Restraint stress (RS) protects auditory function against acoustic trauma by activating glucocorticoid receptors (GR) in the cochlea. In a search for the signaling pathways downstream to GR that may be involved in RS-induced protection we report here (1) a downregulation of phosphorylated extracellular signal-regulated kinases 1 and 2 (pERK 1/2) after the combined treatment of RS and acoustic trauma; (2) activation of phospho-p38 in the auditory nerve after RS; (3) the abolition of these two effects by pretreatment with metyrapone (an inhibitor of corticosterone synthesis) and RU486 (a GR antagonist); and (4) no activation of c-jun-N-terminal kinases 1 and 2 (JNK 1/2), ERK, or p38 after acoustic trauma alone. Thus we demonstrate a GR-dependent ERK-mediated pathway that modulates auditory function after RS and acoustic trauma. These findings reveal new mechanisms that underlie hearing loss and will have implications for the development of pharmacological strategies for protecting against acoustic trauma.
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