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*Compound via MeSH
*Substance via MeSH
Hazardous Substances DB
*MORPHINE

Vol. 281, Issue 1, 109-114, 1997

Antisense Mapping of MOR-1 in Rats: Distinguishing between Morphine and Morphine-6beta -glucuronide Antinociception1

Grace C. Rossi, Liza Leventhal , Ying-Xin Pan, Jessica Cole, Wendy Su, Richard J. Bodnar and Gavril W. Pasternak

The Cotzias Laboratory of Neuro-Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York (G.C.R., L.L., Y.-X.P., W.S., G.W.P.); Departments of Neurology & Neuroscience and Pharmacology, Cornell University Medical College, New York, New York (G.W.P.); Neuropsychology Doctoral Sub Program, City University of New York, New York, New York (L.L., J.C., R.J.B.); and Department of Psychology, Queens College, City University of New York, Flushing, New York (R.J.B.)

In an effort to correlate the recently cloned MOR-1 receptor with the pharmacological actions of morphine and morphine-6beta -glucuronide (M6G), we have used an antisense paradigm. Rats were injected intracerebroventricularly (i.c.v.) with antisense oligodeoxynucleotides on days 1, 3 and 5 and tested for analgesia on day 6 after administration of morphine or M6G i.c.v. or after microinjection of morphine directly into either the periaqueductal gray or the locus coeruleus. When given i.c.v., the antisense oligodeoxynucleotide targeting the 5'-untranslated region of exon 1 significantly decreased the analgesic actions of morphine administered i.c.v. or microinjected directly into the periaqueductal gray or locus coeruleus, with the most profound inhibition occurring in the periaqueductal gray. Thus, antisense oligodeoxynucleotides administered into the lateral ventricle can diffuse into the brainstem and interfere with morphine actions. A mismatch antisense oligodeoxynucleotide with the same base composition in which the sequence of four bases was changed was inactive. This same exon 1 antisense oligodeoxynucleotide, which was active against morphine analgesia, failed to block M6G analgesia. In contrast, antisense sequences from exons 2 and 3 decreased M6G, and not morphine, analgesia. The antisense oligodeoxynucleotide against exon 4 slightly decreased both morphine and M6G antinociception. These results confirm the antisense mapping studies on exons 1, 2 and 3 of MOR-1 in mice, which implied the presence of a novel µ receptor subtype responsible for M6G analgesia that may represent a splice variant of MOR-1. Unlike in mice, the probe against exon 4 had a small effect on M6G analgesia.


Copyright © by The American Society for Pharmacology and Experimental Therapeutics



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