title: Muscle IL1β Drives Ischemic Myalgia via ASIC3-Mediated Sensory Neuron Sensitization.
abstract: Musculoskeletal pain is a significantly common clinical complaint. Although it is known that muscles are quite sensitive to alterations in blood flow/oxygenation and a number of muscle pain disorders are based in problems of peripheral perfusion, the mechanisms by which ischemic-like conditions generate myalgia remain unclear. We found, using a multidisciplinary experimental approach, that ischemia and reperfusion injury (I/R) in male Swiss Webster mice altered ongoing and evoked pain-related behaviors in addition to activity levels through enhanced muscle interleukin-1 beta (IL1β)/IL1 receptor signaling to group III/IV muscle afferents. Peripheral sensitization depended on acid-sensing ion channels (ASICs) because treatment of sensory afferents in vitro with IL1β-upregulated ASIC3 in single cells, and nerve-specific knock-down of ASIC3 recapitulated the results of inhibiting the enhanced IL1β/IL1r1 signaling after I/R, which was also found to regulate afferent sensitization and pain-related behaviors. This suggests that targeting muscle IL1β signaling may be a potential analgesic therapy for ischemic myalgia.
  
  
  
  Here, we have described a novel pathway whereby increased inflammation within the muscle tissue during ischemia/reperfusion injury sensitizes group III and IV muscle afferents via upregulation of acid-sensing ion channel 3 (ASIC3), leading not only to alterations in mechanical and chemical responsiveness in individual afferents, but also to pain-related behavioral changes. Furthermore, these I/R-induced changes can be prevented using an afferent-specific siRNA knock-down strategy targeting either ASIC3 or the upstream mediator of its expression, interleukin 1 receptor 1. Therefore, this knowledge may contribute to the development of alternative therapeutics for muscle pain and may be especially relevant to pain caused by issues of peripheral circulation, which is commonly observed in disorders such as complex regional pain syndrome, sickle cell anemia, or fibromyalgia.
authors.affiliation: Department of Anesthesia, Division of Pain Management, Cincinnati Children's Hospital Medical Center, and.
authors.forename: Jessica L
authors.identifier: 0000-0003-4577-4934
authors.initials: JL
authors.lastname: Ross
authors.affiliation: Department of Anesthesia, Division of Pain Management, Cincinnati Children's Hospital Medical Center, and.
authors.forename: Luis F
authors.identifier: 0000-0003-4225-4060
authors.initials: LF
authors.lastname: Queme
authors.affiliation: Department of Anesthesia, Division of Pain Management, Cincinnati Children's Hospital Medical Center, and.
authors.forename: Elysia R
authors.identifier: 0000-0002-7113-7552
authors.initials: ER
authors.lastname: Cohen
authors.affiliation: Department of Anesthesia, Division of Pain Management, Cincinnati Children's Hospital Medical Center, and.
authors.forename: Kathryn J
authors.identifier: 0000-0002-7936-3714
authors.initials: KJ
authors.lastname: Green
authors.affiliation: Department of Anesthesia, Division of Pain Management, Cincinnati Children's Hospital Medical Center, and.
authors.forename: Peilin
authors.initials: P
authors.lastname: Lu
authors.affiliation: Department of Anesthesia, Division of Pain Management, Cincinnati Children's Hospital Medical Center, and.
authors.forename: Aaron T
authors.initials: AT
authors.lastname: Shank
authors.affiliation: Department of Anesthesia, Division of Pain Management, Cincinnati Children's Hospital Medical Center, and.
authors.forename: Suzie
authors.initials: S
authors.lastname: An
authors.affiliation: Department of Anesthesia, Division of Pain Management, Cincinnati Children's Hospital Medical Center, and.
authors.forename: Renita C
authors.identifier: 0000-0002-4638-0200
authors.initials: RC
authors.lastname: Hudgins
authors.affiliation: Department of Anesthesia, Division of Pain Management, Cincinnati Children's Hospital Medical Center, and Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio 45229 michael.jankowski@cchmc.org.
authors.forename: Michael P
authors.identifier: 0000-0002-4700-096X
authors.initials: MP
authors.lastname: Jankowski
mesh_terms: D062565:Acid Sensing Ion Channels / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D019054:Evoked Potentials, Motor / Q000502:physiology; D005727:Ganglia, Spinal / Q000166:cytology; D006930:Hyperalgesia / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology; D053583:Interleukin-1beta / Q000378:metabolism* / Q000494:pharmacology; D007511:Ischemia / Q000150:complications*; D008297:Male; D051379:Mice; D018482:Muscle, Skeletal / Q000378:metabolism*; D063806:Myalgia / Q000188:drug therapy / Q000209:etiology*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D010147:Pain Measurement; D034741:RNA, Small Interfering / Q000494:pharmacology; D017472:Receptors, Interleukin-1 / Q000378:metabolism; D058477:Receptors, Purinergic P2X3 / Q000378:metabolism; D015427:Reperfusion Injury / Q000150:complications; D012677:Sensation / Q000187:drug effects; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D062565:Acid Sensing Ion Channels; D053583:Interleukin-1beta; D009419:Nerve Tissue Proteins; D034741:RNA, Small Interfering; D017472:Receptors, Interleukin-1; D058477:Receptors, Purinergic P2X3
keywords: ASICs; behavior; cytokines; electrophysiology; siRNAs; signaling