TY - JOUR
T1 - Morphine-induced trafficking of a mu-opioid receptor interacting protein in rat locus coeruleus neurons
AU - Jaremko, Kellie M.
AU - Thompson, Nicholas L.
AU - Reyes, Beverly A.S.
AU - Jin, Jay
AU - Ebersole, Brittany
AU - Jenney, Christopher B.
AU - Grigson, Patricia S.
AU - Levenson, Robert
AU - Berrettini, Wade H.
AU - Van Bockstaele, Elisabeth J.
N1 - Funding Information:
This project was supported by the National Institutes of Health grant P20 DA # 025995 and DA # 05186 to W.H.B. and DA # 009082 to E.V.B. This project was also funded, in part, by a grant from the Pennsylvania Department of Health using Tobacco CURE Funds to R.L. and P.S.G. The Department specifically disclaims responsibility for any analyses, interpretations or conclusions. We also would to thank Christain Njatcha and Dr. Bill Freeman expert technical assistance.
PY - 2014/4/3
Y1 - 2014/4/3
N2 - Opiate addiction is a devastating health problem, with approximately 2. million people currently addicted to heroin or non-medical prescription opiates in the United States alone. In neurons, adaptations in cell signaling cascades develop following opioid actions at the mu opioid receptor (MOR). A novel putative target for intervention involves interacting proteins that may regulate trafficking of MOR. Morphine has been shown to induce a re-distribution of a MOR-interacting protein Wntless (WLS, a transport molecule necessary for secretion of neurotrophic Wnt proteins), from cytoplasmic to membrane compartments in rat striatal neurons. Given its opiate-sensitivity and its well-characterized molecular and cellular adaptations to morphine exposure, we investigated the anatomical distribution of WLS and MOR in the rat locus coeruleus (LC)-norepinephrine (NE) system. Dual immunofluorescence microscopy was used to test the hypothesis that WLS is localized to noradrenergic neurons of the LC and that WLS and MOR co-exist in common LC somatodendritic processes, providing an anatomical substrate for their putative interactions. We also hypothesized that morphine would influence WLS distribution in the LC. Rats received saline, morphine or the opiate agonist [. d-Ala2, N-Me-Phe4, Gly-ol5]-enkephalin (DAMGO), and tissue sections through the LC were processed for immunogold-silver detection of WLS and MOR. Statistical analysis showed a significant re-distribution of WLS to the plasma membrane following morphine treatment in addition to an increase in the proximity of gold-silver labels for MOR and WLS. Following DAMGO treatment, MOR and WLS were predominantly localized within the cytoplasmic compartment when compared to morphine and control. In a separate cohort of rats, brains were obtained from saline-treated or heroin self-administering male rats for pulldown co-immunoprecipitation studies. Results showed an increased association of WLS and MOR following heroin exposure. As the LC-NE system is important for cognition as well as decisions underlying substance abuse, adaptations in WLS trafficking and expression may play a role in modulating MOR function in the LC and contribute to the negative sequelae of opiate exposure on executive function.
AB - Opiate addiction is a devastating health problem, with approximately 2. million people currently addicted to heroin or non-medical prescription opiates in the United States alone. In neurons, adaptations in cell signaling cascades develop following opioid actions at the mu opioid receptor (MOR). A novel putative target for intervention involves interacting proteins that may regulate trafficking of MOR. Morphine has been shown to induce a re-distribution of a MOR-interacting protein Wntless (WLS, a transport molecule necessary for secretion of neurotrophic Wnt proteins), from cytoplasmic to membrane compartments in rat striatal neurons. Given its opiate-sensitivity and its well-characterized molecular and cellular adaptations to morphine exposure, we investigated the anatomical distribution of WLS and MOR in the rat locus coeruleus (LC)-norepinephrine (NE) system. Dual immunofluorescence microscopy was used to test the hypothesis that WLS is localized to noradrenergic neurons of the LC and that WLS and MOR co-exist in common LC somatodendritic processes, providing an anatomical substrate for their putative interactions. We also hypothesized that morphine would influence WLS distribution in the LC. Rats received saline, morphine or the opiate agonist [. d-Ala2, N-Me-Phe4, Gly-ol5]-enkephalin (DAMGO), and tissue sections through the LC were processed for immunogold-silver detection of WLS and MOR. Statistical analysis showed a significant re-distribution of WLS to the plasma membrane following morphine treatment in addition to an increase in the proximity of gold-silver labels for MOR and WLS. Following DAMGO treatment, MOR and WLS were predominantly localized within the cytoplasmic compartment when compared to morphine and control. In a separate cohort of rats, brains were obtained from saline-treated or heroin self-administering male rats for pulldown co-immunoprecipitation studies. Results showed an increased association of WLS and MOR following heroin exposure. As the LC-NE system is important for cognition as well as decisions underlying substance abuse, adaptations in WLS trafficking and expression may play a role in modulating MOR function in the LC and contribute to the negative sequelae of opiate exposure on executive function.
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U2 - 10.1016/j.pnpbp.2013.12.003
DO - 10.1016/j.pnpbp.2013.12.003
M3 - Article
C2 - 24333843
AN - SCOPUS:84891121385
SN - 0278-5846
VL - 50
SP - 53
EP - 65
JO - Progress in Neuro-Psychopharmacology and Biological Psychiatry
JF - Progress in Neuro-Psychopharmacology and Biological Psychiatry
ER -