Physical activity and the endocannabinoid system: an overview

Abstract

Recognized as a “disease modifier”, physical activity (PA) is increasingly viewed as a more holistic, cost-saving method for prevention, treatment and management of human disease conditions. The traditional view that PA engages the monoaminergic and endorphinergic systems has been challenged by the discovery of the endocannabinoid system (ECS), composed of endogenous lipids, their target receptors, and metabolic enzymes. Indeed, direct and indirect evidence suggests that the ECS might mediate some of the PA-triggered effects throughout the body. Moreover, it is now emerging that PA itself is able to modulate ECS in different ways. Against this background, in the present review we shall discuss evidence of the cross-talk between PA and the ECS, ranging from brain to peripheral districts and highlighting how ECS must be tightly regulated during PA, in order to maintain its beneficial effects on cognition, mood, and nociception, while avoiding impaired energy metabolism, oxidative stress, and inflammatory processes.

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References

  1. 1.

    Howley ET (2001) Type of activity: resistance, aerobic and leisure versus occupational PA. Med Sci Sports Exerc 33:S364–S369 (discussion S419–420)

    CAS  PubMed  Google Scholar 

  2. 2.

    Romijn JA et al (1993) Regulation of endogenous fat and carbohydrate metabolism in relation to exercise intensity and duration. Am J Physiol 265:E380–E391

    CAS  PubMed  Google Scholar 

  3. 3.

    Yau SY et al (2012) Effects of voluntary running on plasma levels of neurotrophins, hippocampal cell proliferation and learning and memory in stressed rats. Neuroscience 222:289–301

    CAS  PubMed  Google Scholar 

  4. 4.

    Knab AM, Lightfoot JT (2010) Does the difference between physically active and couch potato lie in the dopamine system? Int J Biol Sci 6:133–150

    CAS  PubMed Central  PubMed  Google Scholar 

  5. 5.

    Nijs J et al (2012) Dysfunctional endogenous analgesia during exercise in patients with chronic pain: to exercise or not to exercise? Pain Physician 151:ES205–213

    Google Scholar 

  6. 6.

    Gleeson M, Walsh NP (2012) British Association of Sport and Exercise Sciences. The BASES expert statement on exercise, immunity, and infection. J Sports Sci 30:321–324

    PubMed  Google Scholar 

  7. 7.

    Pedersen L, Hojman P (2012) Muscle-to-organ cross talk mediated by myokines. Adipocyte 1:164–167

    PubMed Central  PubMed  Google Scholar 

  8. 8.

    Voss MW et al (2011) Exercise, brain, and cognition across the life span. J Appl Physiol 111:1505–1513

    PubMed Central  PubMed  Google Scholar 

  9. 9.

    Mora S et al (2007) Physical activity and reduced risk of cardiovascular events: potential mediating mechanisms. Circulation 116:2110–2118

    CAS  PubMed Central  PubMed  Google Scholar 

  10. 10.

    Alexanderson H, Lundberg IE (2012) Exercise as a therapeutic modality in patients with idiopathic inflammatory myopathies. Curr Opin Rheumatol 24:201–207

    PubMed  Google Scholar 

  11. 11.

    Church T (2011) Exercise in obesity, metabolic syndrome, and diabetes. Prog Cardiovasc Dis 53:412–418

    PubMed  Google Scholar 

  12. 12.

    Proske U, Morgan DL (2001) Muscle damage from eccentric exercise: mechanism, mechanical signs, adaptation and clinical applications. J Physiol 537:333–345

    CAS  PubMed Central  PubMed  Google Scholar 

  13. 13.

    Zaldivar F et al (2006) Constitutive pro- and anti-inflammatory cytokine and growth factor response to exercise in leukocytes. J Appl Physiol 100:1124–1133

    CAS  PubMed  Google Scholar 

  14. 14.

    Carek PJ et al (2011) Exercise for the treatment of depression and anxiety. Int J Psychiatry Med 41:15–28

    PubMed  Google Scholar 

  15. 15.

    Waters RP et al (2013) Selection for increased voluntary wheel-running affects behavior and brain monoamines in mice. Brain Res 1508:9–22

    CAS  PubMed Central  PubMed  Google Scholar 

  16. 16.

    Milman S et al (2012) Opioid receptor blockade prevents exercise-associated autonomic failure in humans. Diabetes 61:1609–1615

    CAS  PubMed Central  PubMed  Google Scholar 

  17. 17.

    Howlett AC et al (2010) CB(1) cannabinoid receptors and their associated proteins. Curr Med Chem 17:1382–1393

    CAS  PubMed Central  PubMed  Google Scholar 

  18. 18.

    Pertwee RG et al (2010) International union of basic and clinical pharmacology. LXXIX. Cannabinoid receptors and their ligands: beyond CB1 and CB2. Pharmacol Rev 62:588–631

    CAS  PubMed Central  PubMed  Google Scholar 

  19. 19.

    Devane WA et al (1992) Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 258:1946–1949

    CAS  PubMed  Google Scholar 

  20. 20.

    Sugiura T et al (1995) 2-Arachidonoylglycerol: a possible endogenous cannabinoid receptor ligand in brain. Biochem Biophys Res Commun 215:89–97

    CAS  PubMed  Google Scholar 

  21. 21.

    Mechoulam R et al (1995) Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochem Pharmacol 50:83–90

    CAS  PubMed  Google Scholar 

  22. 22.

    De Petrocellis L, Di Marzo V (2009) An introduction to the endocannabinoid system: from the early to the latest concepts. Best Pract Res Clin Endocrinol Metab 23:1–15

    PubMed  Google Scholar 

  23. 23.

    Hanus et al (2001) 2-arachidonyl glyceryl ether, an endogenous agonist of the cannabinoid CB1 receptor. Proc Natl Acad Sci USA 98:3662–3665

    CAS  PubMed Central  PubMed  Google Scholar 

  24. 24.

    Porter AC et al (2002) Characterization of a novel endocannabinoid, virodhamine, with antagonist activity at the CB1 receptor. J Pharmacol Exp Ther 301:1020–1024

    CAS  PubMed  Google Scholar 

  25. 25.

