[1] In the United States, more than 28 million people run weekly (1). It has been found that over the last several decades, running has experienced a growth in popularity.

[2] From 2018 - 2022 overall race signups increased from 42,738 to 68,720.

[3] Incidence of Running-Related Injuries Per 1000 h of running in Different Types of Runners: The weighted estimate of 17.8 (95 % CI 16.7–19.1) running-related injuries per 1000 h of running in novice runners was significantly greater than the incidence rate of 7.7 (95 % CI 6.9–8.7) in recreational runners.

[4] Epidemiology of injury and illness across all the competitive cycling disciplines: a systematic review and meta-analysis 

[5] A retrospective international study on factors associated with injury, discomfort and pain perception among cyclists. Most cyclists reported no injuries in the past 12 months (63.2%; 95%CI [59.7–66.7%]), 25.3% reported one injury (95%CI [22.2–28.5%]), and 11.5% reported two or more injuries (95%CI [9.2–13.8%]). Injury characteristics are presented in the Table 2.

[6] Running is one of the most widespread activities that gives rise to overuse injuries of the lower back and lower extremities.12,13 Typically, 50% of runners experience an injury each year that prevents them from running for a period of time, and 25% of runners are injured at any given time.5 https://www.sciencedirect.com/science/article/pii/S2095254621000454 

[7] Patellofemoral pain syndrome (16.7%) had the highest prevalence proportion of RRMI, whereas medial tibial stress syndrome (35.0%) had the highest prevalence rate reported in these studies. The most frequently reported RRMIs were patellofemoral pain syndrome and stress fractures.

[8] The ankle joint complex bears a force of approximately five times body weight during stance in normal walking, and up to thirteen times body weight during activities such as running.16

[9]  The peak load through the knee joint is 2-3 BW during walking, 2-5 BW during sit-stand-sit, 4-6 BW during stair climbing, and 7-12 BW during running [12–14].. https://drive.google.com/file/d/1r7sK_LXMnz6mYLvgUHcq7t6wHzXqM4kV/view?usp=drive_link 

[10]Net biomechanical loading at the patellofemoral joint, a major determinant of cartilage stress, is estimated to reach 4.5–7.6 times body weight (BW) during running (2,10,27,29), which is higher than most other everyday activities

[11] The peak knee joint contact force was greater (P < 0.001; Fig. 3a) in running (8.02 ± 1.62 BW) than in walking (2.72 ± 0.41 BW), with a large effect size (d = 3.44).

[12] ​​https://www.au.dk/en/roen@ph.au.dk 

[13] How much running is too much? Identifying high-risk running sessions in a 5200-person cohort study 

[14] Microdamage formation is threshold dependent, with the threshold for its formation depending on the interaction between the number of bone strain cycles, strain magnitude, and the speed at which strain is introduced (strain rate). Once the threshold for microdamage has been surpassed, further increases in bone strain cycles, magnitude, and/or rate result in additional damage. The damage is a natural and useful phenomenon, as it not only helps dissipate energy that may create a fracture but also serves as a stimulus for targeted remodeling (FIGURE 2B). Targeted remodeling refers to site-specific remodeling targeted on areas of damage (possibly via osteocyte apoptosis99), which contrasts the hormonally driven nontargeted (stochastic) remodeling responsible for releasing calcium into the circulation.20 Targeted remodeling involves activation of remodeling units, consisting of an advancing front of bone-resorbing osteoclasts followed by rows of bone-forming osteoblasts. The osteoclasts tunnel toward and remove the damaged tissue, whereas the trailing osteoblasts deposit layers of new bone to create a new bone structural unit. Targeted remodeling maintains homeostasis between microdamage formation and its removal to preserve skeletal mechanical competence, as well as reduces tissue age and enables bone to adapt over time to meet changing demands. The adaptation effectively decreases bone strain for a given load,119,120 so that greater loads can be tolerated before surpassing the threshold for microdamage formation.

[15] Our study suggests that long-term mechanical stress from running may lead to increased thickness and volume in certain knee joint cartilage regions, possibly enhancing the functional adaptability of knee cartilage.

[16] https://www.jospt.org/doi/10.2519/jospt.2017.7137#_i15 

In fact, running at a recreational level was associated with lower odds of hip and/or knee OA compared with individuals running competitively and more sedentary, nonrunning individuals

While competitive running led to an increased association with OA compared with recreational running, nonrunners also had a higher risk of joint degeneration compared with recreational runners.

