Exercise-Induced Changes to the Macrophage Response in the Dorsal Root Ganglia Prevent Neuropathic Pain after Spinal Cord Injury

Spinal cord injury (SCI) induces neuropathic pain that is refractory to treatment. Central and peripheral immune responses to SCI play critical roles in pain development. Although immune responses in the dorsal horn have been implicated in SCI-pain, immune mechanisms in the periphery, especially in the dorsal root ganglia (DRG), where nociceptor cell bodies reside, have not been well studied. Exercise is an immunomodulator, and we showed previously that early exercise after SCI reduces pain development. However, the mechanisms of exercise-mediated pain reduction are not understood. Therefore, we examined the 1) underlying immune differences in the spinal cord and DRG between rats with and without pain and 2) immunomodulatory effects of exercise in pain reduction. Rats were subjected to a unilateral contusion at C5 and tested for pain development using von Frey and mechanical conflict-avoidance paradigms. A subgroup of rats was exercised on forced running wheels starting at 5 days post-injury for 4 weeks. We observed greater microglial activation in the C7–C8 dorsal horn of rats with SCI-induced pain compared to rats with normal sensation, and early exercise reduced this activation independently of pain behavior. Further, abnormal pain sensation strongly correlated with an increased number of DRG macrophages. Importantly, exercise-treated rats that maintain normal sensation also have a lower number of macrophages in the DRG. Our data suggest that macrophage presence in the DRG may be an important effector of pain development, and early wheel walking exercise may mediate pain prevention by modulating the injury-induced macrophage response in the DRG. Further supportive evidence demonstrated that rats that developed pain despite exercise intervention still displayed a significantly elevated number of macrophages in the DRG. Collectively, these data suggest that macrophage presence in the DRG may be an amenable cellular target for future therapies.

• Publication year

  2019

• Venue

  Journal of Neurotrauma

• Publication date

  2019-03-01

• Fields of study

  Biology, Medicine, Environmental Science

• Identifiers
  DOI 10.1089/neu.2018.5819PMID 30152715PMCID PMC6484359
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Neuropathic pain following traumatic spinal cord injury: Models, measurement, and mechanisms

  2017cited by this paper
• Chemokines in neuron–glial cell interaction and pathogenesis of neuropathic pain

  2017cited by this paper
• Neuronal-Glial Interactions Maintain Chronic Neuropathic Pain after Spinal Cord Injury

  2017cited by this paper
• Exercise-induced upregulation of endothelial adhesion molecules in human skeletal muscle and number of circulating cells with remodeling properties.

  2017cited by this paper
• Neuropathic pain after spinal cord injury: the impact of sensorimotor activity

  2017cited by this paper
• Early-onset treadmill training reduces mechanical allodynia and modulates calcitonin gene-related peptide fiber density in lamina III/IV in a mouse model of spinal cord contusion injury

  2016cited by this paper
• Persistent Electrical Activity in Primary Nociceptors after Spinal Cord Injury Is Maintained by Scaffolded Adenylyl Cyclase and Protein Kinase A and Is Associated with Altered Adenylyl Cyclase Regulation

  2016cited by this paper
• Nitroxidative Signaling Mechanisms in Pathological Pain.

  2016cited by this paper
• Pain regulation by non-neuronal cells and inflammation

  2016cited by this paper
• Overexpression of the monocyte chemokine CCL2 in dorsal root ganglion neurons causes a conditioning-like increase in neurite outgrowth and does so via a STAT3 dependent mechanism.

  2016cited by this paper
• Delayed Exercise Is Ineffective at Reversing Aberrant Nociceptive Afferent Plasticity or Neuropathic Pain After Spinal Cord Injury in Rats

  2016cited by this paper
• Neuroplasticity of ascending and descending pathways after somatosensory system injury: reviewing knowledge to identify neuropathic pain therapeutic targets

  2016cited by this paper
• Exercise therapy normalizes BDNF upregulation and glial hyperactivity in a mouse model of neuropathic pain

  2015cited by this paper
• Evidence for a distinct neuro-immune signature in rats that develop behavioural disability after nerve injury

  2015cited by this paper
• Macrophage activation and its role in repair and pathology after spinal cord injury.

