283
Views
1
CrossRef citations to date
0
Altmetric
Review Article

Redox interactions of immune cells and muscle in the regulation of exercise-induced pain and analgesia: implications on the modulation of muscle nociceptor sensory neurons

, ORCID Icon, ORCID Icon, ORCID Icon & ORCID Icon
Pages 645-663 | Received 06 Apr 2021, Accepted 05 Jul 2021, Published online: 19 Jul 2021

References

  • Taylor JL, Butler JE, Gandevia SC. Changes in muscle afferents, motoneurons and motor drive during muscle fatigue. Eur J Appl Physiol. 2000;83(2–3):106–115.
  • Borghi SM, Zarpelon AC, Pinho-Ribeiro FA, et al. Role of TNF-α/TNFR1 in intense acute swimming-induced delayed onset muscle soreness in mice. Physiol Behav. 2014;128:277–287.
  • Dannecker EA, Koltyn KF. Pain during and within hours after exercise in healthy adults. Sports Med. 2014;44(7):921–942.
  • He F, Li J, Liu Z, et al. Redox mechanism of reactive oxygen species in exercise. Front Physiol. 2016;7:486.
  • Inanir A, Sogut E, Ayan M, et al. Evaluation of pain intensity and oxidative stress levels in patients with inflammatory and non-inflammatory back pain. Eur J Gen Med. 2013;10(4):185–190.
  • de Sousa CV, Sales MM, Rosa TS, et al. The antioxidant effect of exercise: a systematic review and meta-analysis. Sports Med. 2017;47(2):277–293.
  • Simioni C, Zauli G, Martelli AM, et al. Oxidative stress: role of physical exercise and antioxidant nutraceuticals in adulthood and aging. Oncotarget. 2018;9(24):17181–17198.
  • Radak Z, Taylor AW, Ohno H, et al. Adaptation to exercise-induced oxidative stress: from muscle to brain. Exerc Immunol Rev. 2001;7:90–107.
  • Chatterjee S. Oxidative stress, inflammation, and disease. In: Dziubla T, and Butterfield DA, editors. Oxidative stress and biomaterials. 1st ed., Amsterdam: Elsevier; 2016; p. 35–58.
  • Kawamura T, Muraoka I. Exercise-induced oxidative stress and the effects of antioxidant intake from a physiological viewpoint. Antioxidants. 2018;7(9):119.
  • Powers SK, Jackson MJ. Exercise-induced oxidative stress: cellular mechanisms and impact on muscle force production. Physiol Rev. 2008;88(4):1243–1276.
  • Liguori I, Russo G, Curcio F, et al. Oxidative stress, aging, and diseases. Clin Interv Aging. 2018;13:757–772.
  • Lima LV, Abner TSS, Sluka KA. Does exercise increase or decrease pain? Central mechanisms underlying these two phenomena. J Physiol. 2017;595(13):4141–4150.
  • Tofas T, Draganidis D, Deli CK, et al. Exercise-induced regulation of redox status in cardiovascular diseases: the role of exercise training and detraining. Antioxidants. 2019;9(1):13.
  • Powers SK, Deminice R, Ozdemir M, et al. Exercise-induced oxidative stress: Friend or foe? J Sport Health Sci. 2020;9(5):415–425.
  • Salminen A, Vihko V. Endurance training reduces the susceptibility of mouse skeletal muscle to lipid peroxidation in vitro. Acta Physiol Scand. 1983;117(1):109–113.
  • Schneider CD, Oliveira ARd. Oxygen free radicals and exercise: mechanisms of synthesis and adaptation to the physical training. Rev Bras Med Esporte. 2004;10(4):314–318.
  • Kincaid B, Bossy-Wetzel E. Forever young: SIRT3 a shield against mitochondrial meltdown, aging, and neurodegeneration. Front Aging Neurosci. 2013;5:48.
  • Gomez-Cabrera M-C, Viña J, Ji LL. Interplay of oxidants and antioxidants during exercise: implications for muscle health. Phys Sportsmed. 2009;37(4):116–123.
  • Rice D, Nijs J, Kosek E, et al. Exercise-induced hypoalgesia in pain-free and chronic pain populations: state of the art and future directions. J Pain. 2019;20(11):1249–1266.
  • Liu J, Chen L, Tu Y, et al. Different exercise modalities relieve pain syndrome in patients with knee osteoarthritis and modulate the dorsolateral prefrontal cortex: a multiple mode MRI study. Brain Behav Immun. 2019;82:253–263.
  • Xiong Y, Xiong Y, Wang Y, et al. Exhaustive-exercise-induced oxidative stress alteration of erythrocyte oxygen release capacity. Can J Physiol Pharmacol. 2018;96(9):953–962.
  • Tanskanen M, Atalay M, Uusitalo A. Altered oxidative stress in overtrained athletes. J Sports Sci. 2010;28(3):309–317.
  • Wang ZQ, Porreca F, Cuzzocrea S, et al. A newly identified role for superoxide in inflammatory pain. J Pharmacol Exp Ther. 2004;309(3):869–878.
