- •Removal of macrophages from muscle prevents development of chronic muscle hyperalgesia induced by repeated acid injections.
- •Blockade of toll-like receptor 4 (TLR4) or activation prevents development of chronic muscle pain.
- •Replacement of 1 acid injection with either lipopolysaccharide or interleukin-6 to mimic macrophage activation results in development of hyperalgesia.
- •Acid, lipopolysaccharide, and interleukin-6 increase the number of macrophages in muscle and induce release of cytokines from cultured macrophages.
- •Thus, macrophages play a critical role in the development of chronic muscle pain.
Purchase one-time access:Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
One-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
- ASICs Mediate Pain and Inflammation in Musculoskeletal Diseases.Physiology (Bethesda ). 2015; 30: 449-459
- Toll-like receptor 4 plays a role in macrophage phagocytosis during peritoneal sepsis.J Pediatr Surg. 2007; 42: 927-932
- A key role for gp130 expressed on peripheral sensory nerves in pathological pain.J Neurosci. 2009; 29: 13473-13483
- Inflammatory monocytes recruited after skeletal muscle injury switch into antiinflammatory macrophages to support myogenesis.J Exp Med. 2007; 204: 1057-1069
- Co-localization of p-CREB and p-NR1 in spinothalamic neurons in a chronic muscle pain model.Neurosci Lett. 2007; 418: 22-27
- Nociceptors are interleukin-1beta sensors.J Neurosci. 2008; 28: 14062-14073
- Epidemiology of chronic musculoskeletal pain.Best Pract Res Clin Rheumatol. 2011; 25: 173-183
- Activation of NMDA receptors in the brainstem, rostral ventromedial medulla, and nucleus reticularis gigantocellularis mediates mechanical hyperalgesia produced by repeated intramuscular injections of acidic saline in rats.Pain. 2010; 11: 378-387
- Changes in expression of NMDA-NR1 receptor subunits in the rostral ventromedial medulla modulates pain behaviors.Pain. 2010; 151: 155-161
- IL-10 cytokine released from M2 macrophages is crucial for analgesic and anti-inflammatory effects of acupuncture in a model of inflammatory muscle pain.Mol Neurobiol. 2015; 51: 19-31
- Eccentric muscle contraction and stretching evoke mechanical hyperalgesia and modulate CGRP and P2X(3) expression in a functionally relevant manner.Pain. 2010; 149: 284-295
- Role of interleukin-6 in chronic muscle hyperalgesic priming.Neuroscience. 2008; 152: 521-525
- Enhanced cytokine-induced mechanical hyperalgesia in skeletal muscle produced by a novel mechanism in rats exposed to unpredictable sound stress.Eur J Pain. 2011; 15: 796-800
- Peptides inhibitors of acid-sensing ion channels.Toxicon. 2007; 49: 271-284
- Acidic buffer induced muscle pain evokes referred pain and mechanical hyperalgesia in humans.Pain. 2008; 140: 254-264
- Acid-sensing ion channels (ASICs) in mouse skeletal muscle afferents are heteromers composed of ASIC1a, ASIC2, and ASIC3 subunits.FASEB J. 2013; 27: 793-802
- ASIC3 is required for development of fatigue-induced hyperalgesia.Mol Neurobiol. 2016; 53: 1020-1030
- Fatigue-enhanced hyperalgesia in response to muscle insult: Induction and development occur in a sex-dependent manner.Pain. 2013; 154: 2668-2676
- The expression of Toll-like receptor 4, 7 and co-receptors in neurochemical sub-populations of rat trigeminal ganglion sensory neurons.Neuroscience. 2015; 310: 686-698
- Skeletal myocytes are a source of interleukin-6 mRNA expression and protein release during contraction: Evidence of fiber type specificity.FASEB J. 2004; 18: 992-994
- Phosphorylation of CREB and mechanical hyperalgesia is reversed by blockade of the cAMP pathway in a time-dependent manner after repeated intramuscular acid injections.J Neurosci. 2003; 23: 5437-5445
- Excitatory and modulatory effects of inflammatory cytokines and neurotrophins on mechanosensitive group IV muscle afferents in the rat.Pain. 2005; 114: 168-176
- Diverse sensory inputs permit priming in the acidic saline model of hyperalgesia.Eur J Pain. 2012; 16: 966-973
- Blockade of Toll-like receptors (TLR2, TLR4) attenuates pain and potentiates buprenorphine analgesia in a rat neuropathic pain model.Neural Plast. 2016; 5238730: 2016
- Reversal of acid-induced and inflammatory pain by the selective ASIC3 inhibitor, APETx2.Br J Pharmacol. 2010; 161: 950-960
- CC-chemokine MIP-1alpha in the spinal cord contributes to nerve injury-induced neuropathic pain.Neurosci Lett. 2010; 484: 17-21
- Extracellular acidosis modulates the endocytosis and maturation of macrophages.Cell Immunol. 2013; 281: 44-50
- Microglia: A sensor for pathological events in the CNS.Trends Neurosci. 1996; 19: 312-318
- Transcriptional regulation of macrophage polarization: enabling diversity with identity.Nat Rev Immunol. 2011; 11: 750-761
- Regular physical activity prevents chronic pain by altering resident muscle macrophage phenotype and increasing IL-10 in mice.Pain. 2016; 157: 70-79
- Dorsal root ganglion neurons innervating skeletal muscle respond to physiological combinations of protons, ATP, and lactate mediated by ASIC, P2X, and TRPV1.J Neurophysiol. 2008; 100: 1184-1201
