid release in the AI [67][68][69] after exercise. ...
Article
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Acute moderate exercise has been shown to induce prolonged changes in functional connectivity (FC) within affect and reward networks. The influence of different exercise intensities on FC has not yet been explored. Twenty-five male athletes underwent 30 min of “low”- ( (LT)) and “high”- () intensity exercise bouts on a treadmill. Resting-state fMRI was acquired at 3 Tesla before and after exercise, together with the Positive and Negative Affect Scale (PANAS). Data of 22 subjects (3 dropouts) were analyzed using the FSL feat pipeline and a seed-to-network-based analysis with the bilateral amygdala as the seed region for determining associated FC changes in the “emotional brain.” Data were analyzed using a repeated measures ANOVA. Comparisons between pre- and post-exercise were analyzed using a one-sample -test, and a paired -test was used for the comparison between “low” and “high” exercise conditions (nonparametric randomization approach, results reported at ). Both exercise interventions induced significant increases in the PANAS positive affect scale. There was a significant interaction effect of amygdalar FC to the right anterior insula, and this amygdalar-insular FC correlated significantly with the PANAS positive affect scale (, ) in the “high”-intensity exercise condition. Our findings suggest that mood changes after exercise are associated with prolonged alterations in amygdalar-insular FC and occur in an exercise intensity-dependent manner.
... For example, participation in physical exercise is thought to stimulate neurobiological responses via the release of endogenous opioids (e.g., endorphins). The "endorphin hypothesis" ascribes the positive changes in mood after exercise to the increased release of β-endorphins (70,71). In their conceptual model, Lubans and colleagues (4) identified physical activity intensity as a potential moderator of this effect. ...
Article
Purpose: High-intensity interval training (HIIT) has emerged as a time-efficient strategy to improve children and adolescents' health-related fitness in comparison to traditional training methods. However, little is known regarding the effects on cognitive function and mental health. Therefore, the aim of this systematic review was to evaluate the effect of HIIT on cognitive function (basic information processing, executive function) and mental health (well-being, ill-being) outcomes for children and adolescents. Methods: A systematic search as conducted, and studies were eligible if they: (1) included a high-intensity interval training protocol: (2) examined cognitive function or mental health outcomes; (3) examined children or adolescents (5-18 years). Separate meta-analyses were conducted for acute and chronic studies, with potential moderators (i.e., study duration, risk of bias, participant age, cognitive demand, and study population) also explored. Results: A total of 22 studies were included in the review. In acute studies, small to moderate effects were found for executive function (SMD = 0.50, 95% CI 0.03 to 0.98, p = .038) and affect (SMD = 0.33, 95% CI 0.05 to 0.62, p = .020), respectively. For chronic studies, small significant effects were found for executive function (SMD = 0.31, 95% CI 0.15 to 0.76, p <.001), well-being (SMD = 0.22, 95% CI 0.02 to 0.41, p = .029), and ill-being (SMD = -0.35, 95% CI -0.68 to -0.03, p =.035). Conclusions: Our review provides preliminary review evidence suggesting that participation in HIIT can improve cognitive function and mental health in children and adolescents. Due to the small number of studies and large heterogeneity, more high-quality research is needed to confirm these findings.
... [ 11 C]carfentanil is an agonist tracer preferably binding in MORs in the high-affinity state (Henriksen and Willoch, 2008). While endogenous opioids compete for binding sites with [ 11 C]carfentanil (Quelch et al., 2014;Saanijoki et al., 2018), at least in rats the basal opioid concentrations are low (Maidment et al., 1989). Thus, [ 11 C]carfentanil BP ND in baseline condition is likely proportional to MOR density, but the exact contributions of MOR density, receptor affinity, and baseline occupancy by endogenous opioids cannot be assessed in a single measurement. ...
Article
Full-text available
Alterations in the brain’s μ-opioid receptor (MOR) system have been associated with several neuropsychiatric diseases. Also healthy individuals vary considerably in MOR availability. Multiple epidemiological factors have been proposed to influence MOR system, but due to small sample sizes the magnitude of their influence remains inconclusive. We compiled [¹¹C]carfentanil positron emission tomography scans from 204 individuals with no neurologic or psychiatric disorders, and estimated the effects of sex, age, body mass index (BMI) and smoking on [¹¹C]carfentanil binding potential using between-subject regression analysis. We also examined hemispheric differences in MOR availability. Older age was associated with increase in MOR availability in frontotemporal areas but decrease in amygdala, thalamus, and nucleus accumbens. The age-dependent increase was stronger in males. MOR availability was globally lowered in smokers but independent of BMI. Finally, MOR availability was higher in the right versus the left hemisphere. The presently observed variation in MOR availability may explain why some individuals are prone to develop MOR-linked pathological states, such as chronic pain or psychiatric disorders. Lateralized MOR system may reflect hemispheric work distribution in central emotion and pain processes.
... In light of this, three months of HIIT increased glucose uptake by the brain of both young adults and the elderly [79]. However, HIIT demonstrated a reduction in opioid receptors in brain regions linked to mood and correlated with a reduction in the feeling of satisfaction after the exercise session [80]. There was also an increase in brain damage markers after HIIT sessions [81]. ...
