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

Abstract

Key points• Unaccustomed strenuous exercise that includes lengthening contraction often causes delayed onset muscle soreness (DOMS), characterised as muscular mechanical hyperalgesia.• 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.• 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.• 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.• 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 hybridisationThe authors E. Terazawa and K. Hirate passed away from illness during the course of this experiment (on 13 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.

Beetroot juice is more beneficial than sodium nitrate for attenuating muscle pain after strenuous eccentric-bias exercise

“…Nonetheless, as described before, a possibility is that BTJ might suppress the release of stimuli thought to sensitize nociceptive neurons in the muscle and ECM (Murase et al 2013), the latter of which, to the best of the current knowledge, is proposed as the main site where muscle pain originates (Crameri et al 2007). However, because muscle tissue samples could not be obtained in this study, this posit is somewhat speculative until confirmed by future studies; we acknowledge that our inability to collect muscle tissue and investigate these mechanisms is a limitation of this study.…”

Nociceptor interleukin 10 receptor 1 is critical for muscle analgesia induced by repeated bouts of eccentric exercise in the rat

“…A number of well-established proalgesic mediators are locally released in muscle after eccentric exercise and thus likely involved in DOMS, including pro-inflammatory cytokines [4], trophic factors [2,35,36] and prostanoids [12]. Importantly, after recovery from this hyperalgesia, rats exhibited attenuated muscle pain upon exposure to a second bout of eccentric exercise.…”

Minimal muscle damage after a marathon and no influence of beetroot juice on inflammation and recovery

“…Nevertheless, AOX effects might not be the main mechanism by which BTJ could benefit recovery; instead this could primarily be through anti-inflammatory effects or reduced proteolysis. In support of an anti-inflammatory mechanism, the betalains in beetroot have been shown to inhibit cyclooxygenase-2 (COX-2) activity, which, via synthesis of prostanoids, play a key role in the development of the acute inflammatory response (Vidal et al 2014), and have been linked to the development of muscle soreness (Murase et al 2013). …”