[17]   Effects of long-term running on the structure and biochemical composition of knee cartilage in males: a cross-sectional study 

[18] Microdamage formation is threshold dependent, with the threshold for its formation depending on the interaction between the number of bone strain cycles, strain magnitude, and the speed at which strain is introduced (strain rate). Once the threshold for microdamage has been surpassed, further increases in bone strain cycles, magnitude, and/or rate result in additional damage. The damage is a natural and useful phenomenon, as it not only helps dissipate energy that may create a fracture but also serves as a stimulus for targeted remodeling (FIGURE 2B). Targeted remodeling refers to site-specific remodeling targeted on areas of damage (possibly via osteocyte apoptosis99), which contrasts the hormonally driven nontargeted (stochastic) remodeling responsible for releasing calcium into the circulation.20 Targeted remodeling involves activation of remodeling units, consisting of an advancing front of bone-resorbing osteoclasts followed by rows of bone-forming osteoblasts. The osteoclasts tunnel toward and remove the damaged tissue, whereas the trailing osteoblasts deposit layers of new bone to create a new bone structural unit. Targeted remodeling maintains homeostasis between microdamage formation and its removal to preserve skeletal mechanical competence, as well as reduces tissue age and enables bone to adapt over time to meet changing demands. The adaptation effectively decreases bone strain for a given load,119,120 so that greater loads can be tolerated before surpassing the threshold for microdamage formation.

[19] Osteoclast activation and resorption in cortical bone takes approximately 4 weeks, and replacement with new bone can take three months and up to a year for full mineralization

[20] Optimal Load for Managing Low-Risk Tibial and Metatarsal Bone Stress Injuries in Runners: The Science Behind the Clinical Reasoning

[21] Once tendons reach their adult length, changes in loading can lead to circumferential growth, enhancing mechanical properties. In humans, two to three months of training can significantly increase tendon stiffness and cross-sectional area. High-intensity training, which involves greater jerk forces, has a more substantial effect than lower intensity exercise, while the type of muscle contraction does not affect tendon stiffness [81].

[22] The final stage of remodeling and maturation begins around four weeks after the injury and continues until the tissue is repaired. During this phase, the ECM is remodeled to create a more organized structure through collagen turnover, realignment, and formation of collagen cross-links. Cell density and vascularity decrease as the tissue repairs. However, animal studies have shown that natural healing leads to tendon biomechanical properties that fail to match normal levels at up to twelve months after injury, depending on the model

[23] Next follows the stage of inflammatory tendon healing, where neutrophils and macrophages invade the haematoma and begin with the phagocytosis of necrotic material and pieces of extracellular matrix. This stage can last between 3 and 7 days after tendon injury. Extrinsic cells from the peritendinous soft tissue such as tendon sheath, fascia, periosteum, and subcutaneous tissue but also intrinsic cells from the epitenon and endotenon migrate and proliferate in the area of tendon injury. Together, they form the granulation tissue present in the so-called proliferative stage. This immature tissue synthesizes mainly collagen type III from the fifth day of tendon healing onward.The initial collagen fibres are not yet oriented in parallel but they already contribute to the biomechanical strength. Up to the fifth week, the amount of collagen increases steadily and the repair callus reaches its largest size [35]. In the fourth week, intrinsic fibroblasts mainly from the endotenon start to proliferate increasingly. After about 40 days, these intrinsic fibroblasts play the most active role in tendon healing, resorbing collagen actively, and producing new collagen at the same time. The tendon tissue matures and the fibres are orientated more longitudinally according to the tension forces. This formative phase lasts for about 2 months.Finally, the maximal biomechanical strength is accomplished in the remodelling phase, when the physiologic load is brought back to the tendon. The collagen fibres become more organized in the longitudinal axis and more cross-linked. Moreover, the type III collagen produced during the formative phase is replaced by the mechanically more resistant type I collagen.

[24] Normal Versus Chronic Adaptations to Aerobic Exercise

[25] The Acquisition of Cardiovascular Adaptation to Aerobic Exercise: When Does It Begin and How Does It Evolve Depending on Intrinsic and Extrinsic Factors?