  2015cited by this paper
• An Intensive Locomotor Training Paradigm Improves Neuropathic Pain following Spinal Cord Compression Injury in Rats

  2015cited by this paper
• Circuitry and plasticity of the dorsal horn--toward a better understanding of neuropathic pain.

  2015cited by this paper
• Temporal kinetics of macrophage polarization in the injured rat spinal cord

  2015cited by this paper
• Early increasing-intensity treadmill exercise reduces neuropathic pain by preventing nociceptor collateral sprouting and disruption of chloride cotransporters homeostasis after peripheral nerve injury

  2015cited by this paper
• Azithromycin drives alternative macrophage activation and improves recovery and tissue sparing in contusion spinal cord injury

  2015cited by this paper
• Central nervous system regenerative failure: role of oligodendrocytes, astrocytes, and microglia.

  2015cited by this paper
• CCL2 Mediates Neuron–Macrophage Interactions to Drive Proregenerative Macrophage Activation Following Preconditioning Injury

  2015cited by this paper
• Exercise after spinal cord injury as an agent for neuroprotection, regeneration and rehabilitation.

  2015cited by this paper
• Acute exercise prevents the development of neuropathic pain and the sprouting of non-peptidergic (GDNF- and artemin-responsive) c-fibers after spinal cord injury.

  2014cited by this paper
• Monocytes in Sterile Inflammation: Recruitment and Functional Consequences

  2014cited by this paper
• IL-4 Signaling Drives a Unique Arginase+/IL-1β+ Microglia Phenotype and Recruits Macrophages to the Inflammatory CNS: Consequences of Age-Related Deficits in IL-4Rα after Traumatic Spinal Cord Injury

  2014cited by this paper
• Neuroinflammatory contributions to pain after SCI: roles for central glial mechanisms and nociceptor-mediated host defense.

  2014cited by this paper
• Pathological pain and the neuroimmune interface

  2014cited by this paper
• Nox2‐dependent signaling between macrophages and sensory neurons contributes to neuropathic pain hypersensitivity

  2014cited by this paper
• Persistent At-Level Thermal Hyperalgesia and Tactile Allodynia Accompany Chronic Neuronal and Astrocyte Activation in Superficial Dorsal Horn following Mouse Cervical Contusion Spinal Cord Injury

  2014cited by this paper
• Global prevalence and incidence of traumatic spinal cord injury

  2014cited by this paper
• TRPV1 channels make major contributions to behavioral hypersensitivity and spontaneous activity in nociceptors after spinal cord injury

  2013cited by this paper
• Exercise Training Attenuates Postoperative Pain and Expression of Cytokines and N-methyl-D-aspartate Receptor Subunit 1 in Rats

  2013cited by this paper
• Acute exercise induces a phenotypic switch in adipose tissue macrophage polarization in diet‐induced obese rats

  2013cited by this paper
• Differential effects of activity dependent treatments on axonal regeneration and neuropathic pain after peripheral nerve injury.

  2013cited by this paper
• Chronic At- and Below-Level Pain after Moderate Unilateral Cervical Spinal Cord Contusion in Rats

  2013cited by this paper
• Neurogenic neuroinflammation: inflammatory CNS reactions in response to neuronal activity

  2013cited by this paper
• Physical Exercise Induces Excess Hsp72 Expression and Delays the Development of Hyperalgesia and Allodynia in Painful Diabetic Neuropathy Rats

  2013cited by this paper
• Phenotypic transitions of macrophages orchestrate tissue repair.

  2013cited by this paper
• A Critical Role for Macrophages Near Axotomized Neuronal Cell Bodies in Stimulating Nerve Regeneration

  2013cited by this paper
• Induction of monocyte chemoattractant protein-1 (MCP-1) and its receptor CCR2 in primary sensory neurons contributes to paclitaxel-induced peripheral neuropathy.

  2013cited by this paper
• Exercise Training Attenuates Neuropathic Pain and Cytokine Expression After Chronic Constriction Injury of Rat Sciatic Nerve

  2012cited by this paper
• The nature and course of sensory changes following spinal cord injury: predictive properties and implications on the mechanism of central pain.