    Huang SM et al (2002) An endogenous capsaicin-like substance with high potency at recombinant and native vanilloid VR1 receptors. Proc Natl Acad Sci USA 99:8400–8405

    CAS  PubMed Central  PubMed  Google Scholar 

  26. 26.

    Brown I et al (2010) Cannabinoid receptor-dependent and -independent anti-proliferative effects of omega-3 ethanolamides in androgen receptor-positive and -negative prostate cancer cell lines. Carcinogenesis 31:1584–1591

    CAS  PubMed Central  PubMed  Google Scholar 

  27. 27.

    Rovito D et al (2013) Omega-3 PUFA ethanolamides DHEA and EPEA induce autophagy through PPARγ activation in MCF-7 breast cancer cells. J Cell Physiol 228:1314–1322

    CAS  PubMed  Google Scholar 

  28. 28.

    Klein TW et al (2003) The cannabinoid system and immune modulation. J Leukoc Biol 74:486–496

    CAS  PubMed  Google Scholar 

  29. 29.

    Patel KD et al (2010) Cannabinoid CB(2) receptors in health and disease. Curr Med Chem 17:1393–1410

    PubMed  Google Scholar 

  30. 30.

    Viscomi MT et al (2009) Selective CB2 receptor agonism protects central neurons from remote axotomy-induced apoptosis through the PI3K/Akt pathway. J Neurosci 29:4564–4570

    CAS  PubMed  Google Scholar 

  31. 31.

    Ross RA (2009) The enigmatic pharmacology of GPR55. Trends Pharmacol Sci 30:156–163

    CAS  PubMed  Google Scholar 

  32. 32.

    Gasperi V et al (2013) GPR55 and its interaction with membrane lipids: comparison with other endocannabinoid-binding receptors. Curr Med Chem 20:64–78

    CAS  PubMed  Google Scholar 

  33. 33.

    Di Marzo V, De Petrocellis L (2010) Endocannabinoids as regulators of transient receptor potential (TRP) channels: a further opportunity to develop new endocannabinoid-based therapeutic drugs. Curr Med Chem 17:1430–1449

    PubMed  Google Scholar 

  34. 34.

    Greco R et al (2010) The endocannabinoid system and migraine. Exp Neurol 224:85–91

    CAS  PubMed  Google Scholar 

  35. 35.

    Maccarrone M et al (2000) Anandamide induces apoptosis in human cells via vanilloid receptors. Evidence for a protective role of cannabinoid receptors. J Biol Chem 275:31938–31945

    CAS  PubMed  Google Scholar 

  36. 36.

    Stock K et al (2012) Neural precursor cells induce cell death of high-grade astrocytomas through stimulation of TRPV1. Nat Med 18:1232–1238

    CAS  PubMed  Google Scholar 

  37. 37.

    Bouaboula M et al (2005) Anandamide induced PPARgamma transcriptional activation and 3T3-L1 preadipocyte differentiation. Eur J Pharmacol 517:174–181

    CAS  PubMed  Google Scholar 

  38. 38.

    Gasperi V et al (2007) Endocannabinoids in adipocytes during differentiation and their role in glucose uptake. Cell Mol Life Sci 64:219–229

    CAS  PubMed  Google Scholar 

  39. 39.

    Rockwell CE et al (2006) Interleukin-2 suppression by 2-arachidonyl glycerol is mediated through peroxisome proliferator-activated receptor gamma independently of cannabinoid receptors 1 and 2. Mol Pharmacol 70:101–111

    CAS  PubMed  Google Scholar 

  40. 40.

    Okamoto Y et al (2004) Molecular characterization of a phospholipase D generating anandamide and its congeners. J Biol Chem 279:5298–5305

    CAS  PubMed  Google Scholar 

  41. 41.

    Ueda N et al (2013) Metabolism of endocannabinoids and related N-acylethanolamines: canonical and alternative pathways. FEBS J 280:1874–1894

    CAS  PubMed  Google Scholar 

  42. 42.

    Gasperi V et al (2014) The fatty acid amide hydrolase in lymphocytes from sedentary and active subjects. Med Sci Sports Exerc 46:24–32

    CAS  PubMed  Google Scholar 

  43. 43.

    Giuffrida A et al (1999) Dopamine activation of endogenous cannabinoid signaling in dorsal striatum. Nat Neurosci 2:358–363

    CAS  PubMed  Google Scholar 

  44. 44.

    Malcher-Lopes R et al (2006) Opposing crosstalk between leptin and glucocorticoids rapidly modulates synaptic excitation via endocannabinoid release. J Neurosci 26:6643–6650

    CAS  PubMed  Google Scholar 

  45. 45.

    Silvestri C, Di Marzo V (2013) The endocannabinoid system in energy homeostasis and the etiopathology of metabolic disorders. Cell Metab 17:475–490

    CAS  PubMed  Google Scholar 

  46. 46.

    Maccarrone M et al (2001) Lipopolysaccharide downregulates fatty acid amide hydrolase expression and increases anandamide levels in human peripheral lymphocytes. Arch Biochem Biophys 393:321–328

    CAS  PubMed  Google Scholar 

  47. 47.

    Liu J et al (2003) Lipopolysaccharide induces anandamide synthesis in macrophages via CD14/MAPK/phosphoinositide 3-kinase/NF-kappaB independently of platelet-activating factor. J Biol Chem 278:45034–45039

    CAS  PubMed  Google Scholar 

  48. 48.

    Maccarrone M et al (2010) Intracellular trafficking of anandamide: new concepts for signaling. Trends Biochem Sci 35:601–608

    CAS  PubMed  Google Scholar 

  49. 49.

    Liu J et al (2006) A biosynthetic pathway for anandamide. Proc Natl Acad Sci USA 103:13345–13350

    CAS  PubMed Central  PubMed  Google Scholar 

  50. 50.

    Simon GM, Cravatt BF (2010) Characterization of mice lacking candidate N-acyl ethanolamine biosynthetic enzymes provides evidence for multiple pathways that contribute to endocannabinoid production in vivo. Mol BioSyst 6(8):1411–1418

    CAS  PubMed Central  PubMed  Google Scholar 

  51. 51.

    Chicca A et al (2012) Evidence for bidirectional endocannabinoid transport across cell membranes. J Biol Chem 287:34660–34682

    CAS  PubMed Central  PubMed  Google Scholar 

  52. 52.

