Ph.D., University of Illinois, Urbana-Champaign
Chronic pain can be initiated by one or more acute stimulations to sensitize neurons into the primed state. In the primed state, the basal nociceptive thresholds of the animal are normal, but in response to another hyperalgesic stimulus, the animal develops enhanced and prolonged hyperalgesia. The exact mechanism of how primed state is formed is not completely understood. Here we showed that spinal PKC/ERK signal pathway is required for neuronal plasticity change, hyperalgesic priming formation and the development of chronic hyperalgesia using acid-induced muscle pain (AIMP) model in mice. We discovered that pERK-positive neurons in the amygdala, spinal cord and dorsal root ganglion (DRG) were significantly increased after 1st acid injection. Inhibition of the pERK activity intrathecally, but not intracerebroventricularly or intramuscularly before 1st acid injection prevented the development of chronic pain induced by 2nd acid injection which suggests hyperalgesic priming signal is stored at spinal cord level. Furthermore, intrathecal injection of PKC but not PKA blocker prevented the development of chronic pain and PKC agonist was sufficient to induce prolonged hyperalgesia response after acid injection. We also found that mTOR-dependent protein synthesis was required for the priming establishment. To test whether hyperalgesic priming leads to synaptic plasticity change, we recorded fEPSPs from spinal cord slices and found enhanced LTP in mice received one acid injection. This LTP enhancement was prevented by inhibition of ERK. These findings show that the activation of PKC/ERK signal pathway and downstream protein synthesis is required for hyperalgesic priming and the consolidation of pain singling.