  2012cited by this paper
• Nociceptors as chronic drivers of pain and hyperreflexia after spinal cord injury: an adaptive-maladaptive hyperfunctional state hypothesis

  2012cited by this paper
• Special issue on microglia and chronic pain.

  2012influential reference
• Herpes Simplex Virus Vector–Mediated Expression of Interleukin-10 Reduces Below-Level Central Neuropathic Pain After Spinal Cord Injury

  2012cited by this paper
• Functional crosstalk in culture between macrophages and trigeminal sensory neurons of a mouse genetic model of migraine

  2012cited by this paper
• Effects of Habitual Exercise on the eHsp72-Induced Release of Inflammatory Cytokines by Macrophages from Obese Zucker Rats

  2012cited by this paper
• Acute and chronic tactile sensory testing after spinal cord injury in rats.

  2012cited by this paper
• Spinal Cord Injury Triggers an Intrinsic Growth-Promoting State in Nociceptors

  2012cited by this paper
• Exercise modulates microRNAs that affect the PTEN/mTOR pathway in rats after spinal cord injury.

  2012cited by this paper
• Plasticity in ascending long propriospinal and descending supraspinal pathways in chronic cervical spinal cord injured rats

  2012cited by this paper
• System x(c)(-) regulates microglia and macrophage glutamate excitotoxicity in vivo.

  2012cited by this paper
• CCL2 Released from Neuronal Synaptic Vesicles in the Spinal Cord Is a Major Mediator of Local Inflammation and Pain after Peripheral Nerve Injury

  2011cited by this paper
• Repertoire of microglial and macrophage responses after spinal cord injury

  2011cited by this paper
• Neuronal and microglial mechanisms of neuropathic pain

  2011cited by this paper
• Detailed characterization of neuro-immune responses following neuropathic injury in mice.

  2011cited by this paper
• Spinal cord injury therapies in humans: an overview of current clinical trials and their potential effects on intrinsic CNS macrophages

  2011cited by this paper
• Chemokines, neuronal-glial interactions, and central processing of neuropathic pain.

  2010influential reference
• The myeloid cells of the central nervous system parenchyma

  2010cited by this paper
• Validity of acute and chronic tactile sensory testing after spinal cord injury in rats.

  2010cited by this paper
• Chronic Spontaneous Activity Generated in the Somata of Primary Nociceptors Is Associated with Pain-Related Behavior after Spinal Cord Injury

  2010cited by this paper
• Chemokines and pain mechanisms.

  2009cited by this paper
• Identification of Two Distinct Macrophage Subsets with Divergent Effects Causing either Neurotoxicity or Regeneration in the Injured Mouse Spinal Cord

  2009cited by this paper
• JNK-Induced MCP-1 Production in Spinal Cord Astrocytes Contributes to Central Sensitization and Neuropathic Pain

  2009cited by this paper
• Forced Exercise as a Rehabilitation Strategy after Unilateral Cervical Spinal Cord Contusion Injury

  2009cited by this paper
• Macrophages Promote Axon Regeneration with Concurrent Neurotoxicity

  2009cited by this paper
• Nociceptors Are Interleukin-1β Sensors

  2008cited by this paper
• Cytokine Mechanisms of Central Sensitization: Distinct and Overlapping Role of Interleukin-1β, Interleukin-6, and Tumor Necrosis Factor-α in Regulating Synaptic and Neuronal Activity in the Superficial Spinal Cord

  2008cited by this paper
• Activity-dependent plasticity: implications for recovery after spinal cord injury.

  2008cited by this paper
• Remote activation of microglia and pro-inflammatory cytokines predict the onset and severity of below-level neuropathic pain after spinal cord injury in rats.

  2008cited by this paper
• Immune cell involvement in dorsal root ganglia and spinal cord after chronic constriction or transection of the rat sciatic nerve.

  2007cited by this paper
• Extended swimming exercise reduces inflammatory and peripheral neuropathic pain in rodents.

