运动训练；CGRP

… exercise training. We also observed increased pain-related expression of SP, CGRP and … , which was reversed after aerobic exercise training. In addition, we confirm the involvement …

BackgroundMigraine is a chronic neurovascular disorder characterized by recurrent headache attacks accompanied by sensory, autonomic, and neuroinflammatory symptoms. Physical exercise has a dual role in migraine, acting both as a trigger and as a non-pharmacological therapeutic intervention. Materials and methodsA narrative literature review was conducted using PubMed, Scopus, Cochrane Library          and Google Scholar. Studies were selected according to their relevance to migraine               and physical exercise. State of knowledgeAcute high-intensity exercise may trigger migraine through increased cortical excitability, metabolic stress, and activation of the trigeminovascular system. In contrast, regular exercise may reduce neuroinflammation, improve mitochondrial function, enhance endogenous pain inhibition, and regulate autonomic balance. These adaptations are associated with lower migraine frequency, duration, and intensity and may involve modulation of calcitonin gene-related peptide, serotonergic pathways, endorphin release, and central sensitization. ConclusionsRegular, individualized physical exercise represents an effective non-pharmacological strategy for migraine prevention. Its benefits depend on exercise type, intensity                       and individual patient characteristics. Understanding the mechanisms underlying both             the triggering and protective effects of exercise may support personalized migraine management.

BACKGROUND Exercise training showed beneficial effects on brain. The purpose of the present study is to evaluate the effect of six weeks of high-intensity interval training (HIIT) and Endurance training (ET) with calcitonin gene-related peptide (CGRP) receptor antagonist on the expression of genes involved in mitochondrial dynamics and apoptosis in hippocampal tissue of male Wistar rats. METHODS In this study, forty-two healthymale Wistar rats (8-week) were randomly divided into 6 groups (n = 7) as follow; 1) Control; 2) HIIT which performed 6 weeks of HIIT; 3) ET which performed 6 weeks of endurance training; 4) CGRPi received 10 mg/kg CGRP receptor antagonist every day at the last 2 weeks; 5) CGRPi-HIIT performed HIIT and received CGRP receptor antagonist; 6) CGRPi-ET performed ET and received CGRP receptor antagonist. Real-time PCR (2-ΔΔCT) and western blotting were employedto measure the expression of genes and protein, respectively. RESULTS HIIT and ET significantly increased Bcl-2, Pgc-1α, Sirt3, and Nrf-1 gene expression in the hippocampal tissue (p < 0.05, p < 0.01, p < 0.01, and p < 0.001, respectively). ET-CGRPi and HIIT-CGRPi significantly increased Sirt3, Pgc-1α, and Nrf-1 gene expression compared to the control group (p < 0.05, p < 0.01, and p < 0.05, respectively). CONCLUSION ET and HIIT-induced physiological alterations in the hippocampus. In fact, this modulation showed protective properties in the hippocampusvia up regulation of Bcl-2, Pgc-1α, Nrf-1, and Sirt3 gene expression. CGRPi did not cause gene or protein changes harmful to mitochondrial dynamic balance and apoptosis in the hippocampus of rats.

Rationale: α-calcitonin gene related peptide (αCGRP), one of the strongest vasodilators, is cardioprotective in hypertension by reducing the elevated blood pressure (BP). Objective: However, we hypothesize that endogenous, physical activity-induced αCGRP has BP-independent cardioprotective effects in chronic hypertension. MMethods and Results: Chronically hypertensive (one-kidney-one-clip surgery) WT and αCGRP-/- sedentary or voluntary wheel running mice were treated with vehicle, αCGRP, or the αCGRP receptor antagonist CGRP8-37. Cardiac function and myocardial phenotype were evaluated echocardiographically and by molecular, cellular and histological analysis, respectively. BP was similar among all hypertensive experimental groups. Endogenous αCGRP limited pathological remodeling and heart failure in sedentary, chronically hypertensive WT mice. In these mice, voluntary wheel running significantly improved myocardial phenotype and function, which was abolished by CGRP8-37 treatment. In αCGRP-/- mice, αCGRP treatment, in contrast to voluntary wheel running, improved myocardial phenotype and function. Specific inhibition of proliferation and myofibroblast differentiation of primary, murine cardiac fibroblasts by αCGRP suggests involvement of these cells in αCGRP-dependent blunting of pathological cardiac remodeling. Conclusions: Endogenous, physical activity-induced αCGRP has BP-independent cardioprotective effects and is crucial for maintaining cardiac function in chronic hypertension. Consequently, inhibiting endogenous αCGRP signaling, as currently approved for migraine prophylaxis, could endanger hypertensive patients.