    Fowler CJ (2012) Anandamide uptake explained? Trends Pharmacol Sci 33:181–185

    CAS  PubMed  Google Scholar 

  53. 53.

    Oddi S et al (2008) Evidence for the intracellular accumulation of anandamide in adiposomes. Cell Mol Life Sci 65:840–850

    CAS  PubMed  Google Scholar 

  54. 54.

    McKinney MK, Cravatt BF (2005) Structure and function of fatty acid amide hydrolase. Annu Rev Biochem 74:411–432

    CAS  PubMed  Google Scholar 

  55. 55.

    Fezza F et al (2008) Fatty acid amide hydrolase: a gate-keeper of the endocannabinoid system. Subcell Biochem 49:101–132

    PubMed  Google Scholar 

  56. 56.

    Wei BQ et al (2006) A second fatty acid amide hydrolase with variable distribution among placental mammals. J Biol Chem 281:36569–36578

    CAS  PubMed  Google Scholar 

  57. 57.

    Bisogno T et al (2003) Cloning of the first sn1-DAG lipases points to the spatial and temporal regulation of endocannabinoid signaling in the brain. J Cell Biol 163:463–468

    CAS  PubMed Central  PubMed  Google Scholar 

  58. 58.

    Dinh TP et al (2002) Brain monoglyceride lipase participating in endocannabinoid inactivation. Proc Natl Acad Sci USA 99:10819–10824

    CAS  PubMed Central  PubMed  Google Scholar 

  59. 59.

    Blankman JL et al (2007) A comprehensive profile of brain enzymes that hydrolyze the endocannabinoid 2-arachidonoylglycerol. Chem Biol 14:1347–1356

    CAS  PubMed Central  PubMed  Google Scholar 

  60. 60.

    Marrs WR et al (2010) The serine hydrolase ABHD6 controls the accumulation and efficacy of 2-AG at cannabinoid receptors. Nat Neurosci 13:951–957

    CAS  PubMed Central  PubMed  Google Scholar 

  61. 61.

    Valdeolivas S et al (2013) The inhibition of 2-arachidonoyl-glycerol (2-AG) biosynthesis, rather than enhancing striatal damage, protects striatal neurons from malonate-induced death: a potential role of cyclooxygenase-2-dependent metabolism of 2-AG. Cell Death Dis 4:e862

    CAS  PubMed Central  PubMed  Google Scholar 

  62. 62.

    Nomura DK (2011) Endocannabinoid hydrolysis generates brain prostaglandins that promote neuroinflammation. Science 334(6057):809–813

    CAS  PubMed Central  PubMed  Google Scholar 

  63. 63.

    Sparling PB, Dietrich A et al (2003) Exercise activates the endocannabinoid system. Neuroreport 14:2209–2211

    CAS  PubMed  Google Scholar 

  64. 64.

    Feuerecker M et al (2012) Effects of exercise stress on the endocannabinoid system in humans under field conditions. Eur J Appl Physiol 112:2777–2781

    CAS  PubMed  Google Scholar 

  65. 65.

    Heyman E et al (2012) Intense exercise increases circulating endocannabinoid and BDNF levels in humans—possible implications for reward and depression. Psychoneuroendocrinology 37:844–851

    CAS  PubMed  Google Scholar 

  66. 66.

    Raichlen DA et al (2012) Wired to run: exercise-induced endocannabinoid signaling in humans and cursorial mammals with implications for the ‘runner’s high’. J Exp Biol 215:1331–1336

    CAS  PubMed  Google Scholar 

  67. 67.

    Raichlen DA et al (2012) Exercise-induced endocannabinoid signaling is modulated by intensity. Eur J Appl Physiol 113:869–875

    PubMed  Google Scholar 

  68. 68.

    Di Marzo V et al (2009) Changes in plasma endocannabinoid levels in viscerally obese men following a 1 year lifestyle modification programme and waist circumference reduction: associations with changes in metabolic risk factors. Diabetologia 52:213–217

    CAS  PubMed  Google Scholar 

  69. 69.

    You T et al (2011) Adipose tissue endocannabinoid system gene expression: depot differences and effects of diet and exercise. Lipids Health Dis 10:194

    CAS  PubMed Central  PubMed  Google Scholar 

  70. 70.

    Hill MN et al (2010) Endogenous cannabinoid signaling is required for voluntary exercise-induced enhancement of progenitor cell proliferation in the hippocampus. Hippocampus 20:513–523

    CAS  PubMed Central  PubMed  Google Scholar 

  71. 71.

    Galdino G et al (2013) The endocannabinoid system mediates aerobic exercise-induced antinociception in rats. Neuropharmacology 77C:313–324

    Google Scholar 

  72. 72.

    De Chiara V et al (2010) Voluntary exercise and sucrose consumption enhance cannabinoid CB1 receptor sensitivity in the striatum. Neuropsychopharmacology 35:374–387

    PubMed Central  PubMed  Google Scholar 

  73. 73.

    Gomes da Silva S et al (2010) Physical exercise in adolescence changes CB1 cannabinoid receptor expression in the rat brain. Neurochem Int 57:492–496

    CAS  PubMed  Google Scholar 

  74. 74.

    Yan ZC et al (2007) Exercise reduces adipose tissue via cannabinoid receptor type 1 which is regulated by peroxisome proliferator-activated receptor-delta. Biochem Biophys Res Commun 354:427–433

    CAS  PubMed  Google Scholar 

  75. 75.

    Middleton FA, Strick PL (2000) Basal ganglia and cerebellar loops: motor and cognitive circuits. Brain Res Brain Res Rev 31:236–250

    CAS  PubMed  Google Scholar 

  76. 76.

    Ade KK, Lovinger DM (2007) Anandamide regulates postnatal development of long-term synaptic plasticity in the rat dorsolateral striatum. J Neurosci 27:2403–2439

    CAS  PubMed  Google Scholar 

  77. 77.

    Su LD et al (2013) Retrograde cPLA(2)α/arachidonic acid/2-AG signaling is essential for cerebellar depolarization-induced suppression of excitation and long-term potentiation. Cerebellum 12:297–299

    CAS  PubMed  Google Scholar 

  78. 78.