  • Hattori H, Subramanian KK, Sakai J, et al. Small-molecule screen identifies reactive oxygen species as key regulators of neutrophil chemotaxis. Proc Natl Acad Sci U S A. 2010;107(8):3546–3551
  • Sandoval R, Lazcano P, Ferrari F, et al. TNF-α Increases production of reactive oxygen species through Cdk5 activation in nociceptive neurons . Front Physiol. 2018;9:65.
  • Munoz FM, Gao R, Tian Y, et al. Neuronal P2X7 receptor-induced reactive oxygen species production contributes to nociceptive behavior in mice. Sci Rep. 2017;7(1):3539.
  • Cunha TM, Verri WA, Jr, Schivo IR, et al. Crucial role of neutrophils in the development of mechanical inflammatory hypernociception. J Leukoc Biol. 2008;83(4):824–832.
  • Kawamura T, Suzuki K, Takahashi M, et al. Involvement of neutrophil dynamics and function in exercise-induced muscle damage and delayed-onset muscle soreness: effect of hydrogen bath. Antioxidants. 2018;7(10):127.
  • Quindry JC, Stone WL, King J, et al. The effects of acute exercise on neutrophils and plasma oxidative stress. Med Sci Sports Exerc. 2003;35(7):1139–1145.
  • Bradic J, Dragojlovic Ruzicic R, Jeremic J, et al. Comparison of training and detraining on redox state of rats: gender specific differences. Gen Physiol Biophys. 2018;37(3):285–297.
  • Sorge RE, LaCroix-Fralish ML, Tuttle AH, et al. Spinal cord toll-like receptor 4 mediates inflammatory and neuropathic hypersensitivity in male but not female mice. J Neurosci. 2011;31(43):15450–15454.
  • Sorge RE, Mapplebeck JC, Rosen S, et al. Different immune cells mediate mechanical pain hypersensitivity in male and female mice. Nat Neurosci. 2015;18(8):1081–1083.
  • Dance A. Why the sexes don’t feel pain the same way. Nature. 2019;567(7749):448–450.
  • Dannecker EA, Liu Y, Rector RS, et al. Sex differences in exercise-induced muscle pain and muscle damage. J Pain. 2012;13(12):1242–1249.
  • Cheung K, Hume P, Maxwell L. Delayed onset muscle soreness: treatment strategies and performance factors. Sports Med. 2003;33(2):145–164.
  • MacIntyre DL, Reid WD, McKenzie DC. Delayed muscle soreness. The inflammatory response to muscle injury and its clinical implications. Sports Med. 1995;20(1):24–40.
  • Byrnes WC, Clarkson PM, White JS, et al. Delayed onset muscle soreness following repeated bouts of downhill running. J Appl Physiol. 1985;59(3):710–715.
  • Hotfiel T, Freiwald J, Hoppe MW, et al. Advances in delayed-onset muscle soreness (DOMS): part i: pathogenesis and diagnostics. Sportverletz Sportschaden. 2018;32(4):243–250.
  • Aoi W, Naito Y, Takanami Y, et al. Oxidative stress and delayed-onset muscle damage after exercise. Free Radic Biol Med. 2004;37(4):480–487.
  • Mueller-Wohlfahrt HW, Haensel L, Mithoefer K, et al. Terminology and classification of muscle injuries in sport: the Munich consensus statement. Br J Sports Med. 2013;47(6):342–350.
  • McBride JM, Kraemer WJ, Triplett-McBride T, et al. Effect of resistance exercise on free radical production. Med Sci Sports Exerc. 1998;30(1):67–72.
  • Tegeder L, Zimmermann J, Meller ST, et al. Release of algesic substances in human experimental muscle pain. Inflamm Res. 2002;51(8):393–402.
  • Murase S, Terazawa E, Queme F, et al. Bradykinin and nerve growth factor play pivotal roles in muscular mechanical hyperalgesia after exercise (delayed-onset muscle soreness). J Neurosci. 2010;30(10):3752–3761.
  • Taguchi T, Sato J, Mizumura K. Augmented mechanical response of muscle thin-fiber sensory receptors recorded from rat muscle-nerve preparations in vitro after eccentric contraction. J Neurophysiol. 2005;94(4):2822–2831.
  • Connolly DA, Sayers SP, McHugh MP. Treatment and prevention of delayed onset muscle soreness. J Strength Cond Res. 2003;17(1):197–208.
  • Close GL, Ashton T, McArdle A, et al. The emerging role of free radicals in delayed onset muscle soreness and contraction-induced muscle injury. Comp Biochem Physiol A Mol Integr Physiol. 2005;142(3):257–266.
  • Dos Santos RS, Veras FP, Ferreira DW, et al. Involvement of the Hsp70/TLR4/IL-6 and TNF-α pathways in delayed-onset muscle soreness. J Neurochem. 2020;155(1):29–44.
  • Pereira BC, Lucas G, da Rocha AL, et al. Eccentric exercise leads to glial activation but not apoptosis in mice spinal cords. Int J Sports Med. 2015;36(5):378–385.
