title: Upregulated glial cell line-derived neurotrophic factor through cyclooxygenase-2 activation in the muscle is required for mechanical hyperalgesia after exercise in rats.
abstract: Unaccustomed strenuous exercise that includes lengthening contraction (LC) often causes delayed onset muscle soreness (DOMS), characterised as muscular mechanical hyperalgesia. Previously we reported that a bradykinin-like substance released from the muscle during exercise plays a pivotal role in triggering the process of muscular mechanical hyperalgesia by upregulating nerve growth factor (NGF) in exercised muscle of rats. We show here that cyclooxygenase (COX)-2 and glial cell line-derived neurotrophic factor (GDNF) are also involved in DOMS. COX-2 inhibitors but not COX-1 inhibitors given orally before LC completely suppressed the development of DOMS, but when given 2 days after LC they failed to reverse the mechanical hyperalgesia. COX-2 mRNA and protein in exercised muscle increased six- to 13-fold in mRNA and 1.7-2-fold in protein 0-12 h after LC. COX-2 inhibitors did not suppress NGF upregulation after LC. Instead, we found GDNF mRNA was upregulated seven- to eight-fold in the exercised muscle 12 h-1 day after LC and blocked by pretreatment of COX-2 inhibitors. In situ hybridisation studies revealed that both COX-2 and GDNF mRNA signals increased at the periphery of skeletal muscle cells 12 h after LC. The accumulation of COX-2 mRNA signals was also observed in small blood vessels. Intramuscular injection of anti-GDNF antibody 2 days after LC partly reversed DOMS. Based on these findings, we conclude that GDNF upregulation through COX-2 activation is essential to mechanical hyperalgesia after exercise.
authors.affiliation: Department of Physical Therapy, College of Life and Health Sciences, Chubu University, Kasugai 487-8501, Japan.
authors.forename: Shiori
authors.initials: S
authors.lastname: Murase
authors.forename: Etsuji
authors.initials: E
authors.lastname: Terazawa
authors.forename: Kenji
authors.initials: K
authors.lastname: Hirate
authors.forename: Hiroki
authors.initials: H
authors.lastname: Yamanaka
authors.forename: Hirosato
authors.initials: H
authors.lastname: Kanda
authors.forename: Koichi
authors.initials: K
authors.lastname: Noguchi
authors.forename: Hiroki
authors.initials: H
authors.lastname: Ota
authors.forename: Fernando
authors.initials: F
authors.lastname: Queme
authors.forename: Toru
authors.initials: T
authors.lastname: Taguchi
authors.forename: Kazue
authors.initials: K
authors.lastname: Mizumura
mesh_terms: D000818:Animals; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D006930:Hyperalgesia / Q000188:drug therapy / Q000378:metabolism*; D008297:Male; D009119:Muscle Contraction; D018485:Muscle Fibers, Skeletal / Q000378:metabolism* / Q000502:physiology; D063806:Myalgia / Q000188:drug therapy / Q000378:metabolism; D020932:Nerve Growth Factor / Q000235:genetics / Q000378:metabolism; D005082:Physical Exertion; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D051100:Glial Cell Line-Derived Neurotrophic Factor; D012333:RNA, Messenger; D020932:Nerve Growth Factor; D051546:Cyclooxygenase 2