Positive feed-forward loops involving PKC and CaMKII in neuropathic pain. This is a simplified scheme demonstrating the persistent activation of PKC and CaMKII in neuropathic pain. Ca²⁺ influx through the activation of the NMDA receptors or TRPV1 leads to increased intracellular Ca²⁺ levels and subsequent activation of PKC and CaMKII. Both PKC and CaMKII can activate the NMDA receptors or TRPV1 via phosphorylation. Such feed-forward mechanisms may be one way for the sustained activation of PKC or CaMKII in neuropathic pain. It is likely that additional mechanisms can activate and/or sustain the activation of PKC and CaMKII, for example, by activating a Gq-coupled receptor or through Ca²⁺ release from the intracellular storage. It should be noted that PKC and CaMKII do not need to be co-expressed or simultaneously activated in a single cell. Whereas the NMDA receptors are expressed in the post-synaptic neurons, the TRPV1 may play a major role in pre-synaptic neurons. For downstream signal transduction, these protein kinases phosphorylate numerous effectors, including transcription factors, receptors, and ion channels.