Article
Full-text available
Evidence suggests that physical exercise has effects on neuronal plasticity as well as overall brain health. This effect has been linked to exercise capacity in modulating the antioxidant status, when the oxidative stress is usually linked to the neuronal damage. Although high-intensity interval training (HIIT) is the training-trend worldwide, its effect on brain function is still unclear. Thus, we aimed to assess the neuroplasticity, mitochondrial, and redox status after one-week HIIT training. Male (C57Bl/6) mice were assigned to non-trained or HIIT groups. The HIIT protocol consisted of three days with short bouts at 130% of maximum speed (Vmax), intercalated with moderate-intensity continuous exercise sessions of 30 min at 60% Vmax. The mass spectrometry analyses showed that one-week of HIIT increased minichromosome maintenance complex component 2 (MCM2), brain derived neutrophic factor (BDNF), doublecortin (DCX) and voltage-dependent anion-selective channel protein 2 (VDAC), and decreased mitochondrial superoxide dismutase 2 (SOD 2) in the hippocampus. In addition, one-week of HIIT promoted no changes in H2O2 production and carbonylated protein concentration in the hippocampus as well as in superoxide anion production in the dentate gyrus. In conclusion, our one-week HIIT protocol increased neuroplasticity and mitochondrial content regardless of changes in redox status, adding new insights into the neuronal modulation induced by new training models.
... Given the centrality of opioid system in hedonia and reward [59] the present results might reflect lowered mood and/or anhedonia in the subjects scoring high on the depression and anxiety scales [60]. Indeed, human PET studies have found that MOR system responds to a variety of rewards ranging from feeding to social interaction and physical exercise [61][62][63][64][65]. In animal models, opioid agonists, and partial agonist buprenorphine reduce symptoms of anxiety and depression [9,10] as well as alleviate the effects of psychological stressors such as separation distress [66]. ...
Article
Major depressive disorder is associated with lowered mood, anxiety, anhedonia, sleep problems, and cognitive impairments. Many of these functions are regulated by μ-opioid receptor (MOR) system. Preclinical, in vivo, and post-mortem studies have however yielded inconclusive results regarding the role of the MOR in depression and anxiety. Moreover, it is not known whether alterations in MOR are already present in subclinical depression and anxiety. In a large-scale retrospective cross-sectional study we pooled data from 135 (113 males and 22 females) healthy subjects whose brain’s MOR availability was measured with positron emission tomography (PET) using an agonist radioligand [¹¹C]carfentanil that has high affinity for MORs. Depressive and anxious symptomology was addressed with BDI-II and STAI-X questionnaires, respectively. Both anxiety and depression scores in the subclinical range were negatively associated with MOR availability in cortical and subcortical areas, notably in amygdala, hippocampus, ventral striatum, and orbitofrontal and cingulate cortices. We conclude that dysregulated MOR availability is involved in altered mood and pathophysiology of depression and anxiety disorders.
... The pathway from exercise to these benefits is complex, but the mesostriatal reward network plays an important role. Physical exercise, whether acute or chronic, is generally considered rewarding, as evidenced by rodents' behavior when given the opportunity to exercise such as on a running wheel (Basso and Morrell, 2015;Belke and Wagner, 2005;Greenwood et al., 2011), by increased striatal dopamine activity following exercise (Basso and Morrell, 2015;Greenwood et al., 2011;Meeusen and Fontenelle, 2012), and by human self-report (Boecker et al., 2008;Saanijoki et al., 2018). For example, wheel running in rats induces a preference for the environment associated with the running, along with plasticity in the VTA and ventral striatum (Greenwood et al., 2011;Herrera et al., 2016). ...
Article
Although research has identified dozens of behavioral and psychosocial strategies for boosting resilience in adults, little is known about the common underlying pathways. A comprehensive review of these strategies using an affective neuroscience approach indicates three distinct general routes to resilience (Fig. 1A): 1) down-regulating the negative (e.g., exposure, cognitive reappraisal) by reducing distress-related responses of the amygdala, hypothalamic-pituitary-adrenal axis, and autonomic nervous system; 2) up-regulating the positive (e.g., optimism, social connectedness) by activating mesostriatal reward pathways, which in turn can buffer the effects of stress; and 3) transcending the self (e.g., mindfulness, religious engagement) by reducing activation in the default mode network, a network associated with self-reflection, mind-wandering, and rumination. Some strategies (e.g., social support) can boost resilience via more than one pathway. Under- or over-stimulation of a pathway can result in vulnerability, such as over-stimulation of the reward pathway through substance abuse. This tripartite model of resilience-building is testable, accounts for a large body of data on adult resilience, and makes new predictions with implications for practice.
... Exercise-induced opioidergic effects have been reported recently in humans: Boecker et al. (2008b) used a PET ligand activation approach and reported reductions in fronto-limbic opioid receptor availability after 2 h of endurance running, indicating an increase in central acting endogenous opioids. These findings were recently confirmed and extended with mu-selective PET ligands (Hiura et al., 2017;Saanijoki et al., 2018). Of course, other neurohumoral mechanisms may play a role as well, but unfortunately, we are not able to dissociate these on the basis of the current data. ...
Article
Physical exercise has positive effects on mood, reduces clinical depression and states of anxiety. While previous work mostly used subjective measures to study the effect of exercise upon emotions, this study for the first time employed BOLD fMRI to unravel associated neuronal changes of the emotional face-processing network in response to acute exercise. 25 male athletes underwent fitness assessments to define two standardized 30 minutes exercise interventions (low and high intensity). The Positive and Negative Affect Schedule was completed pre and post exercise and neuronal responses to neutral, happy and fearful facial expressions were determined using an fMRI-based face-matching paradigm. Complete data sets were acquired in 21 participants (mean age: 27.2 ± 4.2 years). Both exercise interventions induced significant increases of the PANAS positive affect scale. Modulations of brain activation patterns following acute exercise were found only for fearful facial stimuli vs forms: reduced brain activation in posterior cingulate cortex/precuneus for the low condition, and reduced activity in caudate nucleus and ventral anterior putamen for the high condition. In conclusion, this study provides first in vivo evidence that acute strenuous exercise interferes with emotional face-processing brain regions in an emotion-type specific manner.
