European Journal of Applied Physiology

, Volume 113, Issue 4, pp 869–875

Exercise-induced endocannabinoid signaling is modulated by intensity

  • David A. Raichlen
  • Adam D. Foster
  • Alexandre Seillier
  • Andrea Giuffrida
  • Gregory L. Gerdeman
Original Article

Abstract

Endocannabinoids (eCB) are endogenous ligands for cannabinoid receptors that are densely expressed in brain networks responsible for reward. Recent work shows that exercise activates the eCB system in humans and other mammals, suggesting eCBs are partly responsible for the reported improvements in mood and affect following aerobic exercise in humans. However, exercise-induced psychological changes reported by runners are known to be dependent on exercise intensity, suggesting that any underlying molecular mechanism should also change with varying levels of exercise intensity. Here, we examine circulating levels of eCBs following aerobic exercise (treadmill running) in recreationally fit human runners at four different intensities. We show that eCB signaling is indeed intensity dependent, with significant changes in circulating eCBs observed following moderate intensities only (very high and very low intensity exercises do not significantly alter circulating eCB levels). Our results are consistent with intensity-dependent psychological state changes with exercise and therefore support the hypothesis that eCB activity is related to neurobiological effects of exercise. Thus, future studies examining the role of exercise-induced eCB signaling on neurobiology or physiology must take exercise intensity into account.

