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Endomorphins and DAMGO Utilize Different Mechanisms to Produce Analgesia
Author(s) -
Marrone Gina,
Grinnell Steven,
Rossi Grace,
Pintar John,
Majumdar Susruta,
Pan Yingxian,
Pasternak Gavril
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.929.6
Subject(s) - damgo , exon , μ opioid receptor , splice , chemistry , opioid receptor , morphine , receptor , pharmacology , medicine , opioid , endocrinology , biochemistry , gene
There is significant variability among animals in their response to mu opioid receptor (MOR1) analgesics. The mu opioid receptor gene ( OPRM1 ) undergoes extensive alternative splicing, producing several splice variants with 1, 6, and 7 transmembrane (TM) domains. Variants containing 6 TMs lack TM1 and are associated with the exon 11 promoter. We previously showed that mice lacking exon 11 variants respond normally to methadone and morphine, but fentanyl, heroin, and morphine‐6‐glucuronide potency is significantly reduced (Pan et al, 2009). Here, we report that in exon 11 KO mice the DAMGO response is intact both supraspinally and spinally but endomorphin analgesiais significantly reduced. [ 3 H]DAMGO binding in exon 11 KO brain and spinal cord was not significantly altered, but binding of the endomorphin 2 analog 125 I‐DAPP (dmt( 125 I)‐D‐Ala‐Phe‐Phe‐NH 2 ) was reduced.No binding of [ 3 H]DAMGO or 125 I‐DAPP was detected in mice lacking both exon 1 7TM MOR variants and exon 11 6TM variants. In [ 35 S]GTPγS studies of brain and spinal cord binding, max stimulation by DAMGO was equal in wild type and exon 11 KO mice whereas IDAPP stimulation was reduced in exon 11 KO mice. Overall, our results indicate that DAMGO does not recruit 6TM exon 11 variants for binding and analgesia, whereas endomorphins require a mechanism including 6TM exon 11 