... Exercise is a natural reward that alters midbrain nigrostriatal dopamine circuits and dopamine circuits involving emotional evaluation (Greenwood, 2019). Animal studies have shown that acute and chronic exercise increase reward-related dopaminergic activity in the striatum circuit (Greenwood et al., 2011;McMorris, 2016), and strenuous exercise causes the human brain to release opioids (Boecker et al., 2008;Saanijoki et al., 2018). In rats, exercise increases expression of the reward-related plasticity marker DFosB in the dorsal striatum and nucleus accumbens (Herrera et al., 2016), and it increases dopaminergic activity in the ventral tegmental area (Dubreucq et al., 2013). ...
Article
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With the increase in the number of internet users, the problems associated with excessive internet use have become increasingly obvious. Internet addiction can alter neurobiology, and its symptoms can be alleviated through exercise, but whether exercise exerts these effects through neurobiological pathways is unclear. Here, we reviewed the neurobiological mechanisms of exercise-based interventions against internet addiction by searching PubMed and Google Scholar for relevant research using such keywords as “exercise”, “internet addiction”, “hypothalamic-pituitary-adrenal axis”, “neurotrophin”, and “dopamine”. This review summarizes advances in our understanding of the neurobiological processes through which exercise can reduce internet addiction, and our analysis strengthens the idea that exercise-based interventions can be effective in this regard. The available evidence suggests that exercise can increase the levels of neurotrophic factors, cortisol, and neurotransmitters; improve the morphology of specific parts of the central nervous system, such as by stimulating hippocampal neurogenesis; protect the autonomic nervous system; and control the reward urge. In other words, exercise appears to mitigate internet addiction by regulating the neurobiology of the central and autonomic nervous systems. In this way, exercise-based interventions can be recommended for reducing internet addiction.
... In addition, an optimization of body composition (which goes hand in hand with a reduction of the cardiovascular risk profile by reducing body fat and increasing lean mass) as well as a reduction of arterial stiffness and thickness, microvascular inflammation and dyslipidemia have been reported in this context [27]. Additionally, studies indicated that HIIT improved not only QoL but also mood state [28], emotion, pain [29], and cognitive health [30] in different study populations. ...
Article
Full-text available
Purpose To evaluate the impact of high-intensity interval training (HIIT) on health-related outcome parameters in the prehabilitation of patients diagnosed with cancer. Methods A systematic review and meta-analysis of comparative studies on HIIT in cancer prehabilitation conducted by screening standard databases from their inception to March 30, 2020. Outcomes of interest included cardiorespiratory fitness, feasibility, safety, clinical, and patient-reported outcomes. Results Of the 855 identified studies, 8 articles met the inclusion criteria (7 randomized, 1 non-randomized controlled trial) with a total of 896 patients. The study protocols were heterogeneous, but the methodological quality ranged from good to high according to PEDro scale. Meta-analysis revealed a significant improvement of peak oxygen consumption (VO2peak) achieved with HIIT compared to usual care. Furthermore, HIIT was feasible and safe, showing low risk of adverse events and positive effects on health-related outcomes in prehabilitative settings. Conclusion In the phase of prehabilitation, HIIT has potential health benefits in patients diagnosed with cancer and is feasible and safe to perform. Nonetheless, larger randomized controlled trials focusing on long-term effects (such as cancer recurrence or survival rates) are missing, to underline the potential relevance of HIIT for cancer patients.
... Highintensity exercise resulted in a significant decrease of μOR binding in thalamus, A. van Waarde et al. insula, orbitofrontal cortex, hippocampus, and anterior cingulate, i.e., in brain regions involved in pain, reward, and emotional processing. These regional decreases were associated with increased negative emotions, such as irritation, exhaustion, and dissatisfaction (Saanijoki et al. 2018a). ...
Chapter
The opioid system consists of opioid receptors (which mediate the actions of opium), their endogenous ligands (the enkephalins, endorphins, endomorphins, dynorphin, and nociceptin), and the proteins involved in opioid production, transport, and degradation. PET tracers for the various opioid receptor subtypes are available, and changes in regional opioidergic activity have been assessed during both sensory and affective processing in healthy individuals and in various disease conditions such as chronic pain, neurodegeneration, epilepsy, eating disorders, behavioral addiction, and substance abuse. It is not always clear whether observed changes of tracer binding reflect altered release of endogenous opioids or altered opioid receptor expression. This issue may be resolved by studies in experimental animals that combine in vivo PET imaging with ex vivo immunohistochemistry. Some radioligands for opioid receptors have suboptimal kinetics (i.e., slow dissociation from their target protein) or can induce undesired side effects even at low administered doses (sedation, respiratory arrest). Yet, PET offers the unique opportunity of quantifying opioid receptor-mediated signaling in the living human brain. PET imaging has provided evidence for a link between opioid neurotransmission and peripheral immune activation.
... In most cases, the intensity of the high-intensity intervals, as well as the interval-to-recovery ratios, are selected without any reference to a physiological rationale that could justify, for example, whether the amount of work to be performed per interval can be expected to be metabolically feasible or whether the recovery periods suffice to allow sufficient clearance of metabolic byproducts and/or sufficient restitution of energy resources. Consequently, in several cases, researchers have reported either a surprisingly high number of participants stopping before completing the session (e.g., Conraads et al., 2015;Oliveira, Slama, Deslandes, Furtado, & Santos, 2013) or a variety of adverse events such as lightheadedness, migraines, or vomiting (e.g., Saanijoki et al., 2018). ...
