Figure 2

A model for activation of Erk in the induction and expression phases of chronic pain. A. In the induction phase of chronic pain, peripheral injury triggers glutamate release in the ACC synapses. Activation of NMDA receptors leads to an increase in postsynaptic Ca²⁺, and Ca²⁺ binds to CaM and leads to activation of Ca²⁺-stimulated AC1. cAMP, a key second messenger, leads to activation of Erk, and PKA-dependent CREB. New protein synthesis is likely triggered as a consequence of CREB activation. B. In the expression phase of chronic pain (allodynia), a non-noxious stimuli triggers glutamate release in sensitized ACC synapses. Due to synaptic enhancement caused during the induction phase [13], glutamate triggers greater postsynaptic activation because AMPA and NMDA receptor mediated responses are likely enhanced after the injury [13, 23]. Such postsynaptic sensitization makes activation of Erk at distal synaptic sites possible. Activated Erk at synaptic sites may contribute to AMPA receptor modulation, ion channel modulation and other synaptic modifications.