Antisense mapping the MOR-1 opioid receptor: evidence for alternative splicing and a novel morphine-6 beta-glucuronide receptor.
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.
Rossi
G C
GC
George C. Cotzias Laboratory of Neuro-Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Pan
Y X
YX
Brown
G P
GP
Pasternak
G W
GW
D017398:Alternative Splicing; D000698:Analgesia; D000818:Animals; D001483:Base Sequence; D003001:Cloning, Molecular; D015342:DNA Probes; D016373:DNA, Antisense / Q000235:genetics / Q000494:pharmacology*; D005091:Exons; D005772:Gastrointestinal Transit / Q000187:drug effects; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009020:Morphine / Q000494:pharmacology; D009022:Morphine Derivatives / Q000494:pharmacology; D009692:Nucleic Acid Heteroduplexes / Q000235:genetics; D017450:Receptors, Opioid, mu / Q000187:drug effects / Q000235:genetics*
D015342:DNA Probes; D016373:DNA, Antisense; D009022:Morphine Derivatives; D009692:Nucleic Acid Heteroduplexes; D017450:Receptors, Opioid, mu; C035349:morphine-6-glucuronide; D009020:Morphine