Article
High-intensity interval training (HIIT) has garnered attention because of the promise that it may confer health benefits with reduced time commitment compared to prescriptions calling for moderate-intensity continuous exercise. However, the value of HIIT for public health hinges on whether the high intensity of such regimens will be acceptable or tolerable. While the dual-mode theory predicts that exercise performed at an intensity exceeding critical power (i.e., as most HIIT protocols) will induce displeasure tied to the severe homeostatic perturbation, skeptics have countered that the empirical basis of the theory is limited to continuous exercise protocols and that the theory may not be applicable to intermittent exercise such as HIIT. Using four HIIT protocols, designed to expend either 80 % or 60 % of the finite work that can be performed above critical power over either 5-min or 3-min intervals, we demonstrate that affective valence closely tracks rapid changes in oxygen uptake. These data illustrate the link of affect to homeostatic perturbations and highlight the potential utility of ratings of affective valence as a tool for monitoring exercise stress and customizing training regimens.
... [ 11 C]carfentanil is an agonist tracer preferably binding MORs in the high-affinity state (Henriksen and Willoch, 2008;Cumming et al., 2019) and has low test-retest variability in PET imaging (Hirvonen et al., 2009). Although endogenous opioids compete for binding sites with [ 11 C]carfentanil (Quelch et al., 2014;Saanijoki et al., 2018), the basal opioid concentrations are often very low, at least in rats (Maidment et al., 1989). Accordingly, [ 11 C]carfentanil BP ND in baseline likely reflects density of MORs. ...
Article
Full-text available
Seasonal rhythms influence emotion and sociability. The brain μ-opioid receptor (MOR) system modulates a multitude of seasonally varying socioemotional functions, but its seasonal variation remains elusive with no previously reported in vivo evidence. Here, we first conducted a cross-sectional study with previously acquired human [11C]carfentanil PET imaging data (132 male and 72 female healthy subjects) to test whether there was seasonal difference in MOR availability. We then investigated experimentally whether seasonal variation in daylength causally influences brain MOR availability in rats. Rats (six male and three female rats) underwent daylength cycle simulating seasonal changes; control animals (two male and one female rats) were kept under constant daylength. Animals were scanned repeatedly with [11C]carfentanil PET imaging. Seasonally varying daylength had an inverted U-shaped functional relationship with brain MOR availability in humans. Brain regions sensitive to daylength spanned the socio-emotional brain circuits, where MOR availability formed a spring-like peak. In rats, MOR availabilities in the brain neocortex, thalamus and striatum peaked at intermediate daylength. Varying daylength also affected the weight gain and stress hormone. We conclude that the in vivo brain MOR availability in humans and rats shows significant seasonal variation, which is predominately associated with seasonal photoperiodic variation. Given the intimate links between MOR signaling and socioemotional behavior, these results suggest that the MOR system might underlie seasonal variation in human mood and social behavior.SIGNIFICANCE STATEMENTSeasonal rhythms influence emotion and sociability. The brain's μ-opioid receptor (MOR) system modulates numerous seasonally varying socioemotional functions, but its seasonal variation remains elusive. Here we used positron emission tomography to show that MOR levels in both human and rat brains show daylength-dependent seasonal variation. The highest MOR availability was observed at intermediate daylengths. Given the intimate links between MOR signaling and socioemotional behavior, these results suggest that the MOR system might underlie seasonal variation in human mood and social behavior.
... A single baseline PET scan is not sufficient for determining the exact proportions for causal factors to the altered receptor availability which could potentially be affected by changes in receptor density, affinity, or endogenous ligand binding (Henriksen & Willoch, 2008). Although [ 11 C]carfentanil binding is sensitive to endogenous neurotransmitter release triggered by nonpharmacological stimulation including social contact, physical exercise, and feeding (Hiura et al., 2017;Manninen et al., 2017;Saanijoki et al., 2017;Tuulari et al., 2017) these effects are typically in the rank of 5-10% changes in the BP ND . Because [ 11 C]carfentanil scans have high test-retest reproducibility (VAR < 6%, ICC > 0.93) (Hirvonen et al., 2009), the BP ND from baseline [ 11 C]carfentanil scans reflect predominantly tonic MOR availabilities indicating that despite transient modulations in BP ND caused by endogenous ligands (see also Kantonen et al., 2020). ...
Preprint
The endogenous mu-opioid receptor (MOR) system modulates a multitude of social and reward-related functions, and exogenous opiates also influence sex drive in humans and animals. Sex drive shows substantial variation across humans, and it is possible that individual differences in MOR availability underlie interindividual of variation in human sex drive. Here we measured healthy male subjects’ ( n =52) brain’s MOR availability with positron emission tomography (PET) using an agonist radioligand, [ ¹¹ C]carfentanil, that has high affinity for MORs. Sex drive was measured using self-reports of engaging in sexual behaviour (sex with partner and masturbating). Bayesian hierarchical regression analysis revealed that sex drive was positively associated with MOR availability in cortical and subcortical areas, notably in caudate nucleus, hippocampus, and cingulate cortices. These results were replicated in full-volume GLM analysis. These widespread effects are in line with high spatial autocorrelation in MOR expression in human brain. Complementary voxel-based morphometry analysis ( n =108) provided limited evidence for association between sex drive and cortical density in the midcingulate cortex. We conclude that endogenous MOR tone is associated with individual differences in sex drive in human males.
... A single baseline PET scan is not sufficient for determining the exact proportions for causal factors to the altered receptor availability which could potentially be affected by changes in receptor density, affinity, or endogenous ligand binding (Henriksen & Willoch, 2008). Although [ 11 C]carfentanil binding is sensitive to endogenous neurotransmitter release triggered by nonpharmacological stimulation including social contact, physical exercise, and feeding (Hiura et al., 2017;Manninen et al., 2017;Saanijoki et al., 2017;Tuulari et al., 2017) these effects are typically in the rank of 5-10% changes in the BP ND . Because [ 11 C]carfentanil scans have high test-retest reproducibility (VAR < 6%, ICC > 0.93) (Hirvonen et al., 2009), the BP ND from baseline [ 11 C]carfentanil scans reflect predominantly tonic MOR availabilities indicating that despite transient modulations in BP ND caused by endogenous ligands (see also Kantonen et al., 2020). ...
