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.

Prior voluntary wheel running attenuates neuropathic pain

“…1,6,14,15,42 Therefore, we investigated whether prior running normalized the expression of two neuroimmune signaling pathways in the dorsal spinal cord at 3 and 14 days after CCI.…”

“…2,65 The 14-day data are consistent with a previous report that treadmill running after peripheral nerve injury attenuated BDNF expression and restored KCC2 expression in the spinal dorsal horn. 42 Despite the common modulation of such neuroimmune pathways by exercise both before and after nerve injury, the mechanisms may ultimately diverge; exercise after injury must be maintained for reversal of nociceptive hypersensitivity to be sustained. 60 …”

“…1,6,7,12–15,18,31,34,42,54,60 Several studies have reported that neuroimmune signaling, processes that subserve neuropathic pain after nerve injury, 2,21 is suppressed in the neuraxis of rodents exercised after injury. For example, expression of activation markers for microglia (Iba1, CD11b) and astrocytes (GFAP) is decreased in the spinal dorsal horn, 1,6,15,31,42 while pro-inflammatory cytokines tumor necrosis factor and interleukin-1β (IL-1β) are downregulated in the brainstem and sciatic nerve. 7,12,13 Such pro-inflammatory cytokines are produced by reactive macrophages, microglia, and astrocytes, and increase neuroexcitability in nociceptive pathways (e.g.…”

“…2,21,74 Brain derived neurotrophic factor (BDNF) expression is also attenuated in the dorsal root ganglia (DRG) and spinal dorsal horn, and potassium-chloride cotransporter (KCC2) expression is restored in the spinal dorsal horn in exercised rodents. 1,14,42 This pro-nociceptive axis induces disinhibition following downregulation of KCC2 by P2X4 receptor-dependent BDNF release from microglia. 17,66,67 …”

Physical rehabilitation to treat neuropathic pain

“…Regular exercises of moderate intensity tend to favor sensory motor functions and the regeneration potential of injured axons. In summary, results of animal model studies propose this effect of exercise by increased neurotrophin levels, neural activity recoding, peripheral sensory reorganization, supraspinal neuronal excitability change and cortical sensory projections 58 . For example, a study by Cobianchi et al 59 has compared two treadmill running protocols in mice after chronic sciatic nerve constriction injury.…”