Alpha calcitonin gene-related peptide (αCGRP) is one of the strongest vasodilators and, as such, is cardioprotective in chronic hypertension when reducing the associated elevated blood pressure. However, we hypothesize that endogenous, physical activity-induced αCGRP has blood pressure independent cardioprotective effects in chronic hypertension. Chronic hypertension was induced in WT and αCGRP−/− mice by one-kidney one-clip surgery. Chronic hypertensive WT and αCGRP−/− mice lived sedentarily or performed voluntary wheel running and were treated simultaneously with either vehicle, αCGRP or αCGRP receptor antagonist CGRP8–37. Cardiac function and tissue phenotype were evaluated echocardiographically and by ddPCR, Western blotting and histology, respectively. Blood pressure was similar among all hypertensive experimental groups. Endogenous αCGRP limited pathological cardiac remodeling and symptomatic heart failure already in sedentary, chronic hypertensive WT mice. In these mice, voluntary wheel running significantly improved cardiac tissue phenotype and function, that was abolished by CGRP8–37 treatment. In αCGRP−/− mice, αCGRP treatment, in contrast to voluntary wheel running, improved cardiac tissue phenotype and function. Specific inhibition of proliferation and myofibroblast differentiation of primary murine cardiac fibroblasts by αCGRP suggests involvement of these cells in αCGRP-mediated blunting of pathological cardiac remodeling. Endogenous, physical activity-induced αCGRP has blood pressure independent cardioprotective effects and is crucial for maintaining cardiac function in chronic hypertension. Consequently, permanently inhibiting endogenous αCGRP signaling, as currently approved for migraine prophylaxis, could endanger hypertensive patients. Swiss National Science Foundation, Novartis Foundation for Medical-biological Research

It has been reported that hyperpnea-induced bronchoconstriction in guinea pigs is a potential model for exercise-induced asthma in humans. We hypothesized that calcitonin gene-related peptide (CGRP) could modulate leukotriene D4 (LTD4)-induced responses and be involved in the pathophysiology in this asthma model. We measured tracheal (Ptr) and alveolar pressure (PA) using alveolar capsules in open-chested, mechanically ventilated (f = 1 Hz, VT = 9 ml/kg, PEEP = 4 cm H2O) guinea pigs. Animals were intravenously pretreated with saline (SAL), CGRP(8-37) (CGRP receptor antagonist), CGRP, MK-571 (LTD4 receptor antagonist), MK-886 (5-lipoxygenase inhibitor), or CGRP(8-37) + MK-571, and then underwent dry gas hyperpnea challenge (HC, 95% 02-5% CO2, 150 breaths/min, 7 min). We calculated resistance of lung (RL), tissue (Rti), and airway (Raw). HC increased RL, Rti, and Raw in SAL controls (322 +/- 27, 430 +/- 59, 299 +/- 23% baseline, respectively). MK-571, MK-886, and CGRP significantly reduced the responses to HC, while CGRP(8-37) enhanced HC-induced responses. Pretreatment with CGRP(8-37) and MK-571 in combination attenuated HC-induced constriction. In addition, pretreatment with CGRP reduced responses induced by intravenous administration of LTD4. These observations suggest that CGRP might be involved in the pathophysiology of hyperpnea-induced constriction in guinea pigs via modulation of LTD4-elicited responses.