Article
Full-text available
The endogenous mu-opioid receptor (MOR) system modulates a multitude of social and reward-related functions, and exogenous opiates also influence sex drive in humans and animals. Sex drive shows substantial variation across humans, and it is possible that individual differences in MOR availability underlie interindividual of variation in human sex drive. We measured healthy male subjects’ ( n = 52) brain’s MOR availability with positron emission tomography (PET) using an agonist radioligand, [ ¹¹ C]carfentanil, that has high affinity for MORs. Sex drive was measured using self-reports of engaging in sexual behaviour (sex with partner and masturbating). Bayesian hierarchical regression analysis revealed that sex drive was positively associated with MOR availability in cortical and subcortical areas, notably in caudate nucleus, hippocampus, and cingulate cortices. These results were replicated in full-volume GLM analysis. These widespread effects are in line with high spatial autocorrelation in MOR expression in human brain. Complementary voxel-based morphometry analysis ( n = 108) of anatomical MR images provided limited evidence for positive association between sex drive and cortical density in the midcingulate cortex. We conclude that endogenous MOR tone is associated with individual differences in sex drive in human males.
... Third, cancer patients participating in regular exercise during adjuvant therapy felt less pain and symptoms of emotional-related distress. Mood elevation after exercise is probably also modulated by other neural factors and neurotransmitter systems, such as the endocannabinoid system [96]; nevertheless, evidence-based studies in women with breast cancer need to be conducted. ...
Article
Full-text available
Breast cancer was the most common cancer in women worldwide. The aims of the current systematic review and meta‐analysis are: (i) to systematically examine the effects of exercise interventions on mental wellbeing; (ii) to examine the specific effect of the type of supervised exercise and its intensity, volume and frequency on mental wellbeing; and (iii) to explore which interventions are most effective in mental wellbeing among women with breast cancer during active treatment. An electronic literature search was performed using MEDLINE (via PubMed), Embase (Ovid), and Web of Science, we identified 175 full‐text articles. The 57 publications included data from 6988 participants, age ranging from 18 to 78 years (weighted mean: 50.85 years). Compared with the control conditions, exercise training programs were associated with significant reductions in anxiety (d = −0.22, I2 = 53.0%), depression (d = −0.24, I2 = 66.6%), and fatigue (d = −0.47, I2 = 69.8%), as well as increases in body image (d = 0.27, I2 = 69.2%) and quality of life (overall, d = 0.46, I2 =71.6%; emotional function, d = 0.33, I2 = 65.7%; and FACT‐B, d = 0.60, I2 = 76.2%). There were a variety of frequencies, intensities, and durations of supervised exercise programs reported in the included meta‐analytic approach. In addition, we found that concomitant concurrent training, at moderateto‐vigorous intensity, and with a volume ≥150 min/week had benefits on a number of health outcomes, such as fatigue, depression, and quality of life measure by the FACT‐B instrument. These findings have important implications for healthcare providers and multidisciplinary teams involved in mental health management in cancer patients during active treatment.
... Exercise is a natural reward that alters midbrain nigrostriatal dopamine circuits and dopamine circuits involving emotional evaluation (Greenwood, 2019). Animal studies have shown that acute and chronic exercise increase reward-related dopaminergic activity in the striatum circuit (Greenwood et al., 2011;McMorris, 2016), and strenuous exercise causes the human brain to release opioids (Boecker et al., 2008;Saanijoki et al., 2018). In rats, exercise increases expression of the reward-related plasticity marker DFosB in the dorsal striatum and nucleus accumbens (Herrera et al., 2016), and it increases dopaminergic activity in the ventral tegmental area (Dubreucq et al., 2013). ...
... Higher intensity and duration were also connected to the opioid system signaling in positron emission tomography. For example, Saanijoki et al. (2018b) found decreases of μ-opioid receptors-selective radioligand binding in frontolimbic brain regions after high-intensity interval training. The decreased binding was associated with negative mood. ...
Article
A runner's high describes a sense of well-being during endurance exercise characterized by euphoria and anxiolysis. It has been a widespread belief that the release of endogenous opioids, such as endorphins, underlie a runner's high. However, exercise leads to the release of two classes of rewarding molecules, endocannabinoids (eCBs) and opioids. In mice, we have shown that core features of a runner's high depend on cannabinoid receptors but not opioid receptors. In the present study, we aimed to corroborate in humans that endorphins do not play a significant role in the underlying mechanism of a runner's high. Thus, we investigated whether the development of two core features of a runner's high, euphoria and reduced anxiety levels, depend on opioid signaling by using the opioid receptor antagonist naltrexone (NAL) in a double-blind, randomized, placebo (PLA)-controlled experiment. Participants (N=63) exhibited increased euphoria and decreased anxiety after 45 min of running (RUN) on a treadmill in a moderate-intensity range compared to walking (WALK). RUN led to higher plasma levels of the eCBs anandamide (AEA) and 2-arachidonoglycerol (2-AG). Opioid blockade did not prevent the development of euphoria and reduced anxiety as well as elevation of eCB levels following exercise. Moreover, the fraction of participants reporting a subjective runner's high was comparable in the NAL and PLA-treated group. Therefore, this study indicates that the development of a runner's high does not depend on opioid signaling in humans, but makes eCBs strong candidates in humans, as previously shown in mice.