  2007cited by this paper
• Microglia in the adult brain arise from Ly-6ChiCCR2+ monocytes only under defined host conditions

  2007cited by this paper
• The neuropathic pain triad: neurons, immune cells and glia

  2007influential reference
• A role for peripheral afferents in the pathophysiology and treatment of at‐level neuropathic pain in spinal cord injury? A case report

  2007cited by this paper
• Inhibition of MCP-1/CCR2 pathway ameliorates the development of diabetic nephropathy.

  2007cited by this paper
• Monocyte chemoattractant protein‐1 functions as a neuromodulator in dorsal root ganglia neurons

  2007cited by this paper
• Extracellular Signal-Regulated Kinase-Regulated Microglia–Neuron Signaling by Prostaglandin E2 Contributes to Pain after Spinal Cord Injury

  2007influential reference
• Tumor necrosis factor-alpha contributes to below-level neuropathic pain after spinal cord injury.

  2006cited by this paper
• Intra- and Extraneuronal Changes of Immunofluorescence Staining for TNF- and TNFR1 in the Dorsal Root Ganglia of Rat Peripheral Neuropathic Pain Models

  2006cited by this paper
• Tumor necrosis factor–α contributes to below‐level neuropathic pain after spinal cord injury

  2006cited by this paper
• Activated Microglia Contribute to the Maintenance of Chronic Pain after Spinal Cord Injury

  2006influential reference
• ERK is sequentially activated in neurons, microglia, and astrocytes by spinal nerve ligation and contributes to mechanical allodynia in this neuropathic pain model

  2005cited by this paper
• Exercise restores levels of neurotrophins and synaptic plasticity following spinal cord injury.

  2005cited by this paper
• Intraneural injection of interleukin‐1β and tumor necrosis factor‐alpha into rat sciatic nerve at physiological doses induces signs of neuropathic pain

  2005cited by this paper
• Excitatory monocyte chemoattractant protein-1 signaling is up-regulated in sensory neurons after chronic compression of the dorsal root ganglion.

  2005cited by this paper
• Chemokines: Integrators of Pain and Inflammation

  2005cited by this paper
• Passive exercise and fetal spinal cord transplant both help to restore motoneuronal properties after spinal cord transection in rats

  2004cited by this paper
• Exercise‐induced gene expression in soleus muscle is dependent on time after spinal cord injury in rats

  2004cited by this paper
• Three exercise paradigms differentially improve sensory recovery after spinal cord contusion in rats.

  2004cited by this paper
• Impaired neuropathic pain responses in mice lacking the chemokine receptor CCR2

  2003cited by this paper
• Blood monocytes consist of two principal subsets with distinct migratory properties.

  2003cited by this paper
• Experimental Modeling of Spinal Cord Injury: Characterization of a Force-Defined Injury Device

  2003cited by this paper
• Microglia as a source and target of cytokines

  2002cited by this paper
• Bone Marrow Chimeric Rats Reveal the Unique Distribution of Resident and Recruited Macrophages in the Contused Rat Spinal Cord

  2001cited by this paper
• Glial activation: a driving force for pathological pain.

  2001cited by this paper
• Effects of exercise on lymphocytes and cytokines

  2000cited by this paper
• Exercise and the immune system: regulation, integration, and adaptation.

  2000cited by this paper
• Depletion of hematogenous macrophages promotes partial hindlimb recovery and neuroanatomical repair after experimental spinal cord injury.

  1999cited by this paper

• Monocytes, Macrophages, and Exercise Prescription: A New Frontier in Immunomodulation

  2026cites this paper
• Depleting non-resolving neuroinflammation in chronic spinal cord injury attenuates thermal hypersensitivity.

  2026cites this paper
• Blockade of opioid receptors prevents the effect of exercise on neuropathic pain in mice, promoting immunoregulation in the brainstem and prefrontal cortex.

  2025cites this paper
• Pretreatment with dimethyl fumarate prevents chronic pain and its comorbidities via Nrf2 pathway in a rat model of neuropathic pain.

