Received for publication February 27, 2007.
Revised May 25, 2007.
Accepted for publication May 29, 2007.

Human Neural Precursor Cells Express Functional Kappa Opioid Receptors

Abstract

Neural stem cells (NSCs) play an important role in the developing as well as adult brain. NSCs have been shown to migrate towards sites of injury in the brain and to participate in the process of brain repair. Like NSCs, cultured human neural precursor cells (NPCs) are self-renewing, multipotent cells capable of differentiating into neurons, astrocytes and oligodendrocytes and of migrating towards chemotactic stimuli. Cellular and environmental factors are important for NPC proliferation and migration. Expression of kappa opioid receptors (KORs) and mu opioid receptors (MORs) in murine embryonic stem cells and of MORs and delta opioid receptors in rodent neuronal precursors, as well as hippocampal progenitors has been reported by other investigators. In this study, we demonstrated robust expression of KORs in highly enriched (>90% nestin-positive) human fetal brain-derived NPCs. We found that KOR ligands, dynorphin_1-17 and U50,488, but not dynorphin_2-17, stimulated proliferation and migration of NPCs in a concentration-dependent manner. NPC proliferation was maximally stimulated at 10^-14 M dynorphin_1-17 and 10^-12 M U50,488. The KOR selective antagonist, nor-binaltorphimine (nor-BNI), partially blocked the migratory and proliferative effects of KOR agonists supporting, at least in part, the involvement of a KOR-related mechanism. As has been described for rodent P19 embryonal carcinoma stem cells, retinoic acid treatment markedly suppressed KOR mRNA expression in human NPCs. Taken together, the results of this study suggest that activation of KORs alters functional properties of NPCs/NSCs that are relevant to human brain development and repair.

Key words: Dynorphins, Kappa opioid receptors, Migratrion, Neural precursor cells, Proliferation, U50,488