Figure 8.

Model of depolarization-dependent, C-Raf-mediated, self-reinforcing mechanisms driving nociceptor hyperexcitability and reduced opioid responses after SCI. Depolarization of nociceptors (ΔVm) induced by SCI enhances C-Raf activity in IB4⁺ neurons via direct phosphorylation of C-Raf and relief from RKIP inhibition. Active C-Raf promotes hyperexcitability via two different mechanisms acting in parallel. (1) Activation of the MEK-ERK cascade by C-Raf has direct effects on RMP and neuronal excitability. (2) Phosphorylation of AC5/6 by C-Raf reduces the inhibitory effects of Gαi on cAMP generation by AC and downstream PKA/EPAC signaling, which also regulate nociceptor hyperexcitability and RMP. The combined effects of MAPK and cAMP signaling on RMP and hyperexcitability set up positive feedback that maintains OA/SA in nociceptors while also limiting the effectiveness of opioids.