Keywords

AEA 2-AG Positive affect Endurance running Neurogenesis Analgesia 

References

  1. Agarwal N, Pacher P, Tegeder I, Amaya F, Constantin CE, Brenner GJ, Rubino T, Michalski CW, Marsicano G, Monory K, Mackie K, Marian C, Batkai S, Parolaro D, Fischer MJ, Reeh P, Kunos G, Kress M, Lutz B, Woolf CJ, Kuner R (2007) Cannabinoids mediate analgesia largely via peripheral type 1 cannabinoid receptors in nociceptors. Nat Neurosci 10:870–879PubMedCrossRefGoogle Scholar
  2. Aguado T, Monory K, Palzuelos J, Stella N, Cravatt B, Lutz B, Marsicano G, Kokaia Z, Guzman M, Galve-Roperh I (2005) The endocannabinoid system drives neural progenitor proliferation. FASEB Journal 19:1704–1706PubMedGoogle Scholar
  3. Aguado T, Palzuelos J, Monory K, Stella N, Cravatt B, Lutz B, Marsicano G, Kokaia Z, Guzman M, Galve-Roperh I (2006) The endocannabinoid system promotes astroglial differentiation by acting on neural progenitor cells. J Neurosci 26:1551–1561PubMedCrossRefGoogle Scholar
  4. Berger BG, Motl RW (2000) Exercise and mood: a selective review and synthesis of research employing the profile of mood states. J Appl Psychol 12:69–92Google Scholar
  5. Bramble DM, Lieberman DE (2004) Endurance running and the evolution of Homo. Nature 432:345–352PubMedCrossRefGoogle Scholar
  6. Carrier DR (1984) The energetic paradox of human running and hominid evolution. Curr Anthropol 25:483–495CrossRefGoogle Scholar
  7. Dietrich A, McDaniel WF (2004) Endocannabinoids and exercise. Br J Sports Med 38:536–541PubMedCrossRefGoogle Scholar
  8. Dubreucq S, Koehl M, Abrous DN, Marsicano G, Chaouloff F (2010) CB1 receptor deficiency decreases wheel-running activity: consequences on emotional behaviours and hippocampal neurogenesis. Exp Neurol 224:106–113PubMedCrossRefGoogle Scholar
  9. Erickson KI, Voss MW, Prakash RS, Basak C, Szabo A, Chaddock L, Kim JS, Heo S, Alves H, White SM, Wojcicki TR, Mailey E, Vieira VJ, Martin SA, PB D, Woods JA, McAuley E, Kramer AF (2011) Exercise training increases size of hippocampus and improves memory. Proc Nat Acad Sci USA 108:3017–3022PubMedCrossRefGoogle Scholar
  10. Feuerecker M, Hauer D, Toth R, Demetz F, Holzl J et al (2012) Effects of exercise stress on the endocannabinoid system in humans under field conditions. Eur J Appl Physiol 112:2777–2781PubMedCrossRefGoogle Scholar
  11. Fu J, Bottegoni G, Sasso O, Bertorelli R, Rocchia W, Masetti M, Guijarro A, Lodola A, Armirotti A, Garau G, Banderiera T, Reggiani A, Mor M, Cavalli A, Piomelli D (2012) A catalytically silent FAAH-1 variant drives anandamide transport in neurons. Nat Neurosci 15:64–69CrossRefGoogle Scholar
  12. Gerdeman GL (2008) Endocannabinoids at the synapse - retrograde signaling and presynaptic plasiticity in the brain. In: Kofalvi A (ed) Cannabinoids and the Brain. Springer-Verlag, New York, pp 203–236CrossRefGoogle Scholar
  13. Glaser ST, Gatley SJ, Gifford AN (2006) Ex vivo imaging of fatty acid amide hydrolase activity and its inhibition in the mouse brain. J Pharmacol Exp Ther 316:1088–1097PubMedCrossRefGoogle Scholar
  14. Glass M, Dragunow M, Faull RLM (1997) Cannabinoid receptors in the human brain: a detailed anatomical and quantitative autoradiographic study in the fetal, neonatal and adult human brain. Neuroscience 10:1665–1669Google Scholar
  15. Hardison A, Weintraub ST, Giuffrida A (2006) Quantification of endocannabinoids in rat biological samples by GC/MS: technical and theoretical considerations. Prostaglandins Other Lipid Mediat 81:106–112PubMedCrossRefGoogle Scholar
  16. Heyman E, Gamelin FX, Goekint M, Piscitelli F, Roelands B, Leclair E, Di Marzo V, Meeusen R (2012) Intense exercise increases circulating endocannabinoid and BDNF levels in humans: possible implications for reward and depression. Psychoneuroendocrinology 37:844–851PubMedCrossRefGoogle Scholar