  • Pinho-Ribeiro FA, Verri WA, Jr, Chiu IM. Nociceptor sensory neuron-immune interactions in pain and inflammation. Trends Immunol. 2017;38(1):5–19.
  • Schwane JA, Armstrong RB. Effect of training on skeletal muscle injury from downhill running in rats. J Appl Physiol Respir Environ Exerc Physiol. 1983;55(3):969–975.
  • Nikolaidis MG, Paschalis V, Giakas G, et al. Decreased blood oxidative stress after repeated muscle-damaging exercise. Med Sci Sports Exerc. 2007;39(7):1080–1089.
  • Newham DJ, Jones DA, Clarkson PM. Repeated high-force eccentric exercise: effects on muscle pain and damage. J Appl Physiol. 1987;63(4):1381–1386.
  • Gonzalez-Bartholin R, Mackay K, Valladares D, et al. Changes in oxidative stress, inflammation and muscle damage markers following eccentric versus concentric cycling in older adults. Eur J Appl Physiol. 2019;119(10):2301–2312.
  • Jackson MJ, O’Farrell S. Free radicals and muscle damage. Br Med Bull. 1993;49(3):630–641.
  • Gibbings S, Elkins ND, Fitzgerald H, et al. Xanthine oxidoreductase promotes the inflammatory state of mononuclear phagocytes through effects on chemokine expression, peroxisome proliferator-activated receptor-{gamma} sumoylation, and HIF-1{alpha}. J Biol Chem. 2011;286(2):961–975.
  • Anrather J, Racchumi G, Iadecola C. NF-kappaB regulates phagocytic NADPH oxidase by inducing the expression of gp91phox. J Biol Chem. 2006;281(9):5657–5667.
  • Hellsten Y, Frandsen U, Orthenblad N, et al. Xanthine oxidase in human skeletal muscle following eccentric exercise: a role in inflammation. J Physiol. 1997;498(1):239–48.
  • Ferreira LF, Laitano O. Regulation of NADPH oxidases in skeletal muscle. Free Radic Biol Med. 2016;98:18–28.
  • Tang Y, Long J, Liu J. Chapter 8 – hyperglycemia-associated oxidative stress induces autophagy: involvement of the ROS-ERK/JNK-p53 pathway. In: Hayat MA, editor. Autophagy: cancer, other pathologies, inflammation, immunity, infection and aging. Vol. 1, Molecular mechanisms. USA: Academic Press; 2014. p. 105–115.
  • Haslund-Vinding J, McBean G, Jaquet V, et al. NADPH oxidases in oxidant production by microglia: activating receptors, pharmacology and association with disease. Br J Pharmacol. 2017;174(12):1733–1749.
  • Ranchordas MK, Rogerson D, Soltani H, et al. Antioxidants for preventing and reducing muscle soreness after exercise. Cochrane Database Syst Rev. 2017;12:CD009789.
  • Kaminski M, Boal R. An effect of ascorbic acid on delayed-onset muscle soreness. Pain. 1992;50(3):317–321.
  • He F, Hockemeyer JA, Sedlock D. Does combined antioxidant vitamin supplementation blunt repeated bout effect? Int J Sports Med. 2015;36(05):407–413.
  • Connolly DA, Lauzon C, Agnew J, et al. The effects of vitamin C supplementation on symptoms of delayed onset muscle soreness. J Sports Med Phys Fitness. 2006;46(3):462–467.
  • de Oliveira DCX, Rosa FT, Simoes-Ambrosio L, et al. Antioxidant vitamin supplementation prevents oxidative stress but does not enhance performance in young football athletes. Nutrition. 2019;63–64:29–35.
  • Jamurtas AZ, Theocharis V, Tofas T, et al. Comparison between leg and arm eccentric exercises of the same relative intensity on indices of muscle damage. Eur J Appl Physiol. 2005;95(2–3):179–185.
  • Bentley DJ, Ackerman J, Clifford T, et al. Acute and chronic effects of antioxidant supplementation on exercise performance. In: Lamprecht M, editor. Antioxidants in sport nutrition. Boca Raton (FL): CRC Press/Taylor & Francis; 2015. p. 141–151.
  • Braakhuis AJ, Hopkins WG. Impact of dietary antioxidants on sport performance: a review. Sports Med. 2015;45(7):939–955.
  • Higgins MR, Izadi A, Kaviani M. Antioxidants and exercise performance: with a focus on vitamin E and C supplementation. IJERPH. 2020;17(22):8452.
  • Mason SA, Trewin AJ, Parker L, et al. Antioxidant supplements and endurance exercise: current evidence and mechanistic insights. Redox Biol. 2020;35:101471.
  • Powers SK, Duarte J, Kavazis AN, et al. Reactive oxygen species are signalling molecules for skeletal muscle adaptation. Exp Physiol. 2010;95(1):1–9.