[26] Nine subjects participated in an exercise program for 40 min/day, 6 days/wk. The training work rates were kept constant for the first 4 wk. The work rates were then increased to a higher level and kept constant for an additional 5 wk. During both training periods, maximum oxygen uptake (VO2max) increased for the first 3 wk and then remained constant. The half times (tl/2) of the increases in VO2max during the two periods were 10.3 and 10.8 days. These results provide evidence that the adaptation to endurance exercise of the system(s) that limit VO2max is rapid, with a tl/2 of less than 11 days. The total increase in VO2max in the 9 wk of training was 23%. The decreases in the heart rate and blood lactate responses to a standard submaximal exercise test also occurred within the first 2 to 3 wk of each training period.

[27] Compared with rearfoot strike (RFS) runners, the findings reveal that forefoot strike (FFS) runners land with a plantar-flexed ankle and greater hip and knee flexion, enhancing cushioning and reducing knee joint forces, which may lower the risk of knee injuries such as patellofemoral pain syndrome. This FFS improves running efficiency by increasing leg stiffness and generating ankle plantarflexion moments that facilitate elastic rebound. However, the greater reliance on the ankle and calf muscles in FFS running elevates the risk of achilles tendon injuries and plantar fasciitis.

[28] https://www.jsams.org/article/S1440-2440(17)30145-7/abstract 

https://tesble.com/10.1016/j.jsams.2017.01.145 

Changing from a rearfoot strike pattern to a nonrearfoot strike pattern whilst running may be beneficial to reduce load through the knee joint, and appears to be therapeutic for exertional lower leg pain. However, it also results in greater load on the foot and ankle, which may potentially result in injury. Therefore,

caution and an appropriate period of adaptation is recommended if choosing to transition to a non-rearfoot strike pattern. There is currently no evidence to suggest that running with a

non-rearfoot strike pattern reduces injury risk or improves running economy and performance. Further research is needed in these

areas to justify recommendations by many coaches and clinicians

for runners to transition their strike pattern.

[29]  Unfortunately, GM is prone to weakness and inhibition, which negatively affects athletic performance and has been identified as the mechanism responsible (or linked to depending on strength of evidence) for numerous injury types and chronic pain.

[30] https://www.sciencedirect.com/science/article/pii/S1050641116300530?via%3Dihub 

[31]  Strength and Flexibility Self-Assessment and Subsequent Training Injuries Among Runners of the New York City Marathon

[32]  The Gmax and Gmed musculature extensively contribute to weight bearing movements by assisting in load transference through the hip joint,15 supplying local structural stability to the hip joint and maintaining lower extremity alignment of the hip and knee joints.16 Performance deficiency in these selected hip muscles results in altered pelvofemoral biomechanics which is linked to lower extremity pathology.3,17–19 This is highlighted when the hip abductors and external rotators fail to produce sufficient torque during weight bearing movements resulting in excessive hip adduction and internal rotation, an increase in knee valgus angle and pelvic drop.17–20

[33]  The prevalence of LE overuse injuries was 39% lower in the hip and core group compared with control group (prevalence rate ratio, PRR 0.61; 95% CI 0.39 to 0.96) (table 2). No significant difference was observed between the ankle and foot group and control group in the prevalence of LE overuse injuries

[34] Furthermore, it has been noted that people who leaned predominantly on the hip muscles for absorbing impact forces during landing showed limited knee valgus angles, abduction moments, and energy absorption at the knee [14.]. Several studies have reported weakness issues concerning hip extension, external rotation and abduction in those participants showing valgus during dynamic tasks or going on to suffer knee injuries [7., 14.-16.].

Hip abduction and external rotation are predominantly positively influenced through both the gluteus medius (GMe) and gluteus maximus muscle (GMa) [8., 17.].

In general, GMe and GMa muscles are the key muscles contributing pelvic stability and lower extremity function. They are frequently implicated in disorders of the knee, the pelvis, and the hip [18.].

[35]  https://www.education.pitt.edu/faculty/directory/duck-chul-lee/ 

[36] Compared with non-runners, runners had 30% and 45% lower adjusted risks of all-cause and cardiovascular mortality, respectively, with a 3-year life expectancy benefit.

[37] Exercise improves overall metabolic health and reduces the development of T2D (18) by improving glucose tolerance (19), insulin sensitivity (20), and decreasing circulating lipid concentrations (21). Regular physical exercise decreases resting heart rate, blood pressure, and atherogenic markers, and increases physiological cardiac hypertrophy (13–15, 28). Exercise improves myocardial perfusion and increases high-density lipoprotein (HDL) cholesterol levels, all of which reduce stress on the heart and improve cardiovascular function in healthy and diseased individuals (11, 15, 29, 30).