  17. Hill MN, Titterness AK, Morrish AC, Carrier EJ, Lee TTY, Gil-Mohapel J, Gorzalka BB, Hillard CJ, Christie BR (2010) Endogenous cannabinoid signaling is required for voluntary exercise-induced enhancement of progenitor cell proliferation in the hippocampus. Hippocampus 20:513–523PubMedGoogle Scholar
  18. Hillard CJ (2000) Biochemistry and pharmacology of the endocannabinoids arachidonylethanolamide and 2-arachidonylglycerol. Prostaglandins Other Lipid Mediat 61:3–18PubMedCrossRefGoogle Scholar
  19. Hoffman MD, Shepanski MA, Ruble SB, Valic Z, Buckwalter JB, Clifford PS (2004) Intensity and duration threshold for aerobic exercise-induced analgesia to pressure pain. Arch Phys Med Rehabil 85:1183–1187PubMedCrossRefGoogle Scholar
  20. Hohmann AG, Suplita RL (2006) Endocannabinoid mechanisms of pain modulation. AAPS J 8:E693–E708PubMedCrossRefGoogle Scholar
  21. Hohmann AG, Tsou K, Walker JM (1999) Cannabinoid suppression of noxious heat-evoked activity in wide dynamic range neurons in the lumbar dorsal horn of the rat. J Neurophysiol 81:575–583PubMedGoogle Scholar
  22. Hohmann AG, Suplita RL, Bolton NM, Neely MH, Fegley D, Mangieri R, Krey JF, Walker JM, Holmes PV, Crystal JD, Duranti A, Tontini A, Mor M, Tarzia G, Piomelli D (2005) An endocannabinoid mechanism for stress-reduced analgesia. Nature 435:1108–1112PubMedCrossRefGoogle Scholar
  23. Howlett AC, Breivogel CS, Childer SR, Deadwyler SA, Hampson RE, Porrino LJ (2004) Cannabinoids promote embryonic and adult hippocampus neurogenesis and produce anxiolytic- and antidepressant-like effects. Journal of Clinical Investigation 115:3104–3116Google Scholar
  24. Ibrahim MM, Deng H, Zvonok A, Cockayne DA, Kwan J, Mata HP, Vanderha TW, Lai J, Porreca F, Makriyannis A, Malan TP (2003) Activation of CB2 cannabinoid receptors by AM1241 inhibits experimental neuropathic pain: pain inhibition not present in CNS. Proc Nat Acad Sci USA 100:10529–10533PubMedCrossRefGoogle Scholar
  25. Justinova Z, Solinas M, Tanda G, Redhi GH, Goldberg SR (2005) The endogenous cannabinoid anandamide and its synthetic analog R(+)-methanandamide are intravenously self-administered by squirrel monkeys. J Neurosci 25:5645–5650PubMedCrossRefGoogle Scholar
  26. Justinova Z, Yasar S, Redhi GH, Goldberg SR (2011) The endogenous cannabinoid 2-arachidonoylglycerol is intravenously self-administered by squirrel monkeys. J Neurosci 31:7043–7048PubMedCrossRefGoogle Scholar
  27. Katona I, Freund TF (2008) Endocannabinoid signaling as a synaptic circuit breaker in neurological disease. Nat Med 14:923–930PubMedCrossRefGoogle Scholar
  28. Keeney BK, Raichlen DA, Meek TH, Wijeratne RS, Middleton KM, Gerdeman GL, Garland TJ (2008) Differential response to a selective cannabinoid receptor antagonist (SR141716: rimonabant) in female mice from lines selectively bred for high voluntary wheel-running behavior. Behav Pharmacol 19:812–820PubMedCrossRefGoogle Scholar
  29. Keeney BK, Meek TH, Middleton KM, Holness LF, Garland T Jr (2012) Sex differences in cannabinoid receptor-1 (CB1) pharmacology in mice selectively bred for high voluntary wheel-running behavior. Pharmacol Biochem Behav 101:528–537PubMedCrossRefGoogle Scholar
  30. Kim YP, Kim HB, Jang MH, Lim BV, Kim Y, Kim H, Kim SS, Kim EH, Kim CJ (2003) Magnitude- and time-dependence of the effect of treadmill exercise on cell proliferation in the dentate gyrus of rats. Int J Sports Med 24:114–117PubMedCrossRefGoogle Scholar
  31. Kirkcaldy BD, Shephard RJ (1990) Therapeutic implications of exercise. International Journal of Sport Psychology 21:165–184Google Scholar
  32. Koltyn KF (2002) Exercise-induced hypoalgesia and intensity of exercise. Sports Med 32:477–487PubMedCrossRefGoogle Scholar
  33. Lieberman DE, Raichlen DA, Pontzer H, Bramble DM, C-S E (2006) The human gluteus maximus and its role in running. J Exp Biol 209:2143–2155PubMedCrossRefGoogle Scholar