  • Ferraz CR, Carvalho TT, Manchope MF, et al. Therapeutic potential of flavonoids in pain and inflammation: mechanisms of action, pre-clinical and clinical data, and pharmaceutical development. Molecules. 2020;25(3):762.
  • Bisht K, Wagner KH, Bulmer AC. Curcumin, resveratrol and flavonoids as anti-inflammatory, cyto- and DNA-protective dietary compounds. Toxicology. 2010;278(1):88–100.
  • Borghi SM, Pinho-Ribeiro FA, Fattori V, et al. Quercetin inhibits peripheral and spinal cord nociceptive mechanisms to reduce intense acute swimming-induced muscle pain in mice. PLOS One. 2016;11(9):e0162267.
  • Nicol LM, Rowlands DS, Fazakerly R, et al. Curcumin supplementation likely attenuates delayed onset muscle soreness (DOMS). Eur J Appl Physiol. 2015;115(8):1769–1777.
  • Hewlings SJ, Kalman DS. Curcumin: a review of its’ effects on human health. Foods. 2017;6(10):92.
  • Wassmann S, Stumpf M, Strehlow K, et al. Interleukin-6 induces oxidative stress and endothelial dysfunction by overexpression of the angiotensin II type 1 receptor. Circ Res. 2004;94(4):534–541.
  • Willoughby DS, McFarlin B, Bois C. Interleukin-6 expression after repeated bouts of eccentric exercise. Int J Sports Med. 2003;24(1):15–21.
  • Faria FR, Gomes AC, Antunes A, et al. Effects of turmeric extract supplementation on inflammation and muscle damage after a half-marathon race: a randomized, double-blind, placebo-controlled trial. Eur J Appl Physiol. 2020;120(7):1531–1540.
  • Drobnic F, Riera J, Appendino G, et al. Reduction of delayed onset muscle soreness by a novel curcumin delivery system (Meriva®): a randomised, placebo-controlled trial . J Int Soc Sports Nutr. 2014;11:31.
  • Amalraj A, Divya C, Gopi S. The effects of bioavailable curcumin (cureit) on delayed onset muscle soreness induced by eccentric continuous exercise: a randomized, placebo-controlled, double-blind clinical study. J Med Food. 2020;23(5):545–553.
  • de Sa Coutinho D, Pacheco MT, Frozza RL, et al. Anti-inflammatory effects of resveratrol: mechanistic insights. IJMS. 2018;19(6):1812
  • Gülçin I. Antioxidant properties of resveratrol: a structure–activity insight. Innovative Food Sci Emerg Technol. 2010;11(1):210–218.
  • Wang G, Hu Z, Song X, et al. Analgesic and anti-inflammatory activities of resveratrol through classic models in mice and rats. Evid Based Complement Alternat Med. 2017;2017:5197567.
  • Laupheimer MW, Perry M, Benton S, et al. Resveratrol exerts no effect on inflammatory response and delayed onset muscle soreness after a marathon in male athletes: a randomised, double-blind, placebo-controlled pilot feasibility study. Transl Med Unisa. 2014;10:38–42.
  • Ammar A, Turki M, Chtourou H, et al. Pomegranate supplementation accelerates recovery of muscle damage and soreness and inflammatory markers after a weightlifting training session. PLOS One. 2016;11(10):e0160305.
  • Cleary MA, Kimura IF, Sitler MR, et al. Temporal pattern of the repeated bout effect of eccentric exercise on delayed-onset muscle soreness. J Athl Train. 2002;37(1):32–36.
  • Proske U, Morgan DL. Muscle damage from eccentric exercise: mechanism, mechanical signs, adaptation and clinical applications. J Physiol. 2001;537(Pt 2):333–345.
  • Hosseinzadeh M, Andersen OK, Arendt-Nielsen L, et al. Pain sensitivity is normalized after a repeated bout of eccentric exercise. Eur J Appl Physiol. 2013;113(10):2595–2602.
  • Close GL, Ashton T, Cable T, et al. Eccentric exercise, isokinetic muscle torque and delayed onset muscle soreness: the role of reactive oxygen species. Eur J Appl Physiol. 2004;91(5–6):615–621.
  • Pahl HL. Activators and target genes of Rel/NF-kappaB transcription factors. Oncogene. 1999;18(49):6853–6866.
  • Hartung JE, Eskew O, Wong T, et al. Nuclear factor-kappa B regulates pain and COMT expression in a rodent model of inflammation. Brain Behav Immun. 2015;50:196–202.
  • Souza GR, Cunha TM, Silva RL, et al. Involvement of nuclear factor kappa B in the maintenance of persistent inflammatory hypernociception. Pharmacol Biochem Behav. 2015;134:49–56.
  • Vorobjeva N, Prikhodko A, Galkin I, et al. Mitochondrial reactive oxygen species are involved in chemoattractant-induced oxidative burst and degranulation of human neutrophils in vitro. Eur J Cell Biol. 2017;96(3):254–265.
  • Nunes-Silva A, Bernardes PT, Rezende BM, et al. Treadmill exercise induces neutrophil recruitment into muscle tissue in a reactive oxygen species-dependent manner. An intravital microscopy study. PLOS One. 2014;9(5):e96464.
