title: Early increasing-intensity treadmill exercise reduces neuropathic pain by preventing nociceptor collateral sprouting and disruption of chloride cotransporters homeostasis after peripheral nerve injury.
abstract: Activity treatments, such as treadmill exercise, are used to improve functional recovery after nerve injury, parallel to an increase in neurotrophin levels. However, despite their role in neuronal survival and regeneration, neurotrophins may cause neuronal hyperexcitability that triggers neuropathic pain. In this work, we demonstrate that an early increasing-intensity treadmill exercise (iTR), performed during the first week (iTR1) or during the first 2 weeks (iTR2) after section and suture repair of the rat sciatic nerve, significantly reduced the hyperalgesia developing rapidly in the saphenous nerve territory and later in the sciatic nerve territory after regeneration. Nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) expression in sensory neurons and spinal cord was reduced in parallel. iTR prevented the extension of collateral sprouts of saphenous nociceptive calcitonin gene-related peptide fibers within the adjacent denervated skin and reduced NGF expression in the same skin and in the L3 dorsal root ganglia (DRG). Injury also induced Na⁺-K⁺-2Cl⁻ cotransporter 1 (NKCC1) upregulation in DRG, and K⁺-Cl⁻ cotransporter 2 (KCC2) downregulation in lumbar spinal cord dorsal horn. iTR normalized NKCC1 and boosted KCC2 expression, together with a significant reduction of microgliosis in L3-L5 dorsal horn, and a reduction of BDNF expression in microglia at 1 to 2 weeks postinjury. These data demonstrate that specific activity protocols, such as iTR, can modulate neurotrophins expression after peripheral nerve injury and prevent neuropathic pain by blocking early mechanisms of sensitization such as collateral sprouting and NKCC1/KCC2 disregulation.
authors.affiliation: Department of Cell Biology, Physiology and Immunology, and Institute of Neurosciences, Universitat Autònoma de Barcelona, and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Bellaterra, Spain.
authors.forename: Víctor M
authors.initials: VM
authors.lastname: López-Álvarez
authors.forename: Laura
authors.initials: L
authors.lastname: Modol
authors.forename: Xavier
authors.initials: X
authors.lastname: Navarro
authors.forename: Stefano
authors.initials: S
authors.lastname: Cobianchi
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D004195:Disease Models, Animal; D005080:Exercise Test; D005081:Exercise Therapy; D005260:Female; D005727:Ganglia, Spinal / Q000473:pathology; D020932:Nerve Growth Factor / Q000378:metabolism; D009416:Nerve Regeneration / Q000502:physiology*; D009437:Neuralgia / Q000209:etiology / Q000534:rehabilitation*; D010147:Pain Measurement; D017288:Pain Threshold / Q000502:physiology; D059348:Peripheral Nerve Injuries / Q000150:complications; D010812:Physical Stimulation / Q000009:adverse effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011984:Sensory Receptor Cells / Q000378:metabolism*; D012867:Skin / Q000294:innervation; D064466:Solute Carrier Family 12, Member 1 / Q000378:metabolism*; D064506:Solute Carrier Family 12, Member 2 / Q000378:metabolism*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; C578716:Slc12a1 protein, rat; D064466:Solute Carrier Family 12, Member 1; D064506:Solute Carrier Family 12, Member 2; D020932:Nerve Growth Factor; D015740:Calcitonin Gene-Related Peptide