    Kyriakatos A, El Manira A (2007) Long-term plasticity of the spinal locomotor circuitry mediated by endocannabinoid and nitric oxide signaling. J Neurosci 27:12664–12674

    CAS  PubMed  Google Scholar 

  79. 79.

    Song J et al (2012) Gating the polarity of endocannabinoid-mediated synaptic plasticity by nitric oxide in the spinal locomotor network. J Neurosci 32:5097–5105

    CAS  PubMed  Google Scholar 

  80. 80.

    Díaz-Alonso J et al (2012) The CB(1) cannabinoid receptor drives corticospinal motor neuron differentiation through the Ctip2/Satb2 transcriptional regulation axis. J Neurosci 32:16651–16665

    PubMed Central  PubMed  Google Scholar 

  81. 81.

    Newman Z et al (2007) Endocannabinoids mediate muscarine-induced synaptic depression at the vertebrate neuromuscular junction. Eur J Neurosci 25:1619–1630

    PubMed Central  PubMed  Google Scholar 

  82. 82.

    Huerta M et al (2009) Effects of cannabinoids on caffeine contractures in slow and fast skeletal muscle fibers of the frog. J Membr Biol 229:91–99

    CAS  PubMed Central  PubMed  Google Scholar 

  83. 83.

    James RS et al (2011) Variation in expression of calcium-handling proteins is associated with inter-individual differences in mechanical performance of rat (Rattus norvegicus) skeletal muscle. J Exp Biol 214:3542–3548

    CAS  PubMed  Google Scholar 

  84. 84.

    Seebacher F et al (2012) How well do muscle biomechanics predict whole-animal locomotor performance? The role of Ca2+ handling. J Exp Biol 215:1847–1853

    CAS  PubMed  Google Scholar 

  85. 85.

    Mahmmoud YA, Gaster M (2012) Uncoupling of sarcoplasmic reticulum Ca2+-ATPase by N-arachidonoyl dopamine. Members of the endocannabinoid family as thermogenic drugs. Br J Pharmacol 166:2060–2069

    CAS  PubMed Central  PubMed  Google Scholar 

  86. 86.

    Oz M et al (2000) Endogenous cannabinoid anandamide directly inhibits voltage-dependent Ca(2+) fluxes in rabbit T-tubule membranes. Eur J Pharmacol 404:13–20

    CAS  PubMed  Google Scholar 

  87. 87.

    Alptekin A et al (2010) The effects of anandamide transport inhibitor AM404 on voltage-dependent calcium channels. Eur J Pharmacol 634:10–15

    CAS  PubMed  Google Scholar 

  88. 88.

    Wiley JL (2003) Sex-dependent effects of delta 9-tetrahydrocannabinol on locomotor activity in mice. Neurosci Lett 352:77–80

    CAS  PubMed  Google Scholar 

  89. 89.

    Pandolfo P et al (2007) Increased sensitivity of adolescent spontaneously hypertensive rats, an animal model of attention deficit hyperactivity disorder, to the locomotor stimulation induced by the cannabinoid receptor agonist WIN 55,212-2. Eur J Pharmacol 563:141–148

    CAS  PubMed  Google Scholar 

  90. 90.

    Smirnov MS, Kiyatkin EA (2008) Behavioral and temperature effects of delta 9-tetrahydrocannabinol in human-relevant doses in rats. Brain Res 1228:145–160

    CAS  PubMed Central  PubMed  Google Scholar 

  91. 91.

    Dubreucq S et al (2010) CB1 receptor deficiency decreases wheel-running activity: consequences on emotional behaviours and hippocampal neurogenesis. Exp Neurol 224:106–113

    CAS  PubMed  Google Scholar 

  92. 92.

    Tallett AJ et al (2007) Grooming, scratching and feeding: role of response competition in acute anorectic response to rimonabant in male rats. Psychopharmacology 195:27–39

    CAS  PubMed  Google Scholar 

  93. 93.

    Keeney BK et al (2008) Differential response to a selective cannabinoid receptor antagonist (SR141716: rimonabant) in female mice from lines selectively bred for high voluntary wheel-running behaviour. Behav Pharmacol 19:812–820

    CAS  PubMed  Google Scholar 

  94. 94.

    Keeney BK et al (2012) Sex differences in cannabinoid receptor-1 (CB1) pharmacology in mice selectively bred for high voluntary wheel-running behavior. Pharmacol Biochem Behav 101:528–537

    CAS  PubMed  Google Scholar 

  95. 95.

    Maccarrone M et al (2006) Regulation by cannabinoid receptors of anandamide transport across the blood-brain barrier and through other endothelial cells. Thromb Haemost 95:117–127

    CAS  PubMed  Google Scholar 

  96. 96.

    Stranahan AM et al (2008) Central mechanisms of HPA axis regulation by voluntary exercise. Neuromolecular Med 10:118–127

    CAS  PubMed Central  PubMed  Google Scholar 

  97. 97.

    Duric V, Duman RS (2013) Depression and treatment response: dynamic interplay of signaling pathways and altered neural processes. Cell Mol Life Sci 70:39–53

    CAS  PubMed Central  PubMed  Google Scholar 

  98. 98.

    Compagnucci C et al (2013) Type-1 (CB1) cannabinoid receptor promotes neuronal differentiation and maturation of neural stem cells. PLoS One 8(1):e54271

    CAS  PubMed Central  PubMed  Google Scholar 

  99. 99.

    Jiang W et al (2005) Cannabinoids promote embryonic and adult hippocampus neurogenesis and produce anxiolytic- and antidepressant-like effects. J Clin Invest 115:3104–3116

    CAS  PubMed Central  PubMed  Google Scholar 

  100. 100.

    Jin K et al (2004) Defective adult neurogenesis in CB1 cannabinoid receptor knockout mice. Mol Pharmacol 66:204–208

    CAS  PubMed  Google Scholar 

  101. 101.

    Aguado T et al (2006) The endocannabinoid system promotes astroglial differentiation by acting on neural progenitor cells. J Neurosci 26:1551–1561

    CAS  PubMed  Google Scholar 

  102. 102.