... Some of the advantages of exercise therapy include an exercise regimen customized according to the patient's needs and multi-targeted exercise benefits in the overall health of a patient. Neurobiological studies have shown that exercise is rewarding [28][29][30]. This suggests that exercise may get pleasurable and tolerable as one continues with it. ...
Article
Full-text available
Background An animal model of prediabetes that has been developed in our laboratory using a high fat high carbohydrate diet and lack of physical activity displays risk factors for cardiovascular complications. The effect of exercise against these risk factors in this animal model remains unknown. Therefore, we evaluated the effect of intermittent and regular exercise treatment on the risk factors for cardiovascular complications in this animal model of prediabetes. Methods Following prediabetes induction, animals were randomly assigned to the following groups (n = 6): non-diabetic, prediabetic, intermittently exercising prediabetic and regularly exercising prediabetic. Exercise exposure was 7 weeks long. Body weight changes, caloric intake, blood glucose, total cholesterol, and triglyceride concentration was measured after 20 and 29 weeks while blood pressure was only measured after 29 weeks. Plasma endothelial nitric oxide synthase, malonaldehyde, glutathione peroxidase, tumour necrosis factor-alpha and C-reactive protein concentration from the heart were measured 2 weeks post-exercise termination (week 30). Results We found increased body weight, caloric intake and mean arterial pressure in the prediabetic group by comparison to the non-prediabetic group. The same trend was observed in blood glucose and triglyceride concentrations. However, all of these parameters were reduced in the intermittently exercising prediabetic and regularly exercising prediabetic groups. This reduction was further accompanied by a decrease in the endothelial nitric oxide synthase, tumour necrosis factor-alpha and C-reactive protein concentration with improved oxidative stress biomarkers. Conclusions The progression of pre-diabetes to diabetes is slowed or possibly stopped by exercise (regular or intermittent). Additionally, biomarker profiles indicative of cardiovascular disease in pre-diabetics are improved by exercise.
... Με άλλα λόγια, η άσκηση στο «επίπονο επίπεδο» είναι μεταβολικά μη βιώσιμη και πρέπει να τερματιστεί ή να ρυθμιστεί κατάλληλα η έντασή της, προκειμένου να αποτραπεί μία μεταβολική κρίση. Η μεταβολική κρίση είναι μία σοβαρή πάθηση που εκδηλώνεται με μία σειρά αρνητικών συμπτωμάτων, όπως ζαλάδες και εμετούς (Saanijoki et al., 2018) και οδηγεί τον ασκούμενο να σταματήσει την άσκηση προκειμένου να ξεκουραστεί, ενώ εγκυμονεί ο κίνδυνος σωματικής βλάβης (Gibson & Noakes, 2004). Σύμφωνα με τη Θεωρία Διπλής Λειτουργίας, ο τερματισμός της άσκησης επιτυγχάνεται με ένα «κύμα» δυσαρέσκειας που υποχρεώνει τον ασκούμενο να σταματήσει (Roloff et al., 2020). ...
Article
Full-text available
High intensity interval training is a training protocol which can induce significant physiological adaptations for people in a short period of time, which explains its increasing popularity at a worldwide level. This type of training consists of bouts of vigorous training which are interspersed with bouts of low intensity exercise or even passive recovery. In many studies there have been comparisons between high intensity interval training and moderate intensity continuous training concerning the effects on physiological indexes but also on psychological parameters of people. Many researchers have turned their attention to the psychological effects of high intensity interval training since, according to the Dual Mode Theory, when the intensity exceeds a certain point (anaerobic and ventilatory threshold of the participants), pleasure is significantly reduced. The nature of this training protocol is the main purpose for conducting this literature review. Studies were obtained from three electronic data bases (Google Scholar, Scopus, PubMed) with “high intensity interval training” as the main key term. After a thorough examination of the points that were made in every study included, the proponents’ and antagonists’ perspective concerning this training protocol was made clearer. Moreover, the promotion of high intensity interval training is justified by taking into consideration the contemporary social circumstances that impose the use of short training protocols and a long-term adherence to exercise, since many people lack free time because of the rapid social rhythms that occur on a global level. KEY WORDS: high intensity interval training protocol, mood, affective responses, psychological parameters, physiological parameters, moderate intensity continuous training protocol
... Several physiological mechanisms can explain this interrelation, one of which is that the practice of physical activity stimulates the production of the endorphin neurohormone (Harber & Sutton, 1984), which is a substance related to the reduction of depressive and anxiety symptoms and improved self-esteem (Kubryak et al., 2012). However, what is not consensus in literature is the amount of physical activity that provides greater endorphin secretions and the physical activity threshold in which such endorphin secretion is ceased (Saanijoki et al., 2018). In this sense, this physiological mechanism is evidenced in literature; however, there is large field for further investigations. ...
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Background To verify the association between weekly leisure walking time and positive self-rated health in the Brazilian adult and elderly population. Methods This cross-sectional study used information collected in 2019 across all regions of Brazil. This study included 25,785 people aged ≥ 18 years (mean = 51.6; standard deviation = 18.0) from all capitals of the Brazilian states who reported practicing walking as physical activity during leisure time. Self-rated health was the dependent variable (positive or negative). The leisure walking time/week was the main exposure and it was categorized in “150 minutes/week”, “150–299 minutes/week” and “≥ 300 minutes/week”. We used binary logistic regression to estimate odds ratio (OR) and 95% confidence intervals (95% CI) that was adjusted for relevant covariates. Results We found that individuals who reported leisure walking for a period from 150 to 299 minutes/week and those who reported walking for a period ≥ 300 minutes/week were respectively 28% (OR = 1.28. 95% CI [1.10–1.48]) and 52% (OR = 1.52. 95% CI [1.27–1.82]) more likely of perceiving their health positively compared to those who reported walking for a period < 150 minutes/week. Individuals who reported leisure walking time <150 minutes/week had 72.3% (95% CI [70.4–74.1]) probability of perceiving their health positively. Individuals who reported leisure walking time from 150 to 299 minutes/week had 76.6% (95% CI [75.0 –78.3) probability of perceiving their health positively. On the other hand, individuals who reported leisure walking time ≥ 300 minutes/week had 79.2% probability (95% CI [77.1–81.4]) of perceiving their health positively. Conclusion Longer leisure walking time was associated with positive self-rated health among adults and older adults in Brazil.
