Role of Nociceptor αCaMKII in Transition from Acute to Chronic Pain (Hyperalgesic Priming) in Male and Female Rats

We have previously shown that activation of protein kinase C epsilon (PKC epsilon) in male rats induces a chronic, long-lasting change in nociceptors such that a subsequent exposure to proinflammatory mediators produces markedly prolonged mechanical hyperalgesia. This neuroplastic change, hyperalgesic priming, is dependent on activation of cytoplasmic polyadenylation element-binding protein (CPEB), downstream of PKC epsilon, and consequent translation of mRNAs in the peripheral terminal of the nociceptor. Since alpha calmodulin-dependent protein kinase II (alpha CaMKII), a molecule implicated in neuroplasticity, is a target of CPEB and can also affect CPEB function, we investigated its role in the transition from acute to chronic pain. Priming induced by direct activation of PKC epsilon can be prevented by inhibition of alpha CaMKII. In addition, direct activation of alpha CaMKII induces priming, which was not prevented by pretreatment with PKC epsilon antisense, suggesting that alpha CaMKII is downstream of PKC epsilon in the induction of priming. Activation of ryanodine receptors (RyRs), which can lead to activation of alpha CaMKII, also induced priming, in a calcium-and alpha CaMKII-dependent manner. Similarly, inhibition of the RyR and a calcium buffer prevented induction of priming by PKC epsilon. Unlike activation of PKC epsilon, ryanodine and alpha CaMKII induced priming in female as well as male rats. Our results demonstrate a contribution of alpha CaMKII to induction of hyperalgesic priming, a phenomenon implicated in the transition from acute to chronic pain.