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Antisense mapping the MOR-1 opioid receptor: evidence for alternative splicing and a novel morphine-6
G C Rossi1, Y X Pan, G P Brown
1George C. Cotzias Laboratory of Neuro-Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Abstract:
Although MOR-1 encodes a mu opioid receptor, its relationship to the pharmacologically defined mu receptor subtypes has been unclear. Antisense mapping now suggests that these subtypes result from alternative splicing of MOR-1. Three oligodeoxynucleotide probes targeting exon 1 and another oligodeoxynucleotide directed against the coding region of exon 4 block supraspinal morphine analgesia, a mu1 action, while five of six oligodeoxynucleotides directed against exons 2 and 3 are inactive. Inhibition of gastrointestinal transit and spinal morphine analgesia, two mu2 actions, are blocked only by the probe against exon 4 and not by those directed against exon 1. In contrast, the analgesic actions of the extraordinarily potent mu drug morphine-6 beta-glucuronide are blocked by six different antisense oligodeoxynucleotides targeting exons 2 and 3, but not by those acting on exons 1 or 4. These results suggest that the mu1 and mu2 receptor subtypes originally defined in binding and pharmacological studies result from alternative splicing of MOR-1 while morphine-6 beta-glucuronide acts through a novel, previously unidentified receptor which is yet another MOR-1 splice variant.
Insights
The mu opioid receptor (MOR-1) likely generates distinct subtypes (mu1 and mu2) through alternative splicing. Morphine-6 beta-glucuronide may act on a novel MOR-1 splice variant, not previously identified.
Area of Science:
- Pharmacology
- Molecular Biology
- Neuroscience
Background:
- The mu opioid receptor (MOR-1) is crucial for pain modulation.
- The precise molecular basis of pharmacologically defined mu opioid receptor subtypes (mu1, mu2) remains unclear.
Purpose of the Study:
- To investigate whether mu opioid receptor subtypes arise from alternative splicing of the MOR-1 gene.
- To characterize the molecular targets of morphine and morphine-6 beta-glucuronide.
Main Methods:
- Antisense mapping using oligodeoxynucleotide probes targeting different exons of the MOR-1 gene.
- Assessment of the effects of these probes on supraspinal and spinal morphine analgesia, and gastrointestinal transit inhibition.
- Evaluation of probe effects on morphine-6 beta-glucuronide analgesia.
Main Results:
- Probes targeting MOR-1 exon 1 and exon 4 blocked supraspinal morphine analgesia (mu1 action).
- Probes targeting exon 4, but not exon 1, blocked gastrointestinal transit inhibition and spinal morphine analgesia (mu2 actions).
- Morphine-6 beta-glucuronide analgesia was blocked by probes targeting exons 2 and 3, suggesting a novel receptor splice variant.
Conclusions:
- Pharmacologically distinct mu1 and mu2 opioid receptor subtypes likely result from alternative splicing of MOR-1.
- Morphine-6 beta-glucuronide may act via a novel MOR-1 splice variant, distinct from mu1 and mu2 subtypes.