α-Calcitonin gene-related peptide (αCGRP) is released mainly from sensory and motor nerves in response to physiological stimuli. Despite well-documented pharmacological effects, its primary physiological role has thus far remained obscure. Increased lipid content, particularly in skeletal muscle and liver, is strongly implicated in the pathogenesis of insulin resistance, but the physiological regulation of organ lipid is imperfectly understood. Here we report our systematic investigations of the effects of αCGRP on in vitro and in vivo indices of lipid metabolism. In rodents, levels of αCGRP similar to those in the blood markedly stimulated fatty acid β-oxidation and evoked concomitant mobilization of muscle lipid via receptor-mediated activation of muscle lipolysis. αCGRP exerted potent in vivo effects on lipid metabolism in muscle, liver, and the blood via receptor-mediated pathways. Studies with receptor antagonists were consistent with tonic regulation of lipid metabolism by an endogenous CGRP agonist. These data reveal that αCGRP is a newly recognized regulator of lipid availability and utilization in key tissues and that it may elevate the availability of intramyocellular free fatty acids to meet muscle energy requirements generated by contraction by evoking their release from endogenous triglyceride.

… (SP, CGRP) in relation to different levels of physical activity. … to assess the effect of physical activity on tendon healing in … Inversely, the neuronal occurrence of CGRP in the tendon …

Abstract Background Calcitonin gene-related peptide (CGRP) is a powerful neuropeptide that is strongly involved in headache pain pathogenesis by triggering vasodilation, mast cell degranulation and neurogenic inflammation. This evidence has prompted us to investigate the acute influence of endurance exercise on CGRP concentration in blood. Methods The study population consisted of 48 male amateur runners, who ran a half-marathon distance at 75%–85% of maximal oxygen uptake. Blood was drawn before the run (pre-run) and immediately after each runner ended his trial (post-run). The serum concentration of CGRP was measured with a commercial enzyme-linked immunosorbent assay (ELISA) technique. Results Overall, 22/48 subjects (45.8%) reported suffering from headache, three of whom (6.2%) had an exertional headache, whilst 26/48 (54.2%) subjects did not report at least one headache episode during the previous 6 months (i.e. headache-free). All 48 athletes successfully covered the 21.1 km distance. Serum concentration of CGRP significantly increased by 1.5-fold in the entire group, as well as in the headache-positive and headache-free cohorts. Univariate Spearman’s correlation revealed that post-run variation of serum CGRP was significantly and inversely associated with running time (r = −0.30; p = 0.036). Conclusions The serum concentration of CGRP is significantly enhanced by medium-distance endurance exercise and the post-exercise increase is dependent on running intensity. Accordingly, high-exercise intensity might be directly related to triggering both exertional headache and/or migraine episodes.

P. Hasbak, C. Lundby, N.V. Olsen, S. Schifter, and I.L. Kanstrup Department of Clinical Physiology and Nuclear Medicine, University Hospital of Herlev, Herlev; Department of Clinical Physiology and Nuclear Medicine, University Hospital of Glostrup, Glostrup; Department of Clinical Experimental Research, University Hospital of Glostrup, Glostrup; Department of Pharmacology, Panum Institute, University of Copenhagen, Denmark

… acupuncture and exercise affected CGRP concentrations in … effects of exercise and acupuncture on CGRP concentrations … exercise and manual or electro-acupuncture on CGRP …

To determine the potential impact of erenumab, a human anti‐calcitonin gene‐related peptide (CGRP) receptor monoclonal antibody, on total exercise time (TET), time to exercise‐induced angina, and ST depression in a double‐blind, placebo‐controlled study in patients with stable angina due to documented coronary artery disease.

… and calcitonin gene-related peptide (CGRP) from sensory … training on sensory innervation, cutaneous sensory function … exercise training [20] , and changes in the sensory receptors …

Objectives: To detect neuropeptides in human skeletal muscle at rest and after eccentric exercise. Method: Eight healthy subjects participated in the study. Microdialysis of the distal part of the vastus lateralis of the quadriceps muscle and pain evaluation were performed immediately after eccentric exercise, after two days, and at rest. Calcitonin gene related peptide (CGRP) and neuropeptide Y (NPY), representatives of the sensory and autonomic nervous system, were analysed by radioimmunoassay. Results: Overall, the measured concentrations were low, some even below the limit of detection. At rest, CGRP was detected in two of seven samples, but after eccentric exercise it was detected in 27 of 30 samples. At rest, all NPY concentrations were below the limit of detection, but after exercise it was found in six of 30 samples. Conclusion: The significant increase in detectability of CGRP after eccentric exercise may be related to the increased experience of pain. Therefore the occurrence of CGRP after heavy eccentric exercise may be associated with the regulation of delayed onset muscle soreness and possibly also the stimulation of tissue regeneration.

