1. Exercise and pain Walter R. Frontera, MD, PhD Professor and Chair (Inaugural) Department of Physical Medicine and Rehabilitation Vanderbilt University School of Medicine And Medical Director of Rehabilitation Services Vanderbilt University Medical Center

2. No disclosures

3. “ To be ignorant of motion is to be ignorant of nature ” “ There is perhaps nothing in nature older than motion ”

4. Knowledge Base

5. “Exercise and Pain” in PubMed

6. What is the clinical evidence that exercise is analgesic?

7. Forest plots (eight studies, 11 exercise groups) Exercise and knee OA Ryo Tanaka et al. Clin Rehabil 2013;27:1059-1071

8. Non-weight-bearing strengthening exercise Weight-bearing strengthening exercise Aerobic exercise total Exercise and knee OA pain Ryo Tanaka et al. Clin Rehabil 2013;27:1059-1071

10. Central sensitization

11. A description CJ Woolf, Pain 2011 Nociceptor inputs can trigger a prolonged but reversible increase in the excitability and synaptic efficacy of neurons in central nociceptive pathways, the phenomenon of central sensitization. Central sensitization manifests as pain hypersensitivity, particularly dynamic tactile allodynia, secondary punctate or pressure hyperalgesia, aftersensations, and enhanced temporal summation. It can be readily and rapidly elicited in human volunteers by diverse experimental noxious conditioning stimuli to skin, muscles or viscera, and in addition to producing pain hypersensitivity, results in secondary changes in brain activity that can be detected by electrophysiological or imaging techniques.

12. Molecular systems

13. Effects of Exercise on pain at the molecular level? The opiate/endorphin system The endo-cannabinoid system Inflammation and the toll-like receptor (TLR) 4 system

15. Exercise reverses hypersensitivy in neuropathic pain – a rat model (Stagg et al., Anesthesiology 114:940, 2011) Exercise training consisted of running on a 10-lane motor-driven rodent treadmill 5 days per week, for 5 weeks at a speed of 14–16 m/min and an 8% grade. Duration was increased to 30 min/day over 14 days. An electric grid behind the treadmill was activated with a weak current. Mid-brain periaqueductal gray area

16. Exercise reverses hypersensitivy in neuropathic pain – a rat model (Stagg et al., Anesthesiology 114:940, 2011) Exercise training consisted of running on a 10-lane motor- driven rodent treadmill 5 days per week, for 3 or 5 weeks at a speed of 14–16 m/min and an 8% grade). Duration was increased to 30 min/day over 14 days. 10 m/min (lower intensity) or 16 m/min (higher intensity)

17. Immobilization, hyperalgesia and exercise (Chuganji et al., Neurosci Letters 584:66, 2015) Male Wistar rats Immobilized right hindlimb by casting 3 groups: immobilization, immobilization and treadmill exercise, controls Exercise: 30 min/day; 5 days/week Mechanical sensitivity test, 10 times with 4- and 15-g von Frey filaments for paw withdrawal beta-endorphin in hypothalamus and mid-brain periaqueductal gray

18. Immobilization, hyperalgesia and exercise (Chuganji et al., Neurosci Letters 584:66, 2015) Male Wistar rats Immobilized right hindlimb by casting 3 groups: immobilization, immobilization and treadmill exercise, controls Exercise: 30 min/day; 5 days/week Mechanical sensitivity test, 10 times with 4- and 15-g von Frey filaments for paw withdrawal beta-endorphin in hypothalamus and mid-brain periaqueductal gray

19. “The physiological mechanisms explaining endogenous analgesia following exercise … due to the release of endogenous opioids and activation of the (supra)spinal nociceptive inhibitory mechanisms orchestrated by the brain. However, aerobic exercise activates pain facilitation rather than inhibition in some patients with chronic pain and central sensitization (fibromyalgia, whiplash, and chronic fatigue syndrome). Exercising local muscle groups results in increased generalized pain sensitivity in fibromyalgia …”

20. Endocannabinoid system (Raichlen et al., EJAP 113:869, 2013) Natural system that includes: – endogenous ligands including anandamide (AEA) and 2-arachidonylglycerol (2- AG) – CB1 and CB2 cannabinoid receptors (receptors activated by THC) present in brain, muscle, GI tract, liver, adipose tissue, pancreas Ligands released by neurons to modulate synaptic activity and plasticity – Cross blood-brain barrier Activation of this system reduces pain – Linked to stress-induced analgesia – Changes associated with the use of THC

21. First evidence that exercise activates endocannabinoid system (Sparling et al., NeuroReport 14:2209, 2003) Trained young subjects 45 minutes on treadmill or bike at 70-85% max HR Significant increases in runners and cyclists but not in controls that did not exercise

22. Exercise induce increases in eCBs Recreationally fit human runners Treadmill exercise at 4 intensities for 30 minutes Significant increases only at moderate intensities (~70-85% age-adjusted max HR) Raichlen et al., EJAP 113:869, 2013

23. Exercise and endocannabinoids (Heyman et al., Psychoneuroendo 37:844, 2012) Healthy trained cyclists 60 min at 55% W max followed by 30 min at 75% Plasma levels of endocannabinoids Increase in cortisol, brain-derived neurotrophic factor, and endorphins

24. The importance of genetics The Human Gene Map for Performance and Health-Related Fitness Phenotypes: The 2005 Update. RANKINEN et al., MSSE 38:1863, 2006. Heritability estimate for VO 2 max is 47% Variance in exercise behavior explained by genetics 23% to 71% Variability in response to training with aerobic training (0 to 100% increase)