EP2 receptor plays pivotal roles in generating mechanical hyperalgesia after lengthening contraction.

We previously demonstrated that nerve growth factor (NGF) and glial cell line-derived neurotrophic factor (GDNF) were upregulated after lengthening contractions (LC) in exercised muscle through B2 bradykinin receptor activation and cyclooxygenase (COX)-2 upregulation, respectively, and that these trophic factors sensitized nociceptors resulting in mechanical hyperalgesia (delayed-onset muscle soreness, DOMS). Here, we examined the prostaglandin receptor subtype involved in DOMS. The mechanical withdrawal threshold of the exercised muscle was measured before and after LC in rats administered prostaglandin E-2 receptor (EP) antagonists before LC, or in wild-type (WT), EP2 knockout (EP2(-/-)), and IP knockout (IP-/-) mice. The change in expression of NGF, GDNF, or COX-2 mRNA was examined using real-time RT-PCR in the muscle in EP2(-/-) and WT mice. None of the antagonists to EP1, EP3, and EP4 receptors (ONO-8713, ONO-AE5-599, and ONO-AE3-208, respectively) induced a significant difference in DOMS compared with controls in rats. WT and IP-/- mice developed mechanical hyperalgesia after LC, but EP2(-/-) mice did not. Upregulation of NGF, GDNF, and COX-2 mRNA was observed after LC in WT mice but not in EP2(-/-) mice. Injecting an EP2 agonist (ONO-AE1-259-01) into the mouse muscle increased expression of COX-2 mRNA. These results suggest that EP2 contributes to generating mechanical hyperalgesia through positive feedback upregulation of COX-2 expression in muscle after LC.