… Proton-induced CGRP-LI release in skeletal muscle could be of relevance during exercise … dependent release of CGRP from capsaicin-sensitive primary afferent neurons can be evoked …

… Calcitonin gene-related peptide (CGRP) and adrenomedullin (AM) are potent vasorelaxant peptides. This study examined exercise-induced changes in CGRP … Plasma values of CGRP, …

… of afferent neurons in the … of afferent neurons (Brimijoin et al. 1980; Keen et al. 1982). Stimulation causes release of SP, NKA and CGRP from the peripheral endings of afferent neurons, …

Background TWIK-related spinal cord potassium channel (TRESK) background potassium channels have a key role in controlling resting membrane potential and excitability of sensory neurons. A frameshift mutation leading to complete loss of TRESK function has been identified in members of a family suffering from migraine with aura. In the present study, we examined the role of TRESK channels on nociceptor function in mice. Methods Calcium imaging was used to investigate the role of TRESK channels in the modulation of the response evoked by transient receptor potential vanilloid 1 (TRPV1) receptor stimulation in dorsal root ganglion neurons. Release of calcitonin gene-related peptide from trigeminal afferents and changes in meningeal blood flow were also measured. Experiments were performed on wild-type and TRESK knockout animals. Results Inhibition of TRESK increased the TRPV1-mediated calcium signal in dorsal root ganglion neurons and potentiated capsaicin-induced increases in calcitonin gene-related peptide release and meningeal blood flow. Activation of TRESK decreased the capsaicin sensitivity of sensory neurons, leading to an attenuation of capsaicin-induced increase in meningeal blood flow. In TRESK knockout animals, TRPV1-mediated nociceptive reactions were unaffected by pretreatment with TRESK modulators. Conclusions Pharmacological manipulation of TRESK channels influences the TRPV1-mediated functions of nociceptors. Altered TRESK function might contribute to trigeminal nociceptor sensitization in migraine patients.

Chronic pain is typically defined as pain that persists after acute tissue damage and inflammation or as pain that follows a chronic disease process and lasts more than three months. Because of its debilitating impact on the quality of life of patients, recent research aims to investigate the mechanisms behind nociception to discover novel therapeutic agents to alleviate pain. One such target is the neuropeptide calcitonin gene-related peptide (CGRP), which has shown to play an integral role in migraine pathophysiology. Effective treatments of migraines with CGRP antagonists have stimulated our efforts toward checking a possible involvement of CGRP in nonheadache pain conditions such as hypertension, congestive heart failure, Alzheimer's disease, and vascular ischemia. Here, we provide a brief overview of chronic pain, with a particular emphasis on the role of CGRP as a fundamental mediator of nociceptive pain as well as a target for novel therapeutic agents.

The science of migraine pathophysiology has advanced significantly since the 1930’s. Imaging techniques, neurochemical analysis, clinical trials, and the clinical experience of providers treating migraine patients have not only sharpened our understanding of the disease, but have also led to the development of novel neural‐based targets. Targeted therapies such as calcitonin gene‐related peptide (CGRP) antibodies and “Second Generation” CGRP receptor antagonists (Gepants) have not only demonstrated efficacy, but have not resulted in any significant cardiovascular nor other serious adverse events. “First Generation” Gepants were associated with liver toxicity.

Calcitonin Gene Related Peptide (CGRP) is expressed in the cardiovascular system and showed vasodilatory effects. This study aimed to investigate the effects of exercise training and a CGRP antagonist (CGRPi) on the expression of genes involved in mitochondrial dynamics in the aorta. Forty-two male rats were divided into six groups (n=7): 1) Control; 2) Endurance Training (ET); 3) High-Intensity Interval Training (HIIT); 4) CGRP antagonist (CGRPi,10 mg/kg) administered via intraperitoneal injections; 5) CGRPi + ET (CGRPi-ET); and 6) CGRPi + HIIT (CGRPi-HIIT). Protein expression was analyzed using Western blotting, while gene expression was quantified via Real-Time PCR. Both ET and HIIT significantly upregulated eNOS protein and the gene expression of Pgc-1α, Bcl-2, Nrf-1, Sirt3, Parkin, and eNOS. The increase in Bcl-2 expression induced by ET was attenuated by CGRPi in the groups with the combination of CGRPi and ET (P = 0.02). Exercise training enhanced mitochondrial biogenesis by affecting the expression of Pgc-1α, Nrf-1 and Sirt3. While CGRP is known to mediate vasodilation, we indicated that CGRPi did not affect eNOS expression, suggesting that CGRP exerts vasodilatory effects through mechanisms other than eNOS in the aorta. Furthermore, CGRPi does not showed negative effects over genes associated with mitophagy and mitochondrial biogenesis.

