Schematic models of the mechanisms underlying the regulation of CGRP during the development of tolerance to morphine-induced analgesia. A chronic morphine treatment induces the activation of the neuronal CaMKII-nNOS pathway in the SCDH, resulting in an increased NO release. NO can then retrogradly diffuse to the presynaptic nerve terminals to modulate CGRP gene expression either via direct activation of the sGC-cGMP pathway [29, 30] or via the S-nitrosylation  of related nuclear proteins. The effects of glial ERK and p38 on CGRP expression in the SCDH may occur through the regulation of neuronal CaMKII-nNOS signaling. B) In the DRG, chronic morphine enhances the activation of CaMKII, which can then stimulate CGRP gene expression via the modulation of various transcriptional factors.