[38] Exercise-induced immune system response: Anti-inflammatory status on peripheral and central organs 

[39] These associations were consistent regardless of sex, age, BMI, health conditions, smoking status, and alcohol consumption. We estimated PAFs for running and other mortality predictors, such as smoking, overweight/obesity, and chronic diseases. Not running was almost as important as hypertension, accounting for 16% of all-cause and 25% of CVD mortality (Table 2). Also, nonrunners had 3 years’ lower life expectancy compared with runners after adjustment for other mortality predictors.

[40] In the dose-response analyses (Table 3), runners across all 5 quintiles of weekly running time, even the lowest quintile of <51 min/week had lower risks of all-cause and CVD mortality compared with nonrunners. However, these mortality benefits were similar between lower and higher doses of weekly running time. In fact, among runners (after nonrunners were excluded in the analyses), there were no significant differences in HRs of all-cause and CVD mortality across quintiles of weekly running time (all p values >0.10). In additional analyses using weekly running times of <60, 60 to 119, 120 to 179, and ≥180 min, w

[41]  In additional analyses, we found that a minimum of 30-59 minutes per week of running (5-10 minutes per day) was associated with lower risks of all-cause

[42] https://tesble.com/10.1093/eurheartj/ehz897   For male participants, vigorous activity in the low to moderate range was not associated with any appreciable difference in AF incidence. However, at extreme doses of vigorous activity, there was a 12% increase in incident AF (HR at 5000 Vigorous MET-min/wk: 1.12, 95% CI 1.01–1.25).

[43] https://www.ahajournals.org/doi/10.1161/CIRCRESAHA.125.326011 Observational cohort studies over the past 2 decades have identified a consistent signal of increased coronary artery calcification in older men, who have been exposed to high volumes of endurance exercise over their lifetime. The clinical ramifications of these findings are not fully known, as outcomes studies in these athletic populations are needed, but given the strong associations of coronary artery calcification with adverse cardiovascular events, a deeper mechanistic understanding of the link between endurance exercise and coronary artery calcification is needed.

[44] The cardiovascular benefits and physiologic effects of regular exercise are well established (Fig.) (1–6). Additionally, mild-to-moderate regular exercise likely has a preventative effect on the development of cardiovascular disease (CVD), diabetes, and cancer as well as a mortality benefit

[45] https://www.researchgate.net/profile/Mats_Hallgren/publication/278788898_Physical_exercise_and_internet-based_cognitive-behavioural_therapy_in_the_treatment_of_depression_Randomised_controlled_trial/links/5bd452ca92851c6b27926f8f/Physical-exercise-and-internet-based-cognitive-behavioural-therapy-in-the-treatment-of-depression-Randomised-controlled-trial.pdf Exercise and ICBT were more effective than TAU by a general medical practitioner, and both represent promising non-stigmatising treatment alternatives for patients with mild to moderate depression.

[46] https://www.sciencedirect.com/science/article/abs/pii/S0022395614003148?via%3Dihub Add-on exercise is an efficacious treatment for severely depressed inpatients, improving their depressive symptoms and QoL. Initial acceptance of exercise remains a challenge.

[47] https://pmc.ncbi.nlm.nih.gov/articles/PMC5859016/ At micro level, single bouts of exercise impacted positively on cognitive-emotional processes such as mood, rumination, attention and social interactions, and physiological states of tiredness and physical strengths among inpatients with mental disorders. In addition, further improvements were observed, if patients participated in physical activities a second time.

[48] Rumination and Attention significantly improved from pre- to post-assessment, and effect sizes were large (d = 0.80 and greater)... In our opinion, improvements in rumination after a single bout of exercise deserves special attention: By definition, rumination is considered dysfunctional, as it impairs a more straightforward and goal-oriented thinking; accordingly, reducing rumination should be considered a small but important step in patients’ modification of cognitive-emotional concepts (Ahmadpanah et al., 2017a,b).