Regular physical activity exerts cardiovascular protective effects in healthy individuals and those with chronic cardiovascular diseases. Exercise is accompanied by an increased plasma concentration of α-calcitonin gene-related peptide (αCGRP), a 37-amino acid peptide with vasodilatory effects and causative roles in migraine. Moreover, mouse models revealed that loss of αCGRP disrupts physiological adaptation of the cardiovascular system to exercise in normotension and aggravates cardiovascular impairment in primary chronic hypertension, both can be reversed by αCGRP administration. This suggests that αCGRP agonists could be a therapeutic option to mediate the cardiovascular protective effects of exercise in clinical setting where exercise is not possible or contraindicated. Of note, FDA has recently approved αCGRP antagonists for migraine prophylaxis therapy, however, the cardiovascular safety of long-term anti-CGRP therapy in individuals with cardiovascular diseases has yet to be established. Current evidence from preclinical models suggests that chronic αCGRP antagonism may abolish the cardiovascular protective effects of exercise in both normotension and chronic hypertension.

… CGRP and substance P are potent vasodilators in man. Intravenous infusion of either peptide elicits a fall in diastolic blood pressure and tachycardia (Fuller et al., 1987; Struthers et al., …

… effects of the vasodilatory action of CGRP in hypertension, … increase in CGRP evoked by aerobic exercise may facilitate … the changes of CGRP in the effect of aerobic exercise on …

… physiological stimuli, including exercise. Specifically, recent studies indicate that in rat the local concentration of CGRP increases during eccentric exercise, and the increased levels …

… types of skeletal muscles may be affected by the physical exercise [1–3]. The process of … as a potent vasodilator [9]. CGRP-α and CGRP-β are two types of CGRP isoforms, being …

… and calcitonin gene-related peptide (CGRP) in man. The results suggest that exercise gives … potent than other known vasodilators. Further clinical studies also indicated that infusion of …

ABSTRACT Objectives There is conflicting evidence on the effect of physical exercise on migraine development. Present study investigated the impact of treadmill exercise on migraine – associated symptoms and changes in calcitonin gene-related peptide (CGRP) expression in rats with and without maternal deprivation stress (MD). Methods Two days after birth, the male Wistar pups were randomly divided into four groups (n = 6) as follows: intact, exercise, MD, and MD plus exercise. The animals in the MD groups were separated from their dams 4 h per day for 2 weeks. At 8 weeks of age, the rats were exercised on a motor-driven treadmill for 4 weeks. Then, nitroglycerin (NTG) (5 mg/kg/IP) was used to induce migraine and pain-related symptoms were recorded for 90 min. NTG-related thermal hyperalgesia was measured by tail flick and hot plate methods. Finally, immunofluorescence staining of CGRP in trigeminal subnucleus caudalis (Vc) was performed. Results NTG – produced a significant headache symptoms and thermal hypersensitivity, which were aggravated following physical exercise in stressed or unstressed groups. Besides, NTG administration increased CGRP expression in the Vc of rats. Such effect was overpowered by treadmill running only in rats exposed to MD stress. Conclusion These findings highlight the worsening effects of treadmill exercise for migraine in rats with and without MD stress. However, inflammatory response can further exacerbate in stressed rats.

