The contribution of MOR-1 exons 1-4 to morphine and heroin analgesia and dependence.
Although morphine and heroin analgesia is mediated by mu-opioid receptors encoded by the MOR-1 gene, distinct isoforms are involved. Both opioids also induce dependence by acting at mu-opioid receptors, but which variants are utilized is not known. Here, we assayed morphine and heroin analgesia and dependence in mice treated with antisense oligodeoxynucleotides (AO) targeting MOR-1 exons 1-4. Whereas AOs targeting exons 1 and 4 blocked morphine analgesia, those targeting exons 2 and 3 blocked heroin analgesia. Neither morphine nor heroin analgesia was compromised 5 days after the last AO injection. In morphine and heroin dependent mice, only exon 1 AO significantly reduced jumping incidence during naloxone (50mg/kg) precipitated withdrawal. Neither analgesia nor withdrawal jumping was attenuated in controls pretreated with saline or a mismatch oligodeoxynucleotide control sequence. While these data confirm previous reports that morphine and heroin analgesia are not mediated by a single mu-opioid receptor, both opiates nonetheless apparently induce dependence via a mu-opioid receptor isoform containing exon 1. For heroin, the possibility that analgesia and dependence are mediated by distinct mu-opioid receptor isoforms offers the prospect of developing potent opiate analgesics possessing reduced dependence liability.
Neuropsychology Doctoral Subprogram, Queens College, City University of New York, Flushing, NY 11367, United States.
Gad
G
Klein
Grace C
GC
Rossi
Amanda R
AR
Waxman
Carolne
C
Arout
Aaron
A
Juni
Charles E
CE
Inturrisi
Benjamin
B
Kest
D000698:Analgesia; D000701:Analgesics, Opioid / Q000633:toxicity; D000704:Analysis of Variance; D000818:Animals; D005091:Exons; D003932:Heroin / Q000633:toxicity; D006556:Heroin Dependence / Q000235:genetics*; D006358:Hot Temperature; D008297:Male; D051379:Mice; D009020:Morphine / Q000633:toxicity; D009021:Morphine Dependence / Q000235:genetics*; D009043:Motor Activity / Q000187:drug effects; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D016376:Oligonucleotides, Antisense / Q000378:metabolism; D010147:Pain Measurement; D020033:Protein Isoforms; D017450:Receptors, Opioid, mu / Q000235:genetics* / Q000378:metabolism; D013375:Substance Withdrawal Syndrome
D000701:Analgesics, Opioid; D009292:Narcotic Antagonists; D016376:Oligonucleotides, Antisense; C404943:Oprm protein, mouse; D020033:Protein Isoforms; D017450:Receptors, Opioid, mu; D009270:Naloxone; D003932:Heroin; D009020:Morphine