  2025cites this paper
• Emerging role of macrophages in neuropathic pain

  2025cites this paper
• Administration of anti-GFAP antibodies increases CGRP expression and increases pain hypersensitivity in spinal cord injured animals

  2025cites this paper
• Role of Exercise on Inflammation Cytokines of Neuropathic Pain in Animal Models

  2024cites this paper
• Cypin Inhibition as a Therapeutic Approach to Treat Spinal Cord Injury–Induced Mechanical Pain

  2024cites this paper
• Early Mobilization in Neurocritical Care

  2024cites this paper
• A research protocol to study the critical time window for rehabilitation after incomplete spinal cord injury: early vs. late locomotor training

  2024cites this paper
• Neuropathic Pain Induced by Spinal Cord Injury from the Glia Perspective and Its Treatment

  2024cites this paper
• Neurologic dance training and home exercise improve motor-cognitive dual-task function similarly, but through potentially different mechanisms, among breast cancer survivors with chemotherapy-induced neuropathy: Initial results of a randomized, controlled clinical trial

  2024cites this paper
• Mechanisms and Therapeutic Prospects of Microglia-Astrocyte Interactions in Neuropathic Pain Following Spinal Cord Injury

  2024cites this paper
• Treadmill running on neuropathic pain: via modulation of neuroinflammation

  2024cites this paper
• Sex Differences in Pain: Spinal Cord Injury in Female and Male Mice Elicits Behaviors Related to Neuropathic Pain

  2023cites this paper
• Myeloid Cell Association with Spinal Cord Injury-Induced Neuropathic Pain and Depressive-like Behaviors in LysM-eGFP Mice.

  2023cites this paper
• Voluntary wheel running prevents formation of membrane attack complexes and myelin degradation after peripheral nerve injury.

  2023cites this paper
• The Role of Exercise in the Alleviation of Neuropathic Pain Following Traumatic Spinal Cord Injuries: A Systematic Review and Meta-analysis

  2023cites this paper
• Acute or chronic depletion of macrophages in the dorsal root ganglia induces neuropathic pain after unilateral cervical spinal cord injury

  2023influential citation
• Evaluating Pain Behaviours: Widely Used Mechanical and Thermal Methods in Rodents.

  2023cites this paper
• Influence of routine exercise on the peripheral immune system to prevent and alleviate pain

  2023cites this paper
• Spinal cord injury in mice amplifies anxiety: a novel light-heat conflict test exposes increased salience of anxiety over heat

  2023cites this paper
• Attenuation of SCI-Induced Hypersensitivity by Intensive Locomotor Training and Recombinant GABAergic Cells

  2023cites this paper
• Anxiety-like behaviors in mice unmasked: Revealing sex differences in anxiety using a novel light-heat conflict test

  2023cites this paper
• Effect of Acute Physical Interventions on Pathophysiology and Recovery After Spinal Cord Injury: A Comprehensive Review of the Literature

  2022cites this paper
• Cell transplantation for reducing neuropathic pain after SCI

  2022cites this paper
• Peripheral mechanisms contributing to central neuropathic pain following SCI

  2022cites this paper
• Exercise as a therapeutic intervention for neuropathic pain after spinal cord injury

  2022cites this paper
• Behavioral assays of pain in rodent models of spinal cord injury

  2022cites this paper
• Dorsal horn neuronal sparing predicts the development of at-level mechanical allodynia following cervical spinal cord injury in mice.

  2022cites this paper
• Early mobilization in spinal cord injury promotes changes in microglial dynamics and recovery of motor function

  2022cites this paper
• Grafted human ESC-derived astroglia repair spinal cord injury via activation of host anti-inflammatory microglia in the lesion area

  2022cites this paper
• Enhanced nociceptive behavior and expansion of associated primary afferents in a rabbit model of cerebral palsy

  2022cites this paper
• Therapeutic potential of progesterone in spinal cord injury‐induced neuropathic pain: At the crossroads between neuroinflammation and N‐methyl‐D‐aspartate receptor

  2022cites this paper
• The Impact of Activity-Based Interventions on Neuropathic Pain in Experimental Spinal Cord Injury

  2022influential citation
• Sex differences in pain: Spinal cord injury in female and male mice elicits neuropathic pain symptoms

  2022cites this paper
• Preconditioning by voluntary wheel running attenuates later neuropathic pain via Nrf2 antioxidant signaling in rats

  2021cites this paper
• Exercise-Induced Plasticity in Signaling Pathways Involved in Motor Recovery after Spinal Cord Injury

  2021cites this paper
• Cervical spinal cord injury-induced neuropathic pain in male mice is associated with a persistent pro-inflammatory macrophage/microglial response in the superficial dorsal horn.