- Emerging role of Toll-like receptors in the control of pain and itch.Neurosci Bull. 2012; 28: 131-144
- Mechanisms involved in IL-6-induced muscular mechanical hyperalgesia in mice.Pain. 2010; 151: 345-355
- Altered visceral sensation in response to somatic pain in the rat.Gastroenterology. 2004; 126: 1082-1089
- ASIC3, an acid-sensing ion channel, is expressed in metaboreceptive sensory neurons.Mol Pain. 2005; 1: 35
- Exploring the full spectrum of macrophage activation.Nat Rev Immunol. 2008; 8: 958-969
- Macrophage response to peripheral nerve injury: The quantitative contribution of resident and hematogenous macrophages.Lab Invest. 2003; 83: 175-185
- Rapid response of identified resident endoneurial macrophages to nerve injury.Am J Pathol. 2001; 159: 2187-2197
- Further evidence for a crucial role of resident endoneurial macrophages in peripheral nerve disorders: Lessons from acrylamide-induced neuropathy.Glia. 2008; 56: 1005-1016
- Discovery and validation of a new class of small molecule Toll-like receptor 4 (TLR4) inhibitors.PLoS One. 2013; 8: e65779
- Cutting edge: Endotoxin tolerance in mouse peritoneal macrophages correlates with down-regulation of surface toll-like receptor 4 expression.J Immunol. 2000; 164: 3476-3479
- Evidence that interleukin-6 is produced in human skeletal muscle during prolonged running.J Physiol. 1998; 508: 949-953
- Increased glutamate and decreased glycine release in the rostral ventromedial medulla during induction of a pre-clinical model of chronic widespread muscle pain.Neurosci Lett. 2009; 457: 141-145
- Neuroglial activation repertoire in the injured brain: graded response, molecular mechanisms and cues to physiological function.Brain Res Brain Res Rev. 1999; 30: 77-105
- Tumor necrosis factor causes persistent sensitization of joint nociceptors to mechanical stimuli in rats.Arthritis Rheum. 2010; 62: 3806-3814
- Intramuscular injection of tumor necrosis factor-alpha induces muscle hyperalgesia in rats.Pain. 2003; 104: 579-588
- The role of proinflammatory cytokines in the generation and maintenance of joint pain.Ann N Y Acad Sci. 2010; 1193: 60-69
- Effects of NMDA and non-NMDA ionotropic glutamate receptor antagonists on the development and maintenance of hyperalgesia induced by repeated intramuscular injection of acidic saline.Pain. 2002; 98: 69-78
- Excitatory amino acid concentrations increase in the spinal cord dorsal horn after repeated intramuscular injection of acidic saline.Pain. 2005; 119: 142-149
- Unilateral intramuscular injections of acidic saline produce a bilateral, long-lasting hyperalgesia.Muscle Nerve. 2001; 24: 37-46
- Regular physical activity prevents development of chronic pain and activation of central neurons.J Appl Physiol. 2013; 114: 725-733
- Chronic hyperalgesia induced by repeated acid injections in muscle is abolished by the loss of ASIC3, but not ASIC1.Pain. 2003; 106: 229-239
- Recent findings on how proinflammatory cytokines cause pain: peripheral mechanisms in inflammatory and neuropathic hyperalgesia.Neurosci Lett. 2004; 361: 184-187
- Descending facilitatory pathways from the RVM initiate and maintain bilateral hyperalgesia after muscle insult.Pain. 2008; 136: 331-339
- Acid-sensing ion channels contribute to the effect of acidosis on the function of dendritic cells.J Immunol. 2011; 186: 3686-3692
- cAMP/protein kinase A activates cystic fibrosis transmembrane conductance regulator for ATP release from rat skeletal muscle during low pH or contractions.PLoS One. 2012; 7: e50157
- P2X4 receptors mediate PGE2 release by tissue-resident macrophages and initiate inflammatory pain.EMBO J. 2010; 29: 2290-2300
- The liposome-mediated macrophage ‘suicide’ technique.J Immunol Methods. 1989; 124: 1-6
- Liposomes for specific depletion of macrophages from organs and tissues.Methods Mol Biol. 2010; 605: 189-203
- Trigeminal nociceptors express TLR-4 and CD14: A mechanism for pain due to infection.J Dent Res. 2006; 85: 49-53
- ASIC1 and ASIC3 play different roles in the development of hyperalgesia after inflammatory muscle injury.J Pain. 2010; 11: 210-218
- Monocytes/macrophages control resolution of transient inflammatory pain.J Pain. 2014; 15: 496-506
- The effect of toll-like receptor 4 on macrophage cytokines during endotoxin induced uveitis.Int J Mol Sci. 2012; 13: 7508-7520
- Pregabalin reduces muscle and cutaneous hyperalgesia in two models of chronic muscle pain in rats.J Pain. 2007; 8: 422-429
- Intraneural injection of interleukin-1beta and tumor necrosis factor-alpha into rat sciatic nerve at physiological doses induces signs of neuropathic pain.Pain. 2005; 116: 257-263
- Annexin A2 binds to endosomes and negatively regulates TLR4-triggered inflammatory responses via the TRAM-TRIF pathway.Sci Rep. 2015; 5: 15859
- Acute cytokine response to systemic adenoviral vectors in mice is mediated by dendritic cells and macrophages.Mol Ther. 2001; 3: 697-707
Wei-Yi Gong and Ramy E. Abdelhamid contributed equally to the report.
Funded by the National Institutes of Health Grant #AR061371.
The authors have no conflicts of interest to declare.