[49] The findings of this study reveal a significant association

between depressive symptoms, rumination, and physical exercise

among college students. Higher levels of physical exercise are

associated with reduced rumination and lower depressive

symptomatology. This finding further substantiates the positive

impact of physical exercise in mitigating rumination and

alleviating depressive symptoms. Rumination and depressive

symptoms demonstrated a positive correlation, with symptom

rumination, compulsive thinking, and reflective pondering

exhibiting moderate correlations (0.644, 0.534, 0.491, all P<0.001).

Rumination likely mediates the relationship between physical

exercise and depressive symptoms, with the mediating effects of

physical exercise differing across various rumination factors.

[50] Using trained male college students running on a treadmill or cycling on a stationary bike for 50 min at 70–80% of maximum heart rate, we report here the first evidence that exercise of moderate intensity activates the endocannabinoid system,

[51] https://pmc.ncbi.nlm.nih.gov/articles/PMC10159215/  69%–77%  studies with endurance runners reported that only 69% to 77% of the participants experienced a runner’s high at least once in the past

[52] Endogenous neuropeptides were first identified and named by two independent laboratories in the mid-1970s. In Scotland, the laboratory of John Hughes and Hans Kosterlitz isolated a small peptide sequence from brain tissue isolated from pig and termed it “enkephalin.”6,7

[53] https://pmc.ncbi.nlm.nih.gov/articles/PMC10566433/ - A history of jogging and running—the boom of the 1970s

[54] as all palatable foods stimulate endorphin release in the brain this is the most likely mechanism to account for the elevation of mood.

[55] Collectively these results indicate that the activation of μ receptors by EM-1 modifies parameters associated with ejaculation (increases ejaculation latency and reduces the number of ejaculations) confirming that opioids are released during sexual behavior.

https://tesble.com/10.1016/0014-2999(77)90359-4 

[56] Endorphins, Sexuality, and Reproduction - There is evidence in the literature indicating the role of endorphins in sexuality. Opioid peptides may have both excitatory and inhibitory effects on sexual performance and behaviors (Argiolas & Melis, 2013; Bancroft, 2005). According to animal studies (Melis et al., 1999; van Furth et al., 1995), when opioid peptides are released in response to stress, they impose their inhibitory effects by acting in the medial preoptic area and the paraventricular nucleus that, in turn, impairs sexual performance. It is suggested that endorphins regulate the release of other hormones, such as sex hormones, prolactin, and growth hormone, that are involved in sexual function and attachment (Bancroft, 2005; Esch & Stefano, 2005). It has also been suggested that this may be relevant to the low level of sexual desire in people with symptoms of depression (Dornan & Malsbury, 1989).

[57] Social Laughter Triggers Endogenous Opioid Release in Humans -Social laughter releases immunoenhancers (such as β-endorphins), but it also increases the activity of natural killer cells (lymphocytes) and lowers cortisol levels in blood circulation (Berk et al., 1989).

[58] Therapeutic Benefits of Laughter in Mental Health: A Theoretical Review endorphins secreted by laughter can help when people are uncomfortable or in a depressed mood...Laughter therapy physiologically reduces the level of stress hormones, increases the level of health promoting-hormones such as endorphins, and strengthens the immune system by increasing the number of T-lymphocytes through activation of natural killer cells

[59] https://pubmed.ncbi.nlm.nih.gov/6265777/ — https://tesble.com/10.1056/NEJM198109033051006 1981 study Our results show that exercise increases plasma levels of beta-endorphin (Beta-EP) and its precursor beta-lipotropin (Beta-LPH), and that training augments that effect.

[60] Endocannabinoid signaling at the periphery: 50 years after THC

In 1964, the psychoactive ingredient of Cannabis sativa, Δ9-tetrahydrocannabinol (THC), was isolated. Nearly 30 years later the endogenous counterparts of THC, collectively termed endocannabinoids (eCBs), were discovered: N-arachidonoylethanolamine (anandamide) (AEA) in 1992 and 2-arachidonoylglycerol (2-AG) in 1995. Since then, considerable research has shed light on the impact of eCBs on human health and disease, identifying an ensemble of proteins that bind, synthesize, and degrade them and that together form the eCB system (ECS). eCBs control basic biological processes including cell choice between survival and death and progenitor/stem cell proliferation and differentiation. Unsurprisingly, in the past two decades eCBs have been recognized as key mediators of several aspects of human pathophysiology and thus have emerged to be among the most widespread and versatile signaling molecules ever discovered.