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According to the American Psychiatric Association, in 2018, approximately 2 million Americans were suffering from a substance abuse disorder, defined as substance abuse and dependence (1), related to opioids that were prescribed for pain management (2), while worldwide, it is estimated this approaches 16 million (3). Consequently, exercise clinicians will be increasingly exposed to individuals who have been affected by opioids and should therefore know how these drugs affect physiological functioning and how exercise can play a role in opioid addiction recovery. This review article is intended to provide some of this information.
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... [26] An increase in the endogenous opioid concentrations after exercise has an association with the psychological changes including mood fluctuations, "exercise-induced euphoria," altered pain perception, and decreased stress response. [27] Music therapy ...
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Coronavirus disease 2019 pandemic spreads through inhalation of aerosols or droplets. Therefore, the use of face masks, alcohol-based sanitizers, and most importantly practicing quarantine/ isolation and social distancing are the main modalities for its prevention and control. Although isolation is essential, various psychological effects have been implicated with its practice in most of the age groups. Longstanding isolation and negligible interpersonal interactions can have changes in psychological processes and neurological and morphological changes in the brain. Morphological changes as seen through the neuroimaging studies include reduced volume of the structures involved in the synthesis of various nerve growth factors leading to impaired neurogenesis and subsequently psychological changes which can manifest as mood alterations such as anxiety, depression, feeling demoralized, obsessive thinking, and altered sleep–wake cycles besides others especially, in the vulnerable age groups such as children and the elderly. Although quarantine remains the cornerstone to contain the spread of the pandemic, its psychological impact run simultaneously, which should be, understood, and addressed to ameliorate its long-term impact.
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Objective To evaluate the effects of Physical Therapies (PTs) on improvement in psychosomatic symptoms and quality of life (QOL) in breast cancer patients. Data Sources Seven databases (MEDLINE, EMBASE, Cochrane CENTRAL, China National Knowledge Infrastructure, Wangfang, VIP, and China Biology Medicine disc databases) were systematically searched from the database inception through May 18, 2021. Study Selection Randomized controlled trials (RCTs) which compared acupuncture or exercise with a sham control or usual care for the treatment of aromatase inhibitors (AIs)-related psychosomatic symptoms and QOL. Data Extraction and Synthesis Data were screened and extracted independently using predesigned forms. The quality of RCTs was assessed with the Cochrane Handbook for Systematic Reviews of Interventions. The effect size was calculated via random-effects modeling. The quality of evidence was evaluated with the Grading of Recommendations Assessment, Development and Evaluation approach. Main Outcomes and Measures The score of pain was measured with BPI scale and Western Ontario and the McMaster Universities Index (WOMAC) scale. Emotional state was measured with Pittsburgh Sleep Quality Index (PSQI), Hospital Anxiety and Depression Scale (HADS-A), and Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue). The QOL score was measured by self-reported measurements, including the Functional Assessment of Cancer Therapy-General (FACT-G) scale and 36-Item Short Form Survey (SF-36) scale. Results Eleven RCTs (with 830 patients) were included in the systematic review, and data from 10 RCTs (with 798 patients) were used in the meta-analysis. Results showed acupuncture significantly reduced worst pain scores ( P < 0.00001, I ² = 83.5%) [SMD = −0.81, 95% CI (−1.51, −0.11)], but the effect of exercise therapies was not significant in overall change in worst pain scores ( P =0.006, I ² = 72.3%) [SMD = −0.30, 95% CI (−0.76, 0.16)]. Both acupuncture and exercise resulted in little to no difference in overall change in HADS-A subscale (P = 0.026<0.05, I ² = 79.8%) [WMD = −0.21, 95% CI (−3.44, 3.03)], PSQI subscale (P = 0.488, I ² = 0%) [WMD = 0.98, 95% CI (−0.57, 2.53)], and FACIT-Fatigue subscale (P = 0.022<0.05, I ² = 81.0%) [WMD = 1.6, 95% CI (−5.75, 8.94)]. Exercise (compared with usual care) was associated with improving overall change in health-related QOL (subscales of SF-36 tool) (P = 0, I ² = 72.1%) [WMD = 7.97, 95% CI (5.68, 10.25)] and cancer-specific QOL (subscales of FACT-G tool) (P = 0.304, I ² = 16%) [WMD = 1.16, 95% CI (0.34, 1.97)]. Conclusions and Relevance This systematic review and meta-analysis suggested that based on moderate-level evidence, acupuncture was associated with significant reductions in pain intensity, and exercise might improve QOL in breast cancer patients treated with AIs. However, in psychosomatic symptoms such as anxiety, sleep disturbance, and fatigue, acupuncture and exercise training did not result in significant improvements.
