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Int. J. Mol. Sci. 2013, 14(10), 21114-21139; doi:10.3390/ijms141021114

Crosstalk between Delta Opioid Receptor and Nerve Growth Factor Signaling Modulates Neuroprotection and Differentiation in Rodent Cell Models

1
Department of Biological Sciences, Binghamton University, the State University of New York at Binghamton, Binghamton, NY 13902, USA
2
The Center for Development and Behavioral Neurosciences, Binghamton University, the State University of New York at Binghamton, Binghamton, NY 13902, USA
Current address: Department of Hematology, Christian Medical College, Vellore, Tamil Nadu 632002, India.
*
Author to whom correspondence should be addressed.
Received: 15 August 2013 / Revised: 16 September 2013 / Accepted: 26 September 2013 / Published: 21 October 2013
(This article belongs to the Special Issue Pathology and Treatment of Central Nervous System Diseases)
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Abstract

Both opioid signaling and neurotrophic factor signaling have played an important role in neuroprotection and differentiation in the nervous system. Little is known about whether the crosstalk between these two signaling pathways will affect neuroprotection and differentiation. Previously, we found that nerve growth factor (NGF) could induce expression of the delta opioid receptor gene (Oprd1, dor), mainly through PI3K/Akt/NF-κB signaling in PC12h cells. In this study, using two NGF-responsive rodent cell model systems, PC12h cells and F11 cells, we found the delta opioid neuropeptide [D-Ala2, D-Leu5] enkephalin (DADLE)-mediated neuroprotective effect could be blocked by pharmacological reagents: the delta opioid antagonist naltrindole, PI3K inhibitor LY294002, MAPK inhibitor PD98059, and Trk inhibitor K252a, respectively. Western blot analysis revealed that DADLE activated both the PI3K/Akt and MAPK pathways in the two cell lines. siRNA Oprd1 gene knockdown experiment showed that the upregulation of NGF mRNA level was inhibited with concomitant inhibition of the survival effects of DADLE in the both cell models. siRNA Oprd1 gene knockdown also attenuated the DADLE-mediated neurite outgrowth in PC12h cells as well as phosphorylation of MAPK and Akt in PC12h and F11 cells, respectively. These data together strongly suggest that delta opioid peptide DADLE acts through the NGF-induced functional G protein-coupled Oprd1 to provide its neuroprotective and differentiating effects at least in part by regulating survival and differentiating MAPK and PI3K/Akt signaling pathways in NGF-responsive rodent neuronal cells. View Full-Text
Keywords: GPCR; delta opioid receptor; DADLE; NGF; Akt; MAPK; neuroprotection GPCR; delta opioid receptor; DADLE; NGF; Akt; MAPK; neuroprotection
This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).

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MDPI and ACS Style

Sen, D.; Huchital, M.; Chen, Y.L. Crosstalk between Delta Opioid Receptor and Nerve Growth Factor Signaling Modulates Neuroprotection and Differentiation in Rodent Cell Models. Int. J. Mol. Sci. 2013, 14, 21114-21139.

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