Hyperalgesic priming is a model of the transition from acute to chronic pain, in which previous activation of cell surface receptors or direct activation of protein kinase C epsilon (PKCε) markedly prolongs mechanical hyperalgesia induced by pronociceptive cytokines. We recently demonstrated a role of peripheral protein translation, alpha-calmodulin-dependent protein kinase II (αCaMKII) activation and the ryanodine receptor, in the induction of hyperalgesic priming. In the present study we tested if they also mediate the prolonged phase of PGE2-induced hyperalgesia. We found that inhibition of αCaMKII and local protein translation eliminates the prolonged phase of PGE2 hyperalgesia. While priming induced by receptor agonists or direct activation of PKCε occurs in male but not female rats, activation of αCaMKII and the ryanodine receptor also produces priming in females. As in males, the prolonged phase of PGE2-induced hyperalgesia in female rats is also PKCε-, αCaMKII- and protein translation-dependent. In addition, in both male and female primed rats the prolonged PGE2-induced hyperalgesia was significantly attenuated by inhibition of MEK/ERK. Based on these data we suggest that the mechanisms previously shown to be involved in the induction of the neuroplastic state of hyperalgesic priming also mediate the prolongation of hyperalgesia.