    Aso E et al (2008) BDNF impairment in the hippocampus is related to enhanced despair behavior in CB1 knockout mice. J Neurochem 105:565–572

    CAS  PubMed  Google Scholar 

  103. 103.

    Butovsky E et al (2005) In vivo up-regulation of brain-derived neurotrophic factor in specific brain areas by chronic exposure to Delta-tetrahydrocannabinol. J Neurochem 93:802–811

    CAS  PubMed  Google Scholar 

  104. 104.

    Varvel SA et al (2007) Inhibition of fatty-acid amide hydrolase accelerates acquisition and extinction rates in a spatial memory task. Neuropsychopharmacology 32:1032–1041

    CAS  PubMed  Google Scholar 

  105. 105.

    Mazzola C et al (2009) Fatty acid amide hydrolase (FAAH) inhibition enhances memory acquisition through activation of PPAR-alpha nuclear receptors. Learn Mem 16:332–337

    CAS  PubMed Central  PubMed  Google Scholar 

  106. 106.

    Goonawardena AV et al (2011) Pharmacological elevation of anandamide impairs short-term memory by altering the neurophysiology in the hippocampus. Neuropharmacology 61:1016–1025

    CAS  PubMed Central  PubMed  Google Scholar 

  107. 107.

    Chiew KS, Braver TS (2011) Positive affect versus reward: emotional and motivational influences on cognitive control. Front Psychol 2:279

    PubMed Central  PubMed  Google Scholar 

  108. 108.

    Ganon-Elazar E, Akirav I (2012) Cannabinoids prevent the development of behavioral and endocrine alterations in a rat model of intense stress. Neuropsychopharmacology 37(2):456–466

    CAS  PubMed Central  PubMed  Google Scholar 

  109. 109.

    Campeau S et al (2010) Hypothalamic pituitary adrenal axis responses to low-intensity stressors are reduced after voluntary wheel running in rats. J Neuroendocrinol 22:872–888

    CAS  PubMed  Google Scholar 

  110. 110.

    Bisicchia E et al (2013) Activation of type-2 cannabinoid receptor inhibits neuroprotective and antiinflammatory actions of glucocorticoid receptor α: when one is better than two. Cell Mol Life Sci 70:2191–2204

    CAS  PubMed  Google Scholar 

  111. 111.

    Elbatsh MM et al (2012) Antidepressant-like effects of Δ9-tetrahydrocannabinol and rimonabant in the olfactory bulbectomised rat model of depression. Pharmacol Biochem Behav 102:357–365

    CAS  PubMed  Google Scholar 

  112. 112.

    Bortolato M et al (2007) Antidepressant-like activity of the fatty acid amide hydrolase inhibitor URB597 in a rat model of chronic mild stress. Biol Psychiatry 62:1103–1110

    CAS  PubMed  Google Scholar 

  113. 113.

    Le Foll B et al (2009) The future of endocannabinoid-oriented clinical research after CB1 antagonists. Psychopharmacology 205:171–174

    PubMed Central  PubMed  Google Scholar 

  114. 114.

    Martin M et al (2002) Involvement of CB1 cannabinoid receptors in emotional behaviour. Psychopharmacology 159:379–387

    CAS  PubMed  Google Scholar 

  115. 115.

    Steiner MA et al (2008) Antidepressant-like behavioral effects of impaired cannabinoid receptor type 1 signaling coincide with exaggerated corticosterone secretion in mice. Psychoneuroendocrinology 33:54–67

    CAS  PubMed Central  PubMed  Google Scholar 

  116. 116.

    Dubreucq S et al (2012) Ventral tegmental area cannabinoid type-1 receptors control voluntary exercise performance. Biol Psychiatry 73:895–903

    PubMed  Google Scholar 

  117. 117.

    Solinas M et al (2008) The endocannabinoid system in brain reward processes. Br J Pharmacol 154:369–383

    CAS  PubMed Central  PubMed  Google Scholar 

  118. 118.

    Smith MA et al (2008) Aerobic exercise decreases the positive-reinforcing effects of cocaine. Drug Alcohol Depend 98:129–135

    CAS  PubMed Central  PubMed  Google Scholar 

  119. 119.

    Buchowski MS et al (2011) Aerobic exercise training reduces cannabis craving and use in non-treatment seeking cannabis-dependent adults. PLoS One 6:e17465

    CAS  PubMed Central  PubMed  Google Scholar 

  120. 120.

    Smith SL, Rasmussen EB (2010) Effects of 2-AG on the reinforcing properties of wheel activity in obese and lean Zucker rats. Behav Pharmacol 21:292–300

    CAS  PubMed  Google Scholar 

  121. 121.

    Drew LJ et al (2002) Activation of spinal cannabinoid 1 receptors inhibits C-fibre driven hyperexcitable neuronal responses and increases [35S]GTPgammaS binding in the dorsal horn of the spinal cord of noninflamed and inflamed rats. Eur J Neurosci 12:2079–2086

    Google Scholar 

  122. 122.

    Tsou K et al (1996) Suppression of noxious stimulus-evoked expression of Fos protein-like immunoreactivity in rat spinal cord by a selective cannabinoid agonist. Neuroscience 70:791–798

    CAS  PubMed  Google Scholar 

  123. 123.

    Lichtman AH et al (2004) Mice lacking fatty acid amide hydrolase exhibit a cannabinoid receptor-mediated phenotypic hypoalgesia. Pain 109:319–327

    CAS  PubMed  Google Scholar 

  124. 124.

    Caprioli A et al (2012) The novel reversible fatty acid amide hydrolase inhibitor ST4070 increases endocannabinoid brain levels and counteracts neuropathic pain in different animal models. J Pharmacol Exp Ther 342:188–195

    CAS  PubMed  Google Scholar 

  125. 125.

    Ghafouri N et al (2013) Palmitoylethanolamide and stearoylethanolamide levels in the interstitium of the trapezius muscle of women with chronic widespread pain and chronic neck-shoulder pain correlate with pain intensity and sensitivity. Pain 154:1649–1658

    CAS  PubMed  Google Scholar 

  126. 126.

    Blundell JE et al (2012) Role of resting metabolic rate and energy expenditure in hunger and appetite control: a new formulation. Dis Model Mech 5:608–613

    PubMed Central  PubMed  Google Scholar 

  127. 127.

