Prior voluntary wheel running attenuates neuropathic pain

Pain. 2016 Sep;157(9):2012-23. doi: 10.1097/j.pain.0000000000000607.


Exercise is known to exert a systemic anti-inflammatory influence, but whether its effects are sufficient to protect against subsequent neuropathic pain is underinvestigated. We report that 6 weeks of voluntary wheel running terminating before chronic constriction injury (CCI) prevented the full development of allodynia for the ∼3-month duration of the injury. Neuroimmune signaling was assessed at 3 and 14 days after CCI. Prior exercise normalized ipsilateral dorsal spinal cord expression of neuroexcitatory interleukin (IL)-1β production and the attendant glutamate transporter GLT-1 decrease, as well as expression of the disinhibitory P2X4R-BDNF axis. The expression of the macrophage marker Iba1 and the chemokine CCL2 (MCP-1), and a neuronal injury marker (activating transcription factor 3), was attenuated by prior running in the ipsilateral lumbar dorsal root ganglia. Prior exercise suppressed macrophage infiltration and/or injury site proliferation, given decreased presence of macrophage markers Iba1, iNOS (M1), and Arg-1 (M2; expression was time dependent). Chronic constriction injury-driven increases in serum proinflammatory chemokines were suppressed by prior running, whereas IL-10 was increased. Peripheral blood mononuclear cells were also stimulated with lipopolysaccharide ex vivo, wherein CCI-induced increases in IL-1β, nitrite, and IL-10 were suppressed by prior exercise. Last, unrestricted voluntary wheel running, beginning either the day of, or 2 weeks after, CCI, progressively reversed neuropathic pain. This study is the first to investigate the behavioral and neuroimmune consequences of regular exercise terminating before nerve injury. This study suggests that chronic pain should be considered a component of "the diseasome of physical inactivity," and that an active lifestyle may prevent neuropathic pain.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Activating Transcription Factor 3 / metabolism
  • Animals
  • Calcium-Binding Proteins / metabolism
  • Constriction, Pathologic / complications
  • Cytokines / metabolism
  • Disease Models, Animal
  • Excitatory Amino Acid Transporter 2 / metabolism
  • Exercise Movement Techniques / methods*
  • Functional Laterality
  • Ganglia, Spinal / metabolism
  • Ganglia, Spinal / pathology
  • Hyperalgesia / rehabilitation
  • Leukocytes, Mononuclear / metabolism
  • Leukocytes, Mononuclear / pathology
  • Male
  • Microfilament Proteins / metabolism
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism
  • Neuralgia / etiology
  • Neuralgia / pathology
  • Neuralgia / prevention & control*
  • Nitrites / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Purinergic P2X5 / metabolism
  • Sciatic Neuropathy / prevention & control
  • p21-Activated Kinases / metabolism
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • Activating Transcription Factor 3
  • Aif1 protein, rat
  • Atf3 protein, rat
  • Calcium-Binding Proteins
  • Cytokines
  • Excitatory Amino Acid Transporter 2
  • Microfilament Proteins
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nitrites
  • Receptors, Purinergic P2X5
  • Slc1a2 protein, rat
  • p21-Activated Kinases
  • p38 Mitogen-Activated Protein Kinases