Mu-opioid signaling modulates biphasic expression of TrkB and IκBα genes and neurite outgrowth in differentiating and differentiated human neuroblastoma cells.

Chronic opioid exposure leads to changes in gene expression (functional changes), resulting in structural changes in neural circuits that are linked to eventually behavioral changes. Little is known about the cellular and molecular mechanisms of how such changes occur. In this study, we found that mu-opioid [D-Ala(2), N-Me-Phe(4), Gly(5)-ol]-enkephalin (DAMGO) and morphine exposure led to dynamic changes in neural differentiation- and growth-associated genes, IκBα and NTRK2 (TrkB), in differentiating and differentiated human neuroblastoma SH-SY5Y cells. Chromatin immunoprecipitation-polymerase chain reaction (ChIP-PCR) analysis revealed that binding of NF-κB/p65 to the IκBα promoter in living cells was temporally altered when the cells were exposed to morphine. The changes in gene expression correlated with the changes in neurite length of the RA-differentiating and RA-differentiated neuron-like cells. Our findings for the first time showed that TrkB signaling and NF-κB/IκBα signaling temporally correlated with each other in response to single-dose and repeated mu-opioid treatment in differentiating and differentiated human neuron-like cells. The findings from this human cell study in vitro indicate that both relatively high single-dose and chronic opioid exposure may induce the structural changes in the developing human brain and the adult brain by altering the expression of neuronal differentiation- and neurite outgrowth-related genes IκBa and TrkB in vivo.