[61] The type 2 cannabinoid receptor (CB2R) was cloned in 1993 from human promyelocytic leukemia cells of the HL-60 lineage [15], and it was further identified in mice, rats, zebrafish, and dogs [70,71,72,73]. It has an amino acid sequence with approximately 44% homology to CB1R amino acid residues. CB2R is mainly found in cells of the immune system, where its expression levels have been found to be higher than those of CB1R [24,46,74].

[62]  The diverse and powerful effects of many phyto-cannabinoids on the human (and animal) physiology are the result of their binding with the endogenous cannabinoid receptors and are affected by the levels of their endogenous ligands

[63] THC, referred to as a “cannabinoid” (like the dozens of other unique constituents of cannabis), acts on the brain by muscling in on the intrinsic neuronal signaling system, mimicking a key natural player, and basically hijacking it for reasons best known to the plants. Since the time when exogenous cannabinoids revealed their existence, the entire natural complex came to be called the “endogenous cannabinoid system,” or “endocannabinoid system” (ECS).

[64] Exercise-induced euphoria and anxiolysis do not depend on endogenous opioids in humans Sixty-four healthy adults (32 women and 32 men) that regularly perform endurance exercise were recruited for this study. … Participants were randomly assigned to receive either 50 mg of the opioid receptor antagonist NAL (Desitin Arzneimittel GmbH, Germany) (n = 32, men=16, women=16; BMI=22.4 ± 0.5; age=28.1 ± 1.1) or an identical-looking PLA (n = 31, men = 15, women = 16; BMI = 22.3 ± 0.4; age=26.5 ± 1.0) on both days. The dose of NAL was comparable to earlier studies in exercising individuals (Crombie et al., 2018, Koltyn et al., 2014, Strassman et al., 1989). 

[65] When subsequently tested for anxiety-like behavior in the dark–light box test, runners exhibited significantly less anxiety by spending an increased time in the aversive bright area than controls (P = 0.002; Fig. 1B). Runners were also less active and displayed fewer exits from the dark compartment into the lit compartment (RUN, 10.3 ± 0.8 exits; CON, 12.6 ± 0.7 exits; P = 0.040). Next, mice were removed from the dark–light arena and subjected to the hot plate test to study pain sensitivity. Here, runners displayed an increased latency to lick hind paws or jump (first action), suggesting reduced thermal pain sensitivity (P = 0.024; Fig. 1C). After the behavioral testing, mice were returned to their home cage, and all mice received free wheel access for 1 h. Controls now ran significantly more than mice of the running group (RUN, 0.28 ± 0.06 km; CON, 0.55 ± 0.08 km; P = 0.008). We were thus able to demonstrate that acute long-distance running reduces anxiety and pain. Runners were also less active when exposed to running wheels after behavioral testing, which indicates postexercise sedation. Thus, three of the four features (anxiolysis, analgesia, and sedation) of a runner’s high were observable in mice.

[66] CB1 receptor deficiency decreases wheel-running activity: Consequences on emotional behaviours and hippocampal neurogenesis When compared with running CB1+/+ mice, the distance covered weekly by CB1−/− mice was decreased by 30–40%, an observation accounted for by decreased time spent and maximal velocity on the wheels.

[67] Endorphins were embraced as an endogenous biologic explanation for the ‘‘runner’s

high’’ (Sachs, 1980) and ‘‘running addiction’’ (Sachs & Pargman, 1979) because of their reported hypoalgesic effects, their opiatelike structure, and their regulatory roles in central nervous system function and neuroendocrine response to stress (Collu, Ducharme, Barbeau, & Tolis, 1982). This acceptance was bolstered by reports that endorphin-receptor occupancy was altered in rat brain following acute exercise (Barta, Yashpal, & Henry, 1981; Pert &Bowie, 1979; Wardlaw & Frantz, 1980); that naloxone, an opioid

receptor antagonist, affected pain perception after jogging (Haier,Quaid, & Mills, 1981)...