    Rämson R et al (2012) The effect of 4-week training period on plasma neuropeptide Y, leptin and ghrelin responses in male rowers. Eur J Appl Physiol 112:1873–1880

    PubMed  Google Scholar 

  128. 128.

    de Rijke CE et al (2005) Hypothalamic neuropeptide expression following chronic food restriction in sedentary and wheel-running rats. J Mol Endocrinol 35:381–390

    PubMed  Google Scholar 

  129. 129.

    Ghanbari-Niaki A et al (2007) Plasma agouti-related protein (AGRP), growth hormone, insulin responses to a single circuit-resistance exercise in male college students. Peptides 28:1035–1039

    CAS  PubMed  Google Scholar 

  130. 130.

    Pil-Byung C et al (2011) Effects of exercise program on appetite-regulating hormones, inflammatory mediators, lipid profiles, and body composition in healthy men. J Sports Med Phys Fitness 51:654–663

    CAS  PubMed  Google Scholar 

  131. 131.

    Shadid S et al (2006) Diet/Exercise versus pioglitazone: effects of insulin sensitization with decreasing or increasing fat mass on adipokines and inflammatory markers. J Clin Endocrinol Metab 91:3418–3425

    CAS  PubMed  Google Scholar 

  132. 132.

    Bouassida A et al (2010) Review on leptin and adiponectin responses and adaptations to acute and chronic exercise. Br J Sports Med 44:620–630

    CAS  PubMed  Google Scholar 

  133. 133.

    Martins C et al (2007) Effects of exercise on gut peptides, energy intake and appetite. J Endocrinol 193:251–258

    CAS  PubMed  Google Scholar 

  134. 134.

    Broom DR et al (2009) Influence of resistance and aerobic exercise on hunger, circulating levels of acylated ghrelin, and peptide YY in healthy males. Am J Physiol Regul Integr Comp Physiol 296:R29–R35

    CAS  PubMed  Google Scholar 

  135. 135.

    Maccarrone M et al (2010) The endocannabinoid system and its relevance for nutrition. Annu Rev Nutr 30:423–440

    CAS  PubMed  Google Scholar 

  136. 136.

    Kirkham TC et al (2002) Endocannabinoid levels in rat limbic forebrain and hypothalamus in relation to fasting, feeding and satiation: stimulation of eating by 2-arachidonoyl glycerol. Br J Pharmacol 136:550–557

    CAS  PubMed Central  PubMed  Google Scholar 

  137. 137.

    Di Marzo V et al (2001) Leptin-regulated endocannabinoids are involved in maintaining food intake. Nature 410:822–825

    PubMed  Google Scholar 

  138. 138.

    Kola B et al (2005) Cannabinoids and ghrelin have both central and peripheral metabolic and cardiac effects via AMP-activated protein kinase. J Biol Chem 280:25196–25201

    CAS  PubMed  Google Scholar 

  139. 139.

    Gamber KM et al (2005) Cannabinoids augment the release of neuropeptide Y in the rat hypothalamus. Neuropharmacology 49:646–652

    CAS  PubMed  Google Scholar 

  140. 140.

    Osei-Hyiaman D et al (2005) Cocaine- and amphetamine-related transcript is involved in the orexigenic effect of endogenous anandamide. Neuroendocrinology 81:273–282

    CAS  PubMed  Google Scholar 

  141. 141.

    Wiley JL et al (2005) CB1 cannabinoid receptor-mediated modulation of food intake in mice. Br J Pharmacol 145:293–300

    CAS  PubMed Central  PubMed  Google Scholar 

  142. 142.

    Soria-Gómez E et al (2007) Pharmacological enhancement of the endocannabinoid system in the nucleus accumbens shell stimulates food intake and increases c-Fos expression in the hypothalamus. Br J Pharmacol 151:1109–1116

    PubMed Central  PubMed  Google Scholar 

  143. 143.

    Cristino L et al (2013) Obesity-driven synaptic remodeling affects endocannabinoid control of orexinergic neurons. Proc Natl Acad Sci USA 110:E2229–E2238

    CAS  PubMed Central  PubMed  Google Scholar 

  144. 144.

    Zhou D, Shearman LP (2004) Voluntary exercise augments acute effects of CB1-receptor inverse agonist on body weight loss in obese and lean mice. Pharmacol Biochem Behav 77:117–125

    CAS  PubMed  Google Scholar 

  145. 145.

    Chinsomboon J et al (2009) The transcriptional coactivator PGC-1alpha mediates exercise-induced angiogenesis in skeletal muscle. Proc Natl Acad Sci USA 106:21401–21406

    CAS  PubMed Central  PubMed  Google Scholar 

  146. 146.

    Goodpaster BH et al (2003) Enhanced fat oxidation through PA is associated with improvements in insulin sensitivity in obesity. Diabetes 52:2191–2197

    CAS  PubMed  Google Scholar 

  147. 147.

    Lavoie JM, Gauthier MS (2006) Regulation of fat metabolism in the liver: link to non-alcoholic hepatic steatosis and impact of physical exercise. Cell Mol Life Sci 63:1393–1409

    CAS  PubMed  Google Scholar 

  148. 148.

    Perseghin G et al (2007) Habitual physical activity is associated with intrahepatic fat content in humans. Diabetes Care 30:683–688

    CAS  PubMed  Google Scholar 

  149. 149.

    Jeppesen J, Kiens B (2012) Regulation and limitations to fatty acid oxidation during exercise. J Physiol 590:1059–1068

    CAS  PubMed Central  PubMed  Google Scholar 

  150. 150.

    Di Marzo V et al (2009) Role of insulin as a negative regulator of plasma endocannabinoid levels in obese and nonobese subjects. Eur J Endocrinol 161:715–722

    PubMed  Google Scholar 

  151. 151.

    Lindborg KA et al (2010) Effects of in vitro antagonism of endocannabinoid-1 receptors on the glucose transport system in normal and insulin-resistant rat skeletal muscle. Diabetes Obes Metab 12:722–730

    CAS  PubMed  Google Scholar 

  152. 152.

