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.
Klein
Gad
G
Neuropsychology Doctoral Subprogram, Queens College, City University of New York, Flushing, NY 11367, United States.
Rossi
Grace C
GC
Waxman
Amanda R
AR
Arout
Carolne
C
Juni
Aaron
A
Inturrisi
Charles E
CE
Kest
Benjamin
B
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