{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T11:26:43Z","timestamp":1780486003632,"version":"3.54.1"},"reference-count":41,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2013,5,17]],"date-time":"2013-05-17T00:00:00Z","timestamp":1368748800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2013,6]]},"abstract":"<jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"explicit-label\">\n<jats:list-item><jats:p>Unaccustomed strenuous exercise that includes lengthening contraction often causes delayed onset muscle soreness (DOMS), characterised as muscular mechanical hyperalgesia.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>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.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>We showed that pretreatment with cyclooxygenase (COX)\u20102 inhibitors completely suppressed the development of DOMS, but treatment 2 days after lengthening contraction failed to reverse existing mechanical hyperalgesia.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>We demonstrated that COX\u20102 induced upregulation of glial cell line\u2010derived neurotrophic factor (GDNF) and that intramuscularly injected anti\u2010GDNF antibody reduced muscle mechanical hyperalgesia after exercise.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>These results suggest that upregulation of GDNF through COX\u20102 activation is essential to mechanical hyperalgesia after exercise, and is another pathway alongside the bradykinin\u2013nerve growth factor pathway that is involved in DOMS development.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><jats:p><jats:bold>Abstract\u2002<\/jats:bold> 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\u2010like 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)\u20102 and glial cell line\u2010derived neurotrophic factor (GDNF) are also involved in DOMS. COX\u20102 inhibitors but not COX\u20101 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\u20102 mRNA and protein in exercised muscle increased six\u2010 to 13\u2010fold in mRNA and 1.7\u20132\u2010fold in protein 0\u201312 h after LC. COX\u20102 inhibitors did not suppress NGF upregulation after LC. Instead, we found GDNF mRNA was upregulated seven\u2010 to eight\u2010fold in the exercised muscle 12 h\u20131 day after LC and blocked by pretreatment of COX\u20102 inhibitors. <jats:italic>In situ<\/jats:italic> hybridisation studies revealed that both COX\u20102 and GDNF mRNA signals increased at the periphery of skeletal muscle cells 12 h after LC. The accumulation of COX\u20102 mRNA signals was also observed in small blood vessels. Intramuscular injection of anti\u2010GDNF antibody 2 days after LC partly reversed DOMS. Based on these findings, we conclude that GDNF upregulation through COX\u20102 activation is essential to mechanical hyperalgesia after exercise.<\/jats:p>","DOI":"10.1113\/jphysiol.2012.249235","type":"journal-article","created":{"date-parts":[[2013,4,16]],"date-time":"2013-04-16T01:46:13Z","timestamp":1366076773000},"page":"3035-3048","source":"Crossref","is-referenced-by-count":57,"title":["Upregulated glial cell line\u2010derived neurotrophic factor through cyclooxygenase\u20102 activation in the muscle is required for mechanical hyperalgesia after exercise in rats"],"prefix":"10.1113","volume":"591","author":[{"given":"Shiori","family":"Murase","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Etsuji","family":"Terazawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenji","family":"Hirate","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroki","family":"Yamanaka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hirosato","family":"Kanda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koichi","family":"Noguchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroki","family":"Ota","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fernando","family":"Queme","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toru","family":"Taguchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazue","family":"Mizumura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2013,5,17]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4863-05.2006"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1249\/00005768-198412000-00002"},{"key":"e_1_2_6_4_1","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1523\/JNEUROSCI.20-01-00427.2000","article-title":"The glial cell line\u2010derived neurotrophic factor family receptor components are differentially regulated within sensory neurones after nerve injury","volume":"20","author":"Bennett DL","year":"2000","journal-title":"J Neurosci"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1460-9568.2008.06308.x"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2002.025106"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.290.5489.124"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/0896-6273(95)90173-6"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi049247p"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.173.8.5219"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.2165\/00007256-200333020-00005"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pain.2008.08.013"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpain.2011.04.010"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2012.06.011"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.1991.tb12248.x"},{"key":"e_1_2_6_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pain.2010.10.020"},{"key":"e_1_2_6_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pain.2004.12.020"},{"key":"e_1_2_6_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neulet.2006.03.026"},{"key":"e_1_2_6_19_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.5589-07.2008"},{"key":"e_1_2_6_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpain.2006.06.010"},{"key":"e_1_2_6_21_1","first-page":"571","article-title":"Postnatal roles of glial cell line\u2010derived neurotrophic factor family members in nociceptors plasticity","volume":"60","author":"Malin SA","year":"2008","journal-title":"Sheng Li Xue Bao"},{"key":"e_1_2_6_22_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1726-06.2006"},{"key":"e_1_2_6_23_1","first-page":"GG15","article-title":"Effects of glial cell line\u2010derived neurotrophic factor (GDNF) on the mechanical response of rat muscle thin\u2010fibre receptors in vitro","author":"Mizumura K","year":"2011","journal-title":"SfN's 41st Annual Meeting"},{"key":"e_1_2_6_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(00)80966-6"},{"key":"e_1_2_6_25_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3803-09.2010"},{"key":"e_1_2_6_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neures.2004.12.010"},{"key":"e_1_2_6_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejpain.2009.05.009"},{"key":"e_1_2_6_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yexcr.2005.08.009"},{"key":"e_1_2_6_29_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10787-006-1495-7"},{"key":"e_1_2_6_30_1","doi-asserted-by":"publisher","DOI":"10.1080\/02640410400021989"},{"key":"e_1_2_6_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0304-3959(03)00115-5"},{"key":"e_1_2_6_32_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.22.13313"},{"key":"e_1_2_6_33_1","doi-asserted-by":"publisher","DOI":"10.1249\/00005768-199105000-00006"},{"key":"e_1_2_6_34_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2004.079483"},{"key":"e_1_2_6_35_1","doi-asserted-by":"publisher","DOI":"10.1080\/08990220500420475"},{"key":"e_1_2_6_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpain.2011.04.003"},{"key":"e_1_2_6_37_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1471-4159.2001.00613.x"},{"key":"e_1_2_6_38_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI200113416"},{"key":"e_1_2_6_39_1","first-page":"53","article-title":"The effects of ibuprofen on delayed muscle soreness and muscular performance after eccentric exercise","volume":"17","author":"Tokmakidis SP","year":"2003","journal-title":"J Strength Cond Res"},{"key":"e_1_2_6_40_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.1990.259.2.C232"},{"key":"e_1_2_6_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2011.03.030"},{"key":"e_1_2_6_42_1","doi-asserted-by":"publisher","DOI":"10.1186\/1744-8069-7-41"}],"container-title":["The Journal of Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1113%2Fjphysiol.2012.249235","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/pdf\/10.1113\/jphysiol.2012.249235","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,14]],"date-time":"2023-10-14T07:33:50Z","timestamp":1697268830000},"score":1,"resource":{"primary":{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/10.1113\/jphysiol.2012.249235"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,5,17]]},"references-count":41,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2013,6]]}},"alternative-id":["10.1113\/jphysiol.2012.249235"],"URL":"https:\/\/doi.org\/10.1113\/jphysiol.2012.249235","archive":["Portico"],"relation":{},"ISSN":["0022-3751","1469-7793"],"issn-type":[{"value":"0022-3751","type":"print"},{"value":"1469-7793","type":"electronic"}],"subject":[],"published":{"date-parts":[[2013,5,17]]}}}