title: Exercise-induced pain requires NMDA receptor activation in the medullary raphe nuclei.
abstract: OBJECTIVE
  Pain in response to physical activity is common in people with chronic musculoskeletal pain and is likely a barrier to regular exercise, which would lead to a sedentary lifestyle. We recently developed a model of exercise-induced pain that is associated with increased activation of neurons in the medullary raphe nuclei, i.e., the nucleus raphe obscurus (NRO) and nucleus raphe pallidus (NRP). Because the NRO and NRP not only modulate motor output but also respond to noxious stimuli, we hypothesized that the NRO and NRP were key nuclei in the interaction between pain and exercise. We tested whether exercise enhances hyperalgesia through activation of N-methyl D-aspartate (NMDA) receptors in the NRO/NRP.
  
  
  METHODS
  Muscle insult was induced by two injections of pH 5.0 saline 5 d apart into one gastrocnemius muscle. We initially tested whether hyperalgesia developed in mice injected with acidic saline (pH 5.0) into the gastrocnemius muscle immediately after a 30-min or 2-h exercise task or 2 h after a 2-h exercise task. Next, we tested whether blockade of NMDA receptors in the NRO/NRP during the exercise task prevented the development of exercise-induced hyperalgesia. Finally, we evaluated changes in phosphorylation of the NR1 subunit of the NMDA receptor (pNR1) after the exercise task at times in which muscle insult was given in behavioral experiments, i.e., immediately after a 30-min or 2-h exercise task or 2 h after the 2-h exercise task.
  
  
  RESULTS
  All exercise conditions enhanced nociception (hyperalgesia) after combining with two injections of pH 5.0 saline. Microinjection of AP5 (1.0-0.1 nmol; 2-amino-5-phophonopenanoate) dose-dependently prevented the development of exercise-induced hyperalgesia. All exercise conditions increased pNR1 in the NRO and NRP.
  
  
  CONCLUSIONS
  Thus, exercise-induced pain in sedentary mice is associated with increased phosphorylation and activation of NMDA receptors in the NRO/NRP, suggesting that changes in central excitability mediate an interaction between unaccustomed exercise and pain.
authors.affiliation: Physical Therapy and Rehabilitation Science Graduate Program, The University of Iowa, Iowa City, IA 52242-1190, USA. Kathleen-sluka@uiowa.edu
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Sluka
authors.forename: Jessica
authors.initials: J
authors.lastname: Danielson
authors.forename: Lynn
authors.initials: L
authors.lastname: Rasmussen
authors.forename: Luis Felipe
authors.initials: LF
authors.lastname: DaSilva
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D005080:Exercise Test; D006930:Hyperalgesia / Q000503:physiopathology*; D007150:Immunohistochemistry; D007273:Injections, Intramuscular; D008526:Medulla Oblongata / Q000166:cytology / Q000502:physiology*; D051379:Mice; D008845:Microinjections; D023421:Models, Animal; D018482:Muscle, Skeletal / Q000294:innervation / Q000503:physiopathology; D059352:Musculoskeletal Pain / Q000503:physiopathology*; D009619:Nociceptors / Q000187:drug effects / Q000502:physiology; D010147:Pain Measurement; D017288:Pain Threshold; D010766:Phosphorylation; D011903:Raphe Nuclei / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D012965:Sodium Chloride
chemical_list: D016194:Receptors, N-Methyl-D-Aspartate; D012965:Sodium Chloride