A survey of 1227 marathon runners found that more than 99% reported pain during a marathon (28% reported pain by mile 13), and the average pain intensity at the primary location of pain (legs for most) during a marathon run was described as ‘‘strong’’ (O’Connor & Dyke, 2007). Opioids released during vigorous exercise might attenuate pain caused by muscle contraction…

https://tesble.com/10.1016/j.mhpa.2009.01.002 

[68] The µ-opioid antagonist naloxone significantly increased overall pain ratings but showed no interaction with exercise intensity. An exploratory analysis suggested an influence of fitness level (as indicated by the functional threshold power) and sex where males showed greater hypoalgesia after high- intensity exercise with increasing fitness levels. This effect was attenuated by naloxone and mirrored by fMRI signal changes in the medial frontal cortex, where activation also varied with fitness level and sex, and was reversed by naloxone. These results indicate that different aerobic exercise intensities have no differential effect on pain in a mixed population sample, but individual factors such as fitness level and sex might play a role.

[69] Bidirectional Association between Physical Activity and Dopamine Across Adulthood—A Systematic Review 

[70] Increased serotonin (5-HT) synthesis, metabolism, and release have also been noted during or following exercise [11], [12], [13].

[71] Stress hormones, adrenaline (epinephrine) and noradrenaline (norepinephrine), are responsible for many adaptations both at rest and during exercise. Since their discovery, thousands of studies have focused on these two catecholamines and their importance in many adaptive processes to different stressors such as exercise, hypoglycaemia, hypoxia and heat exposure, and these studies are now well acknowledged. In fact, since adrenaline and noradrenaline are the main hormones whose concentrations increase markedly during exercise, many researchers have worked on the effect of exercise on these amines and reported 1.5 to >20 times basal concentrations depending on exercise characteristics (e.g. duration and intensity).

[72] Exercise-induced endocannabinoid signaling is modulated by intensity  Our data show that exercise-induced AEA release in the bloodstream is dependent on exercise intensity. Only moderate exercise intensities (~70–85 % of AAMHR) lead to significant changes in circulating levels of AEA. Circulating levels of 2-AG are not influenced by exercise at any intensity.

[73] Blood samples were taken before (baseline) and after each exercising condition. Analyses on the difference between the second and the first baseline sample revealed a significant effect of Exercising Condition on AEA levels [F(2, 28) = 41.991, p < 0.001], with increased AEA after moderate and high intensity exercise compared to after rest (pmod-rest < 0.001; phigh-rest < 0.001)....

We defined moderate intensity as 70% of maximal heart rate (corresponding to 60% of VO2max) and high intensity exercise as 80% of maximal heart rate (corresponding to 75% of VO2max).

[74] Figure 1 Plasma concentrations of endocannabinoids and nonendocannabinoid N-acylethanolamines during exercise and recovery. Values are presented as mean  SD. Blood samples taken

at rest, at the end of the 60-min exercise at 55% Wmax (60 min at

55%), at the end of the time trial (TTat 75%) and after 15 min of

recovery (recovery). Comparable results were obtained when

concentrations were expressed in pmol/mg of lipid extract. Significant difference from rest: **P < 0.01, ***P < 0.001. Significant difference from 60 min at 55%: ##P < 0.01. Significant

difference from TT at 75%: &P < 0.05, &&P < 0.01.

https://pubmed.ncbi.nlm.nih.gov/22029953/ 

[75] It may be that duration of continuous exercise is an important factor in this relationship, a point which is discussed next.  Finally, there was a significant difference between levels of duration of exercise, F (3,178) = 5.39, p = 0.0014. This can be seen in figure 1 where each point represents the length of the exercise session. Specifically, post hoc tests revealed that exercise lasting 0 to 20 minutes (ES = 0.04) resulted in significantly lower effect sizes than exercise lasting 21 to 30 minutes (effect size = 0.41). There were no differences between the other time categories.

https://pubmed.ncbi.nlm.nih.gov/1828608/ 

[76] Generalizable effects were found for bouts ranging from 7 to 35 min, although the lower bound 90% CrI values for bouts less than 30 min were close to zero. Bouts from 40 to 60 min produce increases.., but effects do not generalize. Exercise durations longer than 75 min likely result in decreased PAA (e.g., Hassmen & Blomstrand, 1991), but the smaller K for this subsample warrants some caution in the interpretation of the results.

The 30–35 min duration produced the largest effect ( SDcorr=.33). To assess the extent to which higher ESs associated with studies using lower intensity bouts influenced this generalizable result

Exercise of at least 20–30 min has been suggested as a duration threshold for improvement of PAA (Berger & Motl, 2000). This meta-analysis suggests that shorter and longer bouts, even up to 60 min, result in affective improvement while decreases are likely for durations longer than 75 min,