  2021cites this paper
• A Handful of Details to Ensure the Experimental Reproducibility on the FORCED Running Wheel in Rodents: A Systematic Review

  2021cites this paper
• Exercise Reduces Pain and Deleterious Histological Effects in Fibromyalgia-like Model.

  2021cites this paper
• Systemic gene expression profiles according to pain types in individuals with chronic spinal cord injury

  2021cites this paper
• Acute spinal cord injury: Pathophysiology and pharmacological intervention

  2021cites this paper
• Exercise and Neuropathic Pain: A General Overview of Preclinical and Clinical Research

  2021cites this paper
• Exercise Ameliorates Spinal Cord Injury by Changing DNA Methylation

  2021cites this paper
• Enhanced nociceptive behavior and expansion of associated primary afferents in a rabbit model of cerebral palsy

  2021cites this paper
• Physical exercise mitigates neuropathic changes in an animal model for Charcot-Marie-Tooth disease 1×.

  2021cites this paper
• Redox interactions of immune cells and muscle in the regulation of exercise-induced pain and analgesia: implications on the modulation of muscle nociceptor sensory neurons

  2021cites this paper
• Spinal cord injury in mice impacts central and peripheral pathology in a severity-dependent manner.

  2021cites this paper
• Enhanced nociception in a rabbit model of cerebral palsy

  2021cites this paper
• Plasticity in Cervical Motor Circuits following Spinal Cord Injury and Rehabilitation

  2021cites this paper
• Protocol for rapid onset of mobilisation in patients with traumatic spinal cord injury (PROMPT-SCI) study: a single-arm proof-of-concept trial of early in-bed leg cycling following acute traumatic spinal cord injury

  2021cites this paper
• Mutually beneficial effects of intensive exercise and GABAergic neural progenitor cell transplants in reducing neuropathic pain and spinal pathology in rats with spinal cord injury.

  2020cites this paper
• The gut-brain axis and beyond: Microbiome control of spinal cord injury pain in humans and rodents

  2020cites this paper
• Modelling at‐level allodynia after mid‐thoracic contusion in the rat

  2020cites this paper
• Histological and functional characterization of cervical spinal cord injury after graded contusion

  2020cites this paper
• Intensive Locomotor Training Provides Sustained Alleviation of Chronic Spinal Cord Injury-Associated Neuropathic Pain: A Two-Year Pre-Clinical Study

  2020cites this paper
• Mechanism of exercise-induced analgesia: what we can learn from physically active animals

  2020cites this paper
• At-level allodynia after mid-thoracic contusion in the rat

  2020cites this paper
• Neuroimmune System as a Driving Force for Plasticity Following CNS Injury

  2020cites this paper
• Central Neuropathic Mechanisms in Pain Signaling Pathways: Current Evidence and Recommendations

  2020cites this paper
• Characterization of traumatic spinal cord injury model in relation to neuropathic pain in the rat

  2019cites this paper
• Systemic inflammation in traumatic spinal cord injury.

  2019cites this paper
• The effects and potential mechanisms of locomotor training on improvements of functional recovery after spinal cord injury.

  2019cites this paper
• Cultivating a healthy neuro-immune network: A health psychology approach.

  2019cites this paper
• Adaptive mechanisms driving maladaptive pain: how chronic ongoing activity in primary nociceptors can enhance evolutionary fitness after severe injury

  2019cites this paper
• Neuropathic pain after spinal cord injury and physical exercise in animal models: a systematic review and meta-analysis.

  2019cites this paper
• Inhibition of NOX2 signaling limits pain-related behavior and improves motor function in male mice after spinal cord injury: Participation of IL-10/miR-155 pathways.

  2019cites this paper
• Sham surgeries for central and peripheral neural injuries persistently enhance pain-avoidance behavior as revealed by an operant conflict test.

  2019cites this paper