… CGRP, antidromic vasodilation could not be produced in skeletal muscles. This CGRP-related antidromic vasodilation … flow to muscle during muscle exercise. There is evidence that …

… In addition to this effect, CGRP may also cause vasodilation of resistance vessels and this may explain the decrease in intra-arterial blood pressure present after 15±30 min of …

Abstract Objectives We assessed the relationships between CGRP, lactate and fat regulation. Methods We evaluated the effect of intracerebroventricular (i.c.v.) injection of lactate and acute exercise on brain CGRP expression, and its concentration in serum/cerebrospinal fluid (SCF) in rats. Results Injection of lactate up-regulated CGRP expression in the cortex and CSF and activated p38-mitogen-activated protein kinases (p38-MAPK) pathway. Co-injection of lactate and sb203580, deterred lactate-induced up-regulation of CGRP in the brain and CSF. Exercise increased the CGRP expression in the brain and CSF and up-regulated fat metabolism. Inhibition of lactate entrance into the brain using alpha-cyano-4-hydroxycinnamate (4-CIN) diminished exercise-induced CGRP up-regulation in the brain and CSF. Reducing the circulating blood lactate by pre-treatment of the animals with dichloroacetate (DCA) had no effect on exercise-induced increase in CGRP expression or fat metabolism during exercise. Conclusions Lactate probably acts as one of a signalling molecule in the brain to regulate fat metabolism during exercise.

… CGRP during exercise, whether the brain and serum CGRP content could be affected by exercise … Compared with the C group, acute exercise significantly increased CGRP …

Osteoarthritis (OA) is a chronic degenerative joint disease characterized by cartilage breakdown, subchondral bone remodeling, and inflammation. Mechanical stress, such as exercise, can influence OA progression, acting as either a therapeutic intervention or a risk factor depending on intensity. The sensory neuropeptide αCGRP plays a role in modulating cartilage, bone, and inflammatory responses, making it a potential mediator of exercise effects on OA. This study investigated the impact of αCGRP deficiency and exercise intensity on OA progression in a post-traumatic murine model. OA was induced in male αCGRP knockout (KO) and wild type (C57Bl/6J) mice via destabilization of the medial meniscus (DMM). Mice underwent moderate or intense treadmill exercise for up to 6 weeks (8 weeks post-surgery). Histological analyses were performed to assess cartilage degradation. Subchondral and metaphyseal bone morphology as well as cartilage stiffness were evaluated by nanoCT and atomic force microscopy (AFM), respectively. Serum inflammatory markers were analyzed using multiplex immunoassays. Serum levels of proinflammatory markers were elevated in αCGRP-deficient mice, particularly after intense exercise, independent of OA progression. DMM surgery induced significant cartilage degradation. Gross cartilage morphology was not influenced by exercise intensity or αCGRP deficiency, but αCGRP deficiency prevented articular cartilage extracellular matrix stiffening after DMM and intense exercise. Subchondral bone sclerosis was induced by αCGRP deficiency and DMM but mitigated by intense exercise. In metaphyseal bone, intense exercise induced trabecular loss in αCGRP-deficient mice. This study highlights αCGRP as an intrinsic regulator of joint and bone responses to mechanical loading during OA. While cartilage degradation after DMM and treadmill exercise was unaffected by lack of αCGRP, its deficiency altered ECM stiffness, bone remodeling, and inflammatory responses. These findings position αCGRP as a critical regulator of joint homeostasis, particularly for bone health during running exercise and OA progression.

… EP increases serum CGRP levels and CGRP expression in … increases CGRP synthesis in the DRG and promote CGRP … that CGRP synthesis and release are affected by the exercise …

… They also induce the release of calcitonin gene-related peptide (CGRP) from the motor … in muscle are associated with exercise-induced muscle pain. Maximal concentric exercise also …

… can activate muscle nociceptors and trigger the release of CGRP from muscle pain fibers, which in … Many patients with MP and FM complain of exercise-induced muscle pain. Extensive …

… Release of acetylcholine is also enhanced by calcitonin gene-related peptide (CGRP). … Ultrasound did not improve outcome when combined with massage and exercise (class I study) (…

… CGRP relay nociceptive information and that sensitized peripheral neurons release SP and CGRP … It is well known that heavy exercise leads to metabolic changes within the muscle as …

… that CGRP would have similar effects on striated skeletal muscle and determined the effects of CGRP on … Finally, CGRP has been associated with various aspects of exercise and …