Upregulated glial cell line-derived neurotrophic factor through cyclooxygenase-2 activation in the muscle is required for mechanical hyperalgesia after exercise in rats

J Physiol. 2013 Jun 15;591(12):3035-48. doi: 10.1113/jphysiol.2012.249235. Epub 2013 Apr 15.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cyclooxygenase 2 / genetics
  • Cyclooxygenase 2 / metabolism*
  • Cyclooxygenase 2 Inhibitors / pharmacology
  • Cyclooxygenase 2 Inhibitors / therapeutic use
  • Glial Cell Line-Derived Neurotrophic Factor / genetics
  • Glial Cell Line-Derived Neurotrophic Factor / metabolism*
  • Hyperalgesia / drug therapy
  • Hyperalgesia / metabolism*
  • Male
  • Muscle Contraction
  • Muscle Fibers, Skeletal / metabolism*
  • Muscle Fibers, Skeletal / physiology
  • Myalgia / drug therapy
  • Myalgia / metabolism
  • Nerve Growth Factor / genetics
  • Nerve Growth Factor / metabolism
  • Physical Exertion
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Up-Regulation*


  • Cyclooxygenase 2 Inhibitors
  • Glial Cell Line-Derived Neurotrophic Factor
  • RNA, Messenger
  • Nerve Growth Factor
  • Cyclooxygenase 2