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

作者：Murase Shiori; Terazawa Etsuji; Hirate Kenji; Yamanaka Hiroki; Kanda Hirosato; Noguchi Koichi; Ota Hiroki; Queme Fernando; Taguchi Toru; Mizumura Kazue^*

来源：The Journal of Physiology, 2013, 591(12): 3035-3048.

DOI：10.1113/jphysiol.2012.249235

Key points center dot Unaccustomed strenuous exercise that includes lengthening contraction often causes delayed onset muscle soreness (DOMS), characterised as muscular mechanical hyperalgesia. center dot It has been reported that bradykinin triggers upregulation of nerve growth factor in exercised muscle, sensitizing nociceptors and resulting in DOMS, but additional mechanism(s) may be involved. center dot We showed that pretreatment with cyclooxygenase (COX)-2 inhibitors completely suppressed the development of DOMS, but treatment 2 days after lengthening contraction failed to reverse existing mechanical hyperalgesia. center dot We demonstrated that COX-2 induced upregulation of glial cell line-derived neurotrophic factor (GDNF) and that intramuscularly injected anti-GDNF antibody reduced muscle mechanical hyperalgesia after exercise. center dot These results suggest that upregulation of GDNF through COX-2 activation is essential to mechanical hyperalgesia after exercise, and is another pathway alongside the bradykinin-nerve growth factor pathway that is involved in DOMS development. 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.

• 出版日期2013-6