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A Functionally Coupled µ3-Like Opiate Receptor/Nitric Oxide Regulatory Pathway in Human Multi-Lineage Progenitor Cells¹

Neuroscience Research Institute, State University of New York College, Old Westbury, NY 11568

Ongoing studies from our group support the existence and biological importance of a distinct cellular signaling pathway involving endogenously synthesized, chemically authentic, L-morphine, its cognate µ₃ opiate receptor subtype, and constitutive NO synthase. Based on prior studies indicating evolutionary conservation and adaptation of morphinergic/NO-coupled signaling to mediate autocrine/paracrine control of cellular functions, our goal was to determine whether a functionally competent µ₃ opiate receptor/NO-coupled regulatory pathway exists in human multilineage progenitor cells (MLPC) prepared from umbilical cord blood. Real-time PCR analysis indicated significant expression of µ₃ opiate receptor-encoding RNA by undifferentiated human MLPC, in the absence of traditional µ₁ opioid receptor-encoding RNA expression. Unpredictably, confirmatory RT-PCR analyses indicated cellular expression of a splice variant of the previously characterized µ₃ opiate receptor-encoding mRNA. Pharmacological analyses provided critical validating evidence of functional µ₃-like opiate receptor/NO-coupled signaling within primary cultures of undifferentiated human MLPC via morphine-evoke real-time release of NO. Control analyses indicated that morphine-stimulated NO release was markedly inhibited by prior treatment with the opiate antagonist L-naloxone or the constitutive NO synthase inhibitor N(G)-nitro-L-arginine methyl ester and unresponsive to stimulation by the opioid peptide methionine enkephalin. Complementary microarray analysis demonstrated that traditional µ₁, , and opioid receptor gene expression is not detected in both undifferentiated and differentiated MLPC. Chemical differentiation of MLPC into neuronal progenitor cells effected significant phenotypic expression of a variety of neurally-associated genes. Our data provide compelling evidence in support of both the evolutionary primacy and primordial regulatory role of µ₃-like opiate receptor/NO signaling in embryogenesis.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by Grants DA 09010 and MH 47292, and the New York State Empire Innovation Award Program.

² Address correspondence and reprint requests to Dr. George B. Stefano, Neuroscience Research Institute, State University of New York College, P.O. Box 210, Old Westbury, NY 11568. E-mail adddress: gstefano{at}sunynri.org

³ Abbreviations used in this paper: MLPC, multi-lineage progenitor cells; L-NAME, N(G)-nitro-L-arginine methyl ester; cNOS, constitutive nitric oxide synthase; DA, dopamine.