Exercise therapy normalizes BDNF upregulation and glial hyperactivity in a mouse model of neuropathic pain

Abstract

Treatment of neuropathic pain is a clinical challenge likely because of the time-dependent changes in many neurotransmitter systems, growth factors, ionic channels, membrane receptors, transcription factors, and recruitment of different cell types. Conversely, an increasing number of reports have shown the ability of extended and regular physical exercise in alleviating neuropathic pain throughout a wide range of mechanisms. In this study, we investigate the effect of swim exercise on molecules associated with initiation and maintenance of nerve injury-induced neuropathic pain. BALB/c mice were submitted to partial ligation of the sciatic nerve followed by a 5-week aerobic exercise program. Physical training reversed mechanical hypersensitivity, which lasted for an additional 4 weeks after exercise interruption. Swim exercise normalized nerve injury-induced nerve growth factor, and brain-derived neurotrophic factor (BDNF) enhanced expression in the dorsal root ganglion, but had no effect on the glial-derived neurotrophic factor. However, only BDNF remained at low levels after exercise interruption. In addition, exercise training significantly reduced the phosphorylation status of PLCγ-1, but not CREB, in the spinal cord dorsal horn in response to nerve injury. Finally, prolonged swim exercise reversed astrocyte and microglia hyperactivity in the dorsal horn after nerve lesion, which remained normalized after training cessation. Together, these results demonstrate that exercise therapy induces long-lasting analgesia through various mechanisms associated with the onset and advanced stages of neuropathy. Moreover, the data support further studies to clarify whether appropriate exercise intensity, volume, and duration can also cause long-lasting pain relief in patients with neuropathic pain.

TNF-α Differentially Regulates Synaptic Plasticity in the Hippocampus and Spinal Cord by Microglia-Dependent Mechanisms after Peripheral Nerve Injury

“…They may also explain, in part, the fact that exercise is beneficial for chronic pain patients because it reduces pain perception and also exhibits antidepressant and cognition-enhancing effects (Ambrose and Golightly, 2015). Interestingly, exercise increases BDNF expression in the hippocampus, but suppresses BDNF production in the spinal dorsal horn (Mattson, 2012;Almeida et al, 2015). It will be of considerable interest to determine whether there are roles for microglia and TNF-␣ in these beneficial effects of exercise on chronic pain.…”

TNF-α Differentially Regulates Synaptic Plasticity in the Hippocampus and Spinal Cord by Microglia-Dependent Mechanisms after Peripheral Nerve Injury

“…They may also explain, in part, the fact that exercise is beneficial for chronic pain patients because it reduces pain perception and also exhibits antidepressant and cognition-enhancing effects (Ambrose and Golightly, 2015). Interestingly, exercise increases BDNF expression in the hippocampus, but suppresses BDNF production in the spinal dorsal horn (Mattson, 2012;Almeida et al, 2015). It will be of considerable interest to determine whether there are roles for microglia and TNF-␣ in these beneficial effects of exercise on chronic pain.…”

Prior voluntary wheel running attenuates neuropathic pain

“…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 …”