  34. Lieberman DE, Bramble DM, Raichlen DA, Shea JJ (2007) The evolution of endurance running and the tyranny of ethnography: a reply to Pickering and Bunn (2007). J Hum Evol 53:439–442PubMedCrossRefGoogle Scholar
  35. Lieberman DE, Bramble DM, Raichlen DA, Shea JJ (2009) Brains, brawn, and the evolution of human endurance running capabilities. In: Grine F, Leakey REF (eds) The origin of homo. Plenum Press, New York, pp 77–92Google Scholar
  36. Lou S, Liu J, Chang H, Chen P (2008) Hippocampal neurogenesis and gene expression depend on exercise intensity in juvenile rats. Brain Res 1210:48–55PubMedCrossRefGoogle Scholar
  37. Meng ID, Manning BH, Martin WJ, Fields HL (1998) An analgesia circuit activated by cannabinoids. Nature 395:381–383PubMedCrossRefGoogle Scholar
  38. Ogles BM, Masters KS (2003) A typology of marathon runners based on cluster analysis of motivations. J Sports Behav 26:69–85Google Scholar
  39. Piomelli D (2003) The molecular logic of endocannabinoid signalling. Nat Rev Nuerosci 4:873–884CrossRefGoogle Scholar
  40. Raichlen DA, Foster AD, Gerdeman GL, Seillier A, Giuffrida A (2012) Wired to run: exercise-induced endocannabinoid signaling in humans and cursorial mammals and the evolution of the runner’s high. J Exp Biol 215:1331–1336PubMedCrossRefGoogle Scholar
  41. Rasmussen EB, Hillman C (2011) Naloxene and rimonabant reduce the reinforcing properties of exercise in rats. Exp Clin Psychopharmacol 19:389–400PubMedCrossRefGoogle Scholar
  42. Reed J, Ones DS (2006) The effect of acute aerobic exercise on positive activated affect: a meta-analysis. Psychol Sport Exerc 7:477–514CrossRefGoogle Scholar
  43. Richardson JD (2000) Cannabinoids modulate pain by multiple mechanisms of action. J Pain 1:2–14Google Scholar
  44. Sachs M, Pargman D (1979) Running addiction: a depth view. J Sports Behav 2:143–155Google Scholar
  45. Solinas M, Justinova Z, Goldberg SR, Tanda T (2006) Anandamide administration alone and after inhibition of fatty acid amide hydrolase (FAAH) increases dopamine levels in the nucleus accumbens shell in rats. J Neurochem 98:408–419PubMedCrossRefGoogle Scholar
  46. Sparling PB, Giuffrida A, Piomelli D, Rosskopf L, Dietrich A (2003) Exercise activates the endocannabinoid system. Neuro Report 14:2209–2211Google Scholar
  47. Tanaka H, Monahan KD, Seals DR (2001) Age-predicted maximal heart rate revisited. J Am Coll Cardiol 37:153–156PubMedCrossRefGoogle Scholar
  48. Vaughn LK, Denning G, Stuhr KL, Wit H, Hill MN, Hillard CJ (2010) Endocannabinoid signalling: has it got rhythm? Br J Pharmacol 160:530–543PubMedCrossRefGoogle Scholar
  49. Willoughby KA, Moore SF, Martin BR, Ellis EF (1997) The biodisposition and metabolism of anandamide in mice. J Pharmacol Exp Ther 282:243–247PubMedGoogle Scholar
  50. Wolf SA, Bick-Sander A, Fabel K, Leal-Galicia P, Tauber S, Ramirez-Rodriguez G, Muller A, Melnik A, Waltinger TP, Ulrich O, Kempermann G (2010) Cannabinoid receptor CB1 mediates baseline and activity-induced survival of new neurons in adult hippocampal neurogenesis. Cell Commun Signal 8:12PubMedCrossRefGoogle Scholar
  51. Zoerner AA, Gutzki FM, Suchy MT, Beckmann B, Engeli S, Jordan J, Tsikas D (2009) Targeted stable-isotope dilution GC–MS/MS analysis of the endocannabinoid anandamide and other fatty acid ethanol amides in human plasma. J Chromatogr B Biomed Appl 877:2909–2923CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • David A. Raichlen
    • 1
  • Adam D. Foster
    • 1
  • Alexandre Seillier
    • 2
  • Andrea Giuffrida
    • 2
  • Gregory L. Gerdeman
    • 3
  1. 1.School of AnthropologyUniversity of ArizonaTucsonUSA
  2. 2.Department of PharmacologyUniversity of Texas Health Science CenterSan AntonioUSA
  3. 3.Department of BiologyEckerd CollegeSt. PetersburgUSA

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