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For centuries, regular exercise has been acknowledged as a potent stimulus to promote, maintain, and restore healthy functioning of nearly every physiological system of the human body. With advancing understanding of the complexity of human physiology, continually evolving methodological possibilities, and an increasingly dire public health situation, the study of exercise as a preventative or therapeutic treatment has never been more interdisciplinary, or more impactful. During the early stages of the NIH Common Fund Molecular Transducers of Physical Activity Consortium (MoTrPAC) Initiative, the field is well-positioned to build substantially upon the existing understanding of the mechanisms underlying benefits associated with exercise. Thus, we present a comprehensive body of the knowledge detailing the current literature basis surrounding the molecular adaptations to exercise in humans to provide a view of the state of the field at this critical juncture, as well as a resource for scientists bringing external expertise to the field of exercise physiology. In reviewing current literature related to molecular and cellular processes underlying exercise-induced benefits and adaptations, we also draw attention to existing knowledge gaps warranting continued research effort. © 2021 American Physiological Society. Compr Physiol 12:3193-3279, 2022.
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Positron emission tomography (PET) can be used for in vivo measurement of specific neuroreceptors and transporters using radioligands, while voxel-based morphometric analysis of magnetic resonance images allows automated estimation of local grey matter densities. However, it is not known how regional neuroreceptor or transporter densities are reflected in grey matter densities. Here, we analyzed brain scans retrospectively from 325 subjects and compared grey matter density estimates with three different neuroreceptors and transporter availabilities. µ-opioid receptors (MORs) were measured with [ ¹¹ C]carfentanil (162 scans), dopamine D2 receptors with [ ¹¹ C]raclopride (91 scans) and serotonin transporters (SERT) with [ ¹¹ C]MADAM (72 scans). The PET data were modelled with simplified reference tissue model. Voxel-wise correlations between binding potential and grey matter density images were computed. Regional binding of all the used radiotracers was associated with grey matter density in region and ligand-specific manner independently of subjects’ age or sex. These data show that grey matter density and MOR and D2R neuroreceptor / SERT availability are correlated, with effect sizes (r ² ) ranging from 0.04 to 0.69. This suggests that future studies comparing PET outcome measure different groups (such as patients and controls) should take grey matter density differences between the groups into account.
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Introduction: Fibromyalgia (FM) is characterized by multiple symptoms including pain, fatigue, and sleep disorders, altering patient's quality of life. In the absence of effective pharmacological therapy, the last European guidelines recommend a multidisciplinary management based on exercise and education. Thus, our main objective was to measure the effectiveness of a healthcare organization offering a specific program of adapted physical activity combined with a therapeutic education program for FM patients. Methods and Analysis: The From Intent To Move (FIMOUV) study will recruit 330 FM patients randomized into two groups: test and control. The test group will benefit from a 1-month mixed exercise training program supervised at the hospital, followed by 2 months in a community-based relay in a health-sport structure. In addition, each of the two groups will benefit from therapeutic patient education sessions. The main endpoint is the measurement of the level of physical activity by accelerometry at 1 year. The secondary endpoints concern adherence to the practice of physical activity, impact on lifestyle, state of health, and physical capacity, as well as an estimate of the budgetary impact of this management strategy. Discussion: This interventional research will allow us to assess the evolution of behaviors in physical activity after an FM syndrome management based solely on patient education or based on a supervised and adapted practice of physical activity associated with this same therapeutic education program. It seems to be the first study evaluating the impact of its intervention on objective data for measuring physical activity and sedentary behavior via accelerometry among FM patients. Trial registration: ClinicalTrials.gov NCT04107948.
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This paper is the forty-first consecutive installment of the annual anthological review of research concerning the endogenous opioid system, summarizing articles published during 2018 that studied the behavioral effects of molecular, pharmacological and genetic manipulation of opioid peptides and receptors as well as effects of opioid/opiate agonists and antagonists. The review is subdivided into the following specific topics: molecular-biochemical effects and neurochemical localization studies of endogenous opioids and their receptors (2), the roles of these opioid peptides and receptors in pain and analgesia in animals (3) and humans (4), opioid-sensitive and opioid-insensitive effects of nonopioid analgesics (5), opioid peptide and receptor involvement in tolerance and dependence (6), stress and social status (7), learning and memory (8), eating and drinking (9), drug abuse and alcohol (10), sexual activity and hormones, pregnancy, development and endocrinology (11), mental illness and mood (12), seizures and neurologic disorders (13), electrical-related activity and neurophysiology (14), general activity and locomotion (15), gastrointestinal, renal and hepatic functions (16), cardiovascular responses (17), respiration and thermoregulation (18), and immunological responses (19).
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Pathological gambling is a psychiatric disorder and the first recognized behavioral addiction, with similarities to substance use disorders but without the confounding effects of drug-related brain changes. Pathophysiology within the opioid receptor system is increasingly recognized in substance dependence, with higher mu-opioid receptor (MOR) availability reported in alcohol, cocaine and opiate addiction. Impulsivity, a risk factor across the addictions, has also been found to be associated with higher MOR availability. The aim of this study was to characterize baseline MOR availability and endogenous opioid release in pathological gamblers (PG) using [(11)C]carfentanil PET with an oral amphetamine challenge. 14 PG and 15 healthy volunteers (HV) underwent two [(11)C]carfentanil PET scans, before and after an oral administration of 0.5 mg/kg of d-amphetamine. The change in [(11)C]carfentanil binding between baseline and post-amphetamine scans (ΔBPND) was assessed in 10 regions of interest (ROI). MOR availability did not differ between PG and HV groups. As seen previously, oral amphetamine challenge led to significant reductions in [(11)C]carfentanil BPND in 8/10 ROI in HV. PG demonstrated significant blunting of opioid release compared with HV. PG also showed blunted amphetamine-induced euphoria and alertness compared with HV. Exploratory analysis revealed that impulsivity positively correlated with caudate baseline BPND in PG only. This study provides the first evidence of blunted endogenous opioid release in PG. Our findings are consistent with growing evidence that dysregulation of endogenous opioids may play an important role in the pathophysiology of addictions.Neuropsychopharmacology accepted article preview online, 10 November 2015. doi:10.1038/npp.2015.340.
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