    Esposito I et al (2008) The cannabinoid CB1 receptor antagonist rimonabant stimulates 2-deoxyglucose uptake in skeletal muscle cells by regulating the expression of phosphatidylinositol-3-kinase. Mol Pharmacol 74:1678–1686

    CAS  PubMed  Google Scholar 

  153. 153.

    Lipina C et al (2010) Regulation of MAP kinase-directed mitogenic and protein kinase B-mediated signaling by cannabinoid receptor type 1 in skeletal muscle cells. Diabetes 59:375–385

    CAS  PubMed Central  PubMed  Google Scholar 

  154. 154.

    Agudo J et al (2010) Deficiency of CB2 cannabinoid receptor in mice improves insulin sensitivity but increases food intake and obesity with age. Diabetologia 53:2629–2640

    CAS  PubMed  Google Scholar 

  155. 155.

    Aguirre V et al (2002) Phosphorylation of Ser307 in insulin receptor substrate-1 blocks interactions with the insulin receptor and inhibits insulin action. J Biol Chem 277:1531–1537

    CAS  PubMed  Google Scholar 

  156. 156.

    Eckardt K et al (2009) Cannabinoid type 1 receptors in human skeletal muscle cells participate in the negative crosstalk between fat and muscle. Diabetologia 52(4):664–674

    CAS  PubMed  Google Scholar 

  157. 157.

    Fazakerley DJ et al (2010) Kinetic evidence for unique regulation of GLUT4 trafficking by insulin and AMP-activated protein kinase activators in L6 myotubes. J Biol Chem 285(3):1653–1660

    CAS  PubMed Central  PubMed  Google Scholar 

  158. 158.

    Yang J, Holman GD (2006) Long-term metformin treatment stimulates cardiomyocyte glucose transport through an AMP-activated protein kinase-dependent reduction in GLUT4 endocytosis. Endocrinology 147(6):2728–2736

    CAS  PubMed  Google Scholar 

  159. 159.

    Moreno-Navarrete JM et al (2012) The L-α-lysophosphatidylinositol/GPR55 system and its potential role in human obesity. Diabetes 61:281–291

    CAS  PubMed Central  PubMed  Google Scholar 

  160. 160.

    Perwitz N et al (2006) Cannabinoid receptor signaling directly inhibits thermogenesis and alters expression of adiponectin and visfatin. Horm Metab Res 38:356–368

    CAS  PubMed  Google Scholar 

  161. 161.

    Gary-Bobo M et al (2006) The cannabinoid CB1 receptor antagonist rimonabant (SR141716) inhibits cell proliferation and increases markers of adipocyte maturation in cultured mouse 3T3 F442A preadipocytes. Mol Pharmacol 69:471–478

    CAS  PubMed  Google Scholar 

  162. 162.

    Jbilo O et al (2005) The CB1 receptor antagonist rimonabant reverses the diet-induced obesity phenotype through the regulation of lipolysis and energy balance. FASEB J 19:1567–1569

    CAS  PubMed  Google Scholar 

  163. 163.

    Nogueiras R et al (2008) Peripheral, but not central, CB1 antagonism provides food intake-independent metabolic benefits in diet-induced obese rats. Diabetes 57:2977–2991

    CAS  PubMed Central  PubMed  Google Scholar 

  164. 164.

    Fredenrich A, Grimaldi PA (2005) PPAR delta: an uncompletely known nuclear receptor. Diabetes Metab 31:23–27

    CAS  PubMed  Google Scholar 

  165. 165.

    Maccarrone M et al (2004) Differential regulation of fatty acid amide hydrolase promoter in human immune cells and neuronal cells by leptin and progesterone. Eur J Biochem 271:4666–4676

    CAS  PubMed  Google Scholar 

  166. 166.

    Cravatt BF et al (2001) Supersensitivity to anandamide and enhanced endogenous cannabinoid signaling in mice lacking fatty acid amide hydrolase. Proc Natl Acad Sci USA 98:9371–9376

    CAS  PubMed Central  PubMed  Google Scholar 

  167. 167.

    Osei-Hyiaman D et al (2008) Hepatic CB1 receptor is required for development of diet-induced steatosis, dyslipidemia, and insulin and leptin resistance in mice. J Clin Invest 118:3160–3169

    CAS  PubMed Central  PubMed  Google Scholar 

  168. 168.

    Jourdan T et al (2010) CB1 antagonism exerts specific molecular effects on visceral and subcutaneous fat and reverses liver steatosis in diet-induced obese mice. Diabetes 59:926–934

    CAS  PubMed Central  PubMed  Google Scholar 

  169. 169.

    Yasari S et al (2012) Effects of exercise training on molecular markers of lipogenesis and lipid partitioning in fructose-induced liver fat accumulation. J Nutr Metab 2012:181687

    PubMed Central  PubMed  Google Scholar 

  170. 170.

    Simpson RJ (2011) Aging, persistent viral infections, and immunosenescence: can exercise “make space”? Exerc Sport Sci Rev 39:23–33

    PubMed  Google Scholar 

  171. 171.

    Gannon GA et al (2001) Differential cell adhesion molecule expression and lymphocyte mobilisation during prolonged aerobic exercise. Eur J Appl Physiol 84:272–282

    CAS  PubMed  Google Scholar 

  172. 172.

    Pedersen BK et al (1988) Modulation of natural killer cell activity in peripheral blood by physical exercise. Scand J Immunol 27:673–678

    CAS  PubMed  Google Scholar 

  173. 173.

    Scott JP et al (2011) Effect of exercise intensity on the cytokine response to an acute bout of running. Med Sci Sports Exerc 43:2297–2306

    CAS  PubMed  Google Scholar 

  174. 174.

    Timmerman KL et al (2008) Exercise training-induced lowering of inflammatory (CD14+ CD16+) monocytes: a role in the anti-inflammatory influence of exercise? J Leukoc Biol 84:1271–1278

    CAS  PubMed  Google Scholar 

  175. 175.

    Wang J et al (2011) Effect of exercise training intensity on murine T-regulatory cells and vaccination response. Scand J Med Sci Sports 22:643–652

    PubMed  Google Scholar 

  176. 176.

    Kawanishi N et al (2010) 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 16:105–118

    PubMed  Google Scholar 

  177. 177.

