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Differential in vivo internalization of MOR-1 and MOR-1C by morphine
1Laboratory of Molecular Neuropharmacology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA.
Abstract:
The mu opioid receptor MOR-1 is internalized by many mu agonists, but not morphine. To see whether differences in the intracellular carboxy terminus influences internalization, we examined internalization of a splice variant of the mu opioid receptor, MOR-1C, in the lateral septum of the mouse in vivo. Following intracerebroventricular (i.c.v.) saline treatment, MOR-1C-like immunoreactivity (LI) within neurons in naive mice was found predominantly in clusters close to the plasma membrane. Following either intracerebroventricular [d-Ala2, MePhe4,Gly(ol)5]enkephalin (DAMGO) or morphine, MOR-1C-LI clustered into endosomes in the cytoplasm. This effect was suppressed by prior administration of the opioid antagonist naloxone. In contrast, only DAMGO, and not morphine, internalized MOR-1-LI. These results illustrate differences in internalization between two MOR-1 variants that have alternative splicing at the COOH terminus.
Insights
Mu opioid receptor (MOR-1) splice variants show distinct internalization patterns. MOR-1C is internalized by both DAMGO and morphine, unlike MOR-1, highlighting COOH terminus differences.
Area of Science:
- Neuroscience
- Pharmacology
- Molecular Biology
Background:
- Mu opioid receptor (MOR-1) internalization is crucial for receptor regulation.
- Previous studies indicated MOR-1 is internalized by agonists, except morphine.
- Alternative splicing at the COOH terminus may influence receptor trafficking.
Purpose of the Study:
- To investigate the role of the intracellular carboxy terminus in MOR-1 internalization.
- To compare the internalization of MOR-1C splice variant with MOR-1 in vivo.
Main Methods:
- Examined MOR-1C internalization in the mouse lateral septum using intracerebroventricular (i.c.v.) administration.
- Utilized immunohistochemistry to visualize MOR-1C-like immunoreactivity (LI).
- Administered DAMGO, morphine, saline, and naloxone to assess receptor trafficking.
Main Results:
- MOR-1C-LI was primarily located near the plasma membrane in naive mice.
- Both DAMGO and morphine induced MOR-1C-LI internalization into endosomes.
- Naloxone blocked the internalization effect.
- In contrast, only DAMGO, not morphine, internalized MOR-1-LI.
Conclusions:
- Splice variants of MOR-1 exhibit differential internalization responses to agonists.
- Alternative splicing at the COOH terminus significantly impacts MOR-1 trafficking and agonist-induced internalization.
- These findings provide insights into opioid receptor regulation and signaling diversity.