  • Sen CK. Glutathione homeostasis in response to exercise training and nutritional supplements. Mol Cell Biochem. 1999;196(1–2):31–42.
  • Retamoso LT, Silveira MEJ, Lima FD, et al. Increased xanthine oxidase-related ROS production and TRPV1 synthesis preceding DOMS post-eccentric exercise in rats. Life Sci. 2016;152:52–59.
  • Miller BA, Zhang W. TRP channels as mediators of oxidative stress. Adv Exp Med Biol. 2011;704:531–544.
  • Ibi M, Matsuno K, Shiba D, et al. Reactive oxygen species derived from NOX1/NADPH oxidase enhance inflammatory pain. J Neurosci. 2008;28(38):9486–9494.
  • Ndengele MM, Cuzzocrea S, Esposito E, et al. Cyclooxygenases 1 and 2 contribute to peroxynitrite-mediated inflammatory pain hypersensitivity. FASEB J. 2008;22(9):3154–3164.
  • Westlund KN, Kochukov MY, Lu Y, et al. Impact of central and peripheral TRPV1 and ROS levels on proinflammatory mediators and nociceptive behavior. Mol Pain. 2010;6:46.
  • Jafri MS. Mechanisms of myofascial pain. Int Sch Res Notices. 2014;2014:1–16.
  • Sugiyama D, Kang S, Arpey N, et al. Hydrogen peroxide induces muscle nociception via transient receptor potential ankyrin 1 receptors. Anesthesiology. 2017;127(4):695–708.
  • Sugiyama D, Kang S, Brennan TJ. Muscle reactive oxygen species (ROS) contribute to post-incisional guarding via the TRPA1 receptor. PLOS One. 2017;12(1):e0170410.
  • Landmark T, Romundstad P, Borchgrevink PC, et al. Associations between recreational exercise and chronic pain in the general population: evidence from the HUNT 3 study. Pain. 2011;152(10):2241–2247.
  • Landmark T, Romundstad PR, Borchgrevink PC, et al. Longitudinal associations between exercise and pain in the general population – the HUNT pain study. PLOS One. 2013;8(6):e65279.
  • Sluka KA, O’Donnell JM, Danielson J, et al. Regular physical activity prevents development of chronic pain and activation of central neurons. J Appl Physiol. 2013;114(6):725–733.
  • Webb R, Hughes MG, Thomas AW, et al. The ability of exercise-associated oxidative stress to trigger redox-sensitive signalling responses. Antioxidants. 2017;6(3):63.
  • de Azambuja G, Botasso Gomes B, Messias LHD, et al. Swimming physical training prevented the onset of acute muscle pain by a mechanism dependent of PPARγ receptors and CINC-1. Neuroscience. 2020;427:64–74.
  • Pitcher MH, Tarum F, Rauf IZ, et al. Modest amounts of voluntary exercise reduce pain- and stress-related outcomes in a rat model of persistent hind limb inflammation. J Pain. 2017;18(6):687–701.
  • Galdino G, Romero T, Silva JF, et al. Acute resistance exercise induces antinociception by activation of the endocannabinoid system in rats. Anesth Analg. 2014;119(3):702–715.
  • Galdino GS, Duarte ID, Perez AC. Participation of endogenous opioids in the antinociception induced by resistance exercise in rats. Braz J Med Biol Res. 2010;43(9):906–909.
  • Polaski AM, Phelps AL, Kostek MC, et al. Exercise-induced hypoalgesia: a meta-analysis of exercise dosing for the treatment of chronic pain. PLOS One. 2019;14(1):e0210418.
  • Barker AL, Talevski J, Morello RT, et al. Effectiveness of aquatic exercise for musculoskeletal conditions: a meta-analysis. Arch Phys Med Rehabil. 2014;95(9):1776–1786.
  • Saeterbakken AH, Makrygiannis P, Stien N, et al. Dose-response of resistance training for neck-and shoulder pain relief: a workplace intervention study. BMC Sports Sci Med Rehabil. 2020;12(1):8.
  • Koltyn KF, Arbogast RW. Perception of pain after resistance exercise. Br J Sports Med. 1998;32(1):20–24.
  • Burrows NJ, Booth J, Sturnieks DL, et al. Acute resistance exercise and pressure pain sensitivity in knee osteoarthritis: a randomised crossover trial. Osteoarthritis Cartilage. 2014;22(3):407–414.
  • Sluka KA, Frey-Law L, Hoeger Bement M. Exercise-induced pain and analgesia? Underlying mechanisms and clinical translation. Pain. 2018;159(Suppl 1):S91–S97.
  • De Martino E, Zandalasini M, Schabrun S, et al. Experimental muscle hyperalgesia modulates sensorimotor cortical excitability, which is partially altered by unaccustomed exercise. Pain. 2018;159(12):2493–2502.
  • Da Silva Santos R, Galdino G. Endogenous systems involved in exercise-induced analgesia. J Physiol Pharmacol. 2018;69(1):3–13.
