Interleukin-4 mediates the analgesia produced by low-intensity exercise in mice with neuropathic pain

Abstract

Peripheral nerve injury (PNI) activates the immune system, resulting in increased proinflammatory cytokines at the site of injury and in the spinal cord dorsal horn. Exercise modulates the immune system promoting an anti-inflammatory phenotype of macrophages in uninjured muscle, and increases in anti-inflammatory cytokines can promote healing and analgesia. We proposed that PNI will decrease, and treadmill exercise will increase, release of anti-inflammatory cytokines at the site of injury and in the spinal cord. We show that 2 weeks of treadmill exercise improves neuropathic pain behaviors in mice: mechanical hyperalgesia, escape and avoidance behavior, and spontaneous locomotor activity. Peripheral nerve injury reduced anti-inflammatory cytokines (interleukin-4 [IL-4], IL-1ra, and IL-5) at the site of nerve injury and in the spinal dorsal horn, whereas exercise restored IL-4, IL-1ra, and IL-5 concentrations to preinjury levels. IL4 mice and mice treated with IL-4 antibody did not develop analgesia to treadmill exercise. Using immunohistochemical staining of the sciatic nerve, treadmill exercise increased the percentage of M2 macrophages (secretes anti-inflammatory cytokines) and decreased M1 macrophages (secretes proinflammatory cytokines) when compared with sedentary mice. The increased M2 and decreased M1 macrophages in exercised mice did not occur in IL-4 mice. In the spinal cord, PNI increased glial cell activation, brain-derived neurotrophic factor and β-nerve growth factor levels, and decreased IL-4 and IL-1ra levels, whereas treadmill exercise suppressed glial cells activation (Glial Fibrillary Acidic Protein and Iba1 immunoreactivity), reduced brain-derived neurotrophic factor and β-nerve growth factor, and increased IL-4, IL-1ra, and IL-5 concentrations. Our results suggest that IL-4 mediates the analgesia produced by low-intensity exercise by modulating peripheral and central neuroimmune responses in mice with neuropathic pain.

Mechanisms underlying immobilization‐induced muscle pain in rats

“…They are mainly classified into M1 and M2 phenotypes. M1 macrophages release inflammatory cytokines, such as Tumor necrosis factor‐α (TNF‐α), IL‐1β, and IL‐6, and their levels increase in several pain conditions . Our findings suggest that upregulation of IL‐1β mRNA was related to an increase in M1 macrophages and affected muscular hyperalgesia during cast immobilization in this study.…”

“…IL‐1β mRNA expression was increased in immobilized muscle . IL‐1β plays a critical role in various pain states, such as neuropathic pain and osteoarthritis, through upregulation of NGF. Our observations of increased NGF level in immobilized muscle may be due to an accumulation of M1 macrophages as well as upregulation of IL‐1β.…”

“…Macrophages also contribute to noninflammatory muscle pain development in mouse models . They accumulate in the immobilized skeletal muscles and release inflammatory cytokines, such as tumor necrosis factor‐α (TNF‐α), interleukin‐1β (IL‐1β), and IL‐6 . In addition, IL‐1β mRNA expression increases in immobilized muscle .…”

<p>Applying Serum Cytokine Levels to Predict Pain Severity in Cancer Patients</p>

“…29 It has been shown to help mediate analgesic effects of exercising in mice that had neuropathic pain. 30 Little information is available on the direct roles of IFN-γ, IL-23, and IL-5 in pain. IFN-γ plays an important role in the expression of the Major Histocompatibility Complex (MHC), which is a crucial part of the immune system, as it helps in the detection of antigens.…”

Regular physical activity reduces the percentage of spinally projecting neurons that express mu-opioid receptors from the RVM

“…Regular physical activity/exercise is an important and effective non-pharmacological treatment for individuals with chronic pain [3,[8][9][10]26], and large population studies show that people who are physically active have a lower incidence of chronic pain [34,35,69]. In parallel, prior studies show that regular physical activity prevents development of chronic muscle pain, activity-induced pain, and neuropathic pain in animal models [4][5][6]19,37,39,58]. Central inhibitory mechanisms, involving serotonin and opioids, are critical to the analgesia produced by regular physical activity.…”