    Pedersen BK (2009) The diseasome of physical inactivity—and the role of myokines in muscle—fat cross talk. J Physiol 587:5559–5568

    CAS  PubMed Central  PubMed  Google Scholar 

  178. 178.

    Pournot H et al (2011) Time-course of changes in inflammatory response after whole-body cryotherapy multi exposures following severe exercise. PLoS One 6:e22748

    CAS  PubMed Central  PubMed  Google Scholar 

  179. 179.

    Pedersen BK (2012) Muscular interleukin-6 and its role as an energy sensor. Med Sci Sports Exerc 44:392–396

    CAS  PubMed  Google Scholar 

  180. 180.

    Brooks SV et al (2008) Repeated bouts of aerobic exercise lead to reductions in skeletal muscle free radical generation and nuclear factor kappaB activation. J Physiol 586:3979–3990

    CAS  PubMed Central  PubMed  Google Scholar 

  181. 181.

    Cobley JN et al (2011) N-Acetylcysteine’s attenuation of fatigue after repeated bouts of intermittent exercise: practical implications for tournament situations. Int J Sport Nutr Exerc Metab 21:451–461

    CAS  PubMed  Google Scholar 

  182. 182.

    Sun MW et al (2008) Effects of different levels of exercise volume on endothelium-dependent vasodilation: roles of nitric oxide synthase and heme oxygenase. Hypertens Res 31:805–816

    CAS  PubMed  Google Scholar 

  183. 183.

    Radak Z et al (2012) Nitric oxide: is it the cause of muscle soreness? Nitric Oxide 26:89–94

    CAS  PubMed  Google Scholar 

  184. 184.

    Powers SK et al (2011) Reactive oxygen species: impact on skeletal muscle. Compr Physiol 1:941–969

    PubMed Central  PubMed  Google Scholar 

  185. 185.

    Villalta SA et al (2009) Shifts in macrophage phenotypes and macrophage competition for arginine metabolism affect the severity of muscle pathology in muscular dystrophy. Hum Mol Genet 18:482–496

    CAS  PubMed Central  PubMed  Google Scholar 

  186. 186.

    Chiurchiù V, Maccarrone M (2011) Chronic inflammatory disorders and their redox control: from molecular mechanisms to therapeutic opportunities. Antioxid Redox Signal 15:2605–2641

    PubMed  Google Scholar 

  187. 187.

    Coopman K et al (2007) Temporal variation in CB2R levels following T lymphocyte activation: evidence that cannabinoids modulate CXCL12-induced chemotaxis. Int Immunopharmacol 7:360–371

    CAS  PubMed  Google Scholar 

  188. 188.

    Smith SR et al (2000) Effects of cannabinoid receptor agonist and antagonist ligands on production of inflammatory cytokines and anti-inflammatory interleukin-10 in endotoxemic mice. J Pharmacol Exp Ther 293:136–150

    CAS  PubMed  Google Scholar 

  189. 189.

    Cencioni MT et al (2010) Anandamide suppresses proliferation and cytokine release from primary human T-lymphocytes mainly via CB2 receptors. PLoS One 5:e8688

    PubMed Central  PubMed  Google Scholar 

  190. 190.

    Pandey R et al (2009) Endocannabinoids and immune regulation. Pharmacol Res 60:85–92

    CAS  PubMed Central  PubMed  Google Scholar 

  191. 191.

    Maccarrone M et al (2000) Anandamide uptake by human endothelial cells and its regulation by nitric oxide. J Biol Chem 275:13484–13492

    CAS  PubMed  Google Scholar 

  192. 192.

    Tedesco L et al (2010) Cannabinoid receptor stimulation impairs mitochondrial biogenesis in mouse white adipose tissue, muscle, and liver: the role of eNOS, p38 MAPK, and AMPK pathways. Diabetes 59:2826–2836

    CAS  PubMed Central  PubMed  Google Scholar 

  193. 193.

    Mukhopadhyay P et al (2011) Fatty acid amide hydrolase is a key regulator of endocannabinoid-induced myocardial tissue injury. Free Radic Biol Med 50:179–195

    CAS  PubMed Central  PubMed  Google Scholar 

  194. 194.

    Romero TR et al (2012) Involvement of the l-arginine/nitric oxide/cyclic guanosine monophosphate pathway in peripheral antinociception induced by N-palmitoyl-ethanolamine in rats. J Neurosci Res 90:1474–1479

    CAS  PubMed  Google Scholar 

  195. 195.

    Lee CY et al (2008) A comparative study on cannabidiol-induced apoptosis in murine thymocytes and EL-4 thymoma cells. Int Immunopharmacol 8:732–740

    CAS  PubMed  Google Scholar 

  196. 196.

    Kim J et al (2013) Fat to treat fat: emerging relationship between dietary PUFA, endocannabinoids, and obesity. Prostaglandins Other Lipid Mediat 104–105:32–41

    PubMed  Google Scholar 

  197. 197.

    Ailhaud G et al (2006) Temporal changes in dietary fats: role of n-6 polyunsaturated fatty acids in excessive adipose tissue development and relationship to obesity. Prog Lipid Res 45:203–236

    CAS  PubMed  Google Scholar 

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Acknowledgments

We apologize in advance to all investigators whose research could not be appropriately quoted due to space limitations. We wish to thank all colleagues who have contributed over the past 15 years to our studies of the endocannabinoid system and its impact on human health and disease. Financial support from Fondazione TERCAS (Grant n° 2009–2012), Ministero dell’Istruzione, dell’Università e della Ricerca (grant n° PRIN 2010–2011), Fondazione Italiana Sclerosi Multipla (FISM grant 2010), to M.M., and from Regione Lazio (grant n° 00011377/2010–2013) to M.T. is also gratefully acknowledged.

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Correspondence to Valeria Gasperi or Mauro Maccarrone.

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V. Gasperi and M. Maccarrone are equally senior authors.

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Tantimonaco, M., Ceci, R., Sabatini, S. et al. Physical activity and the endocannabinoid system: an overview. Cell. Mol. Life Sci. 71, 2681–2698 (2014). https://doi.org/10.1007/s00018-014-1575-6

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Keywords

  • Adaptive responses
  • Endocannabinoids
  • Exercise
  • Health benefit
  • Physical activity