  • Almeida C, DeMaman A, Kusuda R, et al. Exercise therapy normalizes BDNF upregulation and glial hyperactivity in a mouse model of neuropathic pain. Pain. 2015;156(3):504–513.
  • de Lemos ET, Oliveira J, Pinheiro JP, et al. Regular physical exercise as a strategy to improve antioxidant and anti-inflammatory status: benefits in type 2 diabetes mellitus. Oxid Med Cell Longev. 2012;2012:741545.
  • Mi C, Qin X, Hou Z, et al. Moderate-intensity exercise allows enhanced protection against oxidative stress-induced cardiac dysfunction in spontaneously hypertensive rats. Braz J Med Biol Res. 2019;52(6):e8009.
  • Vezzoli A, Mrakic-Sposta S, Montorsi M, et al. Moderate intensity resistive training reduces oxidative stress and improves muscle mass and function in older individuals. Antioxidants. 2019;8(10):431.
  • Shen J, Fox LE, Cheng J. Swim therapy reduces mechanical allodynia and thermal hyperalgesia induced by chronic constriction nerve injury in rats. Pain Med. 2013;14(4):516–525.
  • Huang PC, Tsai KL, Chen YW, et al. Exercise combined with ultrasound attenuates neuropathic pain in rats associated with downregulation of IL-6 and TNF-α, but with upregulation of IL-10. Anesth Analg. 2017;124(6):2038–2044.
  • Kojda G, Hambrecht R. Molecular mechanisms of vascular adaptations to exercise. Physical activity as an effective antioxidant therapy? Cardiovasc Res. 2005;67(2):187–197.
  • Borghi SM, Zarpelon AC, Pinho-Ribeiro FA, et al. Targeting interleukin-1β reduces intense acute swimming-induced muscle mechanical hyperalgesia in mice . J Pharm Pharmacol. 2014;66(7):1009–1020.
  • Becker CU, Sartorio CL, Campos-Carraro C, et al. Exercise training decreases oxidative stress in skeletal muscle of rats with pulmonary arterial hypertension. Arch Physiol Biochem. 2020;1–9.
  • McDonnell E, Peterson BS, Bomze HM, et al. SIRT3 regulates progression and development of diseases of aging. Trends Endocrinol Metab. 2015;26(9):486–492.
  • Ozden O, Park SH, Wagner BA, et al. SIRT3 deacetylates and increases pyruvate dehydrogenase activity in cancer cells. Free Radic Biol Med. 2014;76:163–172.
  • Paungmali A, Joseph LH, Punturee K, et al. Immediate effects of core stabilization exercise on beta-endorphin and cortisol levels among patients with chronic nonspecific low back pain: a randomized crossover design. J Manipulative Physiol Ther. 2018;41(3):181–188.
  • Winnik S, Gaul DS, Siciliani G, et al. Mild endothelial dysfunction in Sirt3 knockout mice fed a high-cholesterol diet: protective role of a novel C/EBP-β-dependent feedback regulation of SOD2. Basic Res Cardiol. 2016;111(3):33.
  • Tao R, Vassilopoulos A, Parisiadou L, et al. Regulation of MnSOD enzymatic activity by Sirt3 connects the mitochondrial acetylome signaling networks to aging and carcinogenesis. Antioxid Redox Signal. 2014;20(10):1646–1654.
  • Singh CK, Chhabra G, Ndiaye MA, et al. The role of sirtuins in antioxidant and redox signaling. Antioxid Redox Signal. 2018;28(8):643–661.
  • Tsukiyama Y, Ito T, Nagaoka K, et al. Effects of exercise training on nitric oxide, blood pressure and antioxidant enzymes. J Clin Biochem Nutr. 2017;60(3):180–186.
  • Handschin C, Spiegelman BM. The role of exercise and PGC1alpha in inflammation and chronic disease. Nature. 2008;454(7203):463–469.
  • Niess AM, Hartmann A, Grunert-Fuchs M, et al. DNA damage after exhaustive treadmill running in trained and untrained men. Int J Sports Med. 1996;17(6):397–403.
  • Elokda AS, Nielsen DH. Effects of exercise training on the glutathione antioxidant system. Eur J Cardiovasc Prev Rehabil. 2007;14(5):630–637.
  • Miyazaki H, Oh-Ishi S, Ookawara T, et al. Strenuous endurance training in humans reduces oxidative stress following exhausting exercise. Eur J Appl Physiol. 2001;84(1–2):1–6.
  • Adams V, Linke A, Krankel N, et al. Impact of regular physical activity on the NAD(P)H oxidase and angiotensin receptor system in patients with coronary artery disease. Circulation. 2005;111(5):555–562.
  • Lanza IR, Short DK, Short KR, et al. Endurance exercise as a countermeasure for aging. Diabetes. 2008;57(11):2933–2942.
  • Ristow M, Zarse K, Oberbach A, et al. Antioxidants prevent health-promoting effects of physical exercise in humans. Proc Natl Acad Sci U S A. 2009;106(21):8665–8670.
