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.