EGFR dependent subcellular communication was responsible for morphine mediated AC superactivation

Compensatory adenylyl cyclase (AC) superactivation has been postulated to be responsible for the development of morphine tolerance and dependence, the underlying mechanism was demonstrated to comprise c-Src-dependent upregulation of AC5 within the lipid rafts. In the present study, we demonstrated that chronic morphine treatment sensitized EGFR signaling by augmenting EGFR phosphorylation and translocation into ER, which was essential for CRT-MOR tethering within the lipid rafts and AC5 superactivation. Intriguingly, synaptic clustering of CRT-MOR was dependent on EGFR phosphorylation and presumed to implicate in alignment and organization of synaptic compartments. Taken together, our data raised the possibility that an adaptive change in MOR and EGFR signal systems might establish CRT related subcellular communication, the signaling network within brain synaptic zone was proposed to implicate in morphine tolerance and dependence.

► Chronic morphine treatment led to EGFR phosphorylation and translocation into ER.
► Alteration of EGFR promoted ligation of CRT and MOR within the lipid rafts.
► CRT disrupt the coupling of MOR and Gi2, which resulted in AC5 superactivation.
► Cross-talk of MOR and EGFR evoked CRT related signaling within synaptoneurosome.