  • Brandauer J, Andersen MA, Kellezi H, et al. AMP-activated protein kinase controls exercise training- and AICAR-induced increases in SIRT3 and MnSOD. Front Physiol. 2015;6:85.
  • Ilari S, Giancotti LA, Lauro F, et al. Antioxidant modulation of sirtuin 3 during acute inflammatory pain: the ROS control. Pharmacol Res. 2020;157:104851.
  • Kiguchi N, Kobayashi Y, Saika F, et al. Peripheral interleukin-4 ameliorates inflammatory macrophage-dependent neuropathic pain. Pain. 2015;156(4):684–693.
  • Chhaya SJ, Quiros-Molina D, Tamashiro-Orrego AD, et al. Exercise-induced changes to the macrophage response in the dorsal root ganglia prevent neuropathic pain after spinal cord injury. J Neurotrauma. 2019;36(6):877–890.
  • Leung A, Gregory NS, Allen LA, et al. Regular physical activity prevents chronic pain by altering resident muscle macrophage phenotype and increasing interleukin-10 in mice. Pain. 2016;157(1):70–79.
  • Pannell M, Labuz D, Celik MO, et al. Adoptive transfer of M2 macrophages reduces neuropathic pain via opioid peptides. J Neuroinflammation. 2016;13(1):262.
  • Pearce EL, Pearce EJ. Metabolic pathways in immune cell activation and quiescence. Immunity. 2013;38(4):633–643.
  • Tan HY, Wang N, Li S, et al. The reactive oxygen species in macrophage polarization: reflecting its dual role in progression and treatment of human diseases. Oxid Med Cell Longev. 2016;2016:2795090.
  • Muxel SM, Pires-Lapa MA, Monteiro AW, et al. NF-κB drives the synthesis of melatonin in RAW 264.7 macrophages by inducing the transcription of the arylalkylamine-N-acetyltransferase (AA-NAT) gene. PLOS One. 2012;7(12):e52010.
  • Jablonski K, Young NA, Henry C, et al. Physical activity prevents acute inflammation in a gout model by downregulation of TLR2 on circulating neutrophils as well as inhibition of serum CXCL1 and is associated with decreased pain and inflammation in gout patients. PLOS One. 2020;15(10):e0237520.
  • Murata Y, Shimamura T, Hamuro J. The polarization of T(h)1/T(h)2 balance is dependent on the intracellular thiol redox status of macrophages due to the distinctive cytokine production. Int Immunol. 2002;14(2):201–212.
  • Alvarez P, Bogen O, Green PG, et al. Nociceptor interleukin 10 receptor 1 is critical for muscle analgesia induced by repeated bouts of eccentric exercise in the rat. Pain. 2017;158(8):1481–1488.
  • Uceyler N, Valenza R, Stock M, et al. Reduced levels of antiinflammatory cytokines in patients with chronic widespread pain. Arthritis Rheum. 2006;54(8):2656–2664.
  • Poole S, Cunha FQ, Selkirk S, et al. Cytokine-mediated inflammatory hyperalgesia limited by interleukin-10. Br J Pharmacol. 1995;115(4):684–688.
  • Borghi SM, Pinho-Ribeiro FA, Zarpelon AC, et al. Interleukin-10 limits intense acute swimming-induced muscle mechanical hyperalgesia in mice. Exp Physiol. 2015;100(5):531–544.
  • Kawanishi N, Yano H, Yokogawa Y, et al. Exercise training inhibits inflammation in adipose tissue via both suppression of macrophage infiltration and acceleration of phenotypic switching from M1 to M2 macrophages in high-fat-diet-induced obese mice. Exerc Immunol Rev. 2010;16:105–118.
  • Dorneles GP, Haddad DO, Fagundes VO, et al. High intensity interval exercise decreases IL-8 and enhances the immunomodulatory cytokine interleukin-10 in lean and overweight-obese individuals. Cytokine. 2016;77:1–9.
  • Cabral-Santos C, de Lima Junior EA, Fernandes I, et al. Interleukin-10 responses from acute exercise in healthy subjects: a systematic review. J Cell Physiol. 2019;234(7):9956–9965.
  • Batista ML, Jr, Rosa JC, Lopes RD, et al. Exercise training changes IL-10/TNF-alpha ratio in the skeletal muscle of post-MI rats. Cytokine. 2010;49(1):102–108.
  • Calegari L, Nunes RB, Mozzaquattro BB, et al. Exercise training improves the IL-10/TNF-α cytokine balance in the gastrocnemius of rats with heart failure . Braz J Phys Ther. 2018;22(2):154–160.
  • Walton RG, Kosmac K, Mula J, et al. Human skeletal muscle macrophages increase following cycle training and are associated with adaptations that may facilitate growth. Sci Rep. 2019;9(1):969.
  • Ziemann E, Zembron-Lacny A, Kasperska A, et al. Exercise training-induced changes in inflammatory mediators and heat shock proteins in young tennis players. J Sports Sci Med. 2013;12(2):282–289.
  • Soltani N, Marandi SM, Kazemi M, et al. The exercise training modulatory effects on the obesity-induced immunometabolic dysfunctions. Diabetes Metab Syndr Obes. 2020;13:785–810.
  • Naito Y, Takagi T, Higashimura Y. Heme oxygenase-1 and anti-inflammatory M2 macrophages. Arch Biochem Biophys. 2014;564:83–88.
  • Done AJ, Traustadottir T. Nrf2 mediates redox adaptations to exercise. Redox Biol. 2016;10:191–199.
  • Merry TL, Ristow M. Nuclear factor erythroid-derived 2-like 2 (NFE2L2, Nrf2) mediates exercise-induced mitochondrial biogenesis and the anti-oxidant response in mice. J Physiol. 2016;594(18):5195–5207.
  • Wang P, Li CG, Qi Z, et al. Acute exercise stress promotes Ref1/Nrf2 signalling and increases mitochondrial antioxidant activity in skeletal muscle. Exp Physiol. 2016;101(3):410–420.
  • Staurengo-Ferrari L, Badaro-Garcia S, Hohmann MSN, et al. Contribution of Nrf2 modulation to the mechanism of action of analgesic and anti-inflammatory drugs in pre-clinical and clinical stages. Front Pharmacol. 2018;9:1536.
  • Riego G, Redondo A, Leanez S, et al. Mechanism implicated in the anti-allodynic and anti-hyperalgesic effects induced by the activation of heme oxygenase 1/carbon monoxide signaling pathway in the central nervous system of mice with neuropathic pain. Biochem Pharmacol. 2018;148:52–63.
  • Carcole M, Castany S, Leanez S, et al. Treatment with a heme oxygenase 1 inducer enhances the antinociceptive effects of µ-opioid, δ-opioid, and cannabinoid 2 receptors during inflammatory pain. J Pharmacol Exp Ther. 2014;351(1):224–232.
  • Bussmann AJC, Borghi SM, Zaninelli TH, et al. The citrus flavanone naringenin attenuates zymosan-induced mouse joint inflammation: induction of Nrf2 expression in recruited CD45+ hematopoietic cells. Inflammopharmacology. 2019;27(6):1229–1242.
  • Ren C, Qi J, Li W, et al. The effect of moderate-intensity exercise on the expression of HO-1 mRNA and activity of HO in cardiac and vascular smooth muscle of spontaneously hypertensive rats. Can J Physiol Pharmacol. 2016;94(4):448–454.
  • Sun MW, Zhong MF, Gu J, et al. Effects of different levels of exercise volume on endothelium-dependent vasodilation: roles of nitric oxide synthase and heme oxygenase. Hypertens Res. 2008;31(4):805–816.
  • Kurucz A, Bombicz M, Kiss R, et al. Heme oxygenase-1 activity as a correlate to exercise-mediated amelioration of cognitive decline and neuropathological alterations in an aging rat model of dementia. Biomed Res Int. 2018;2018:7212861.
  • Done AJ, Gage MJ, Nieto NC, et al. Exercise-induced Nrf2-signaling is impaired in aging. Free Radic Biol Med. 2016;96:130–138.
  • Ricchetti GA, Williams LM, Foxwell BM. Heme oxygenase 1 expression induced by IL-10 requires STAT-3 and phosphoinositol-3 kinase and is inhibited by lipopolysaccharide. J Leukoc Biol. 2004;76(3):719–726.
  • Niess AM, Passek F, Lorenz I, et al. Expression of the antioxidant stress protein heme oxygenase-1 (HO-1) in human leukocytes. Free Radic Biol Med. 1999;26(1–2):184–192.
  • Durante W. Targeting heme oxygenase-1 in vascular disease. Curr Drug Targets. 2010;11(12):1504–1516.
  • Kruger K, Mooren FC, Pilat C. The immunomodulatory effects of physical activity. Curr Pharm Des. 2016;22(24):3730–3748.
  • Thyfault JP, Bergouignan A. Exercise and metabolic health: beyond skeletal muscle. Diabetologia. 2020;63(8):1464–1474.
  • Ciolac EG, Rodrigues da Silva JM, Vieira RP. Physical exercise as an immunomodulator of chronic diseases in aging. J Phys Act Health. 2020;17(6):662–672.
  • Henriksen M, Klokker L, Graven-Nielsen T, et al. Association of exercise therapy and reduction of pain sensitivity in patients with knee osteoarthritis: a randomized controlled trial. Arthritis Care Res. 2014;66(12):1836–1843.
  • Vaegter HB, Handberg G, Emmeluth C, et al. Preoperative hypoalgesia after cold pressor test and aerobic exercise is associated with pain relief 6 months after total knee replacement. Clin J Pain. 2017;33(6):475–484.
  • Lemley KJ, Hunter SK, Bement MK. Conditioned pain modulation predicts exercise-induced hypoalgesia in healthy adults. Med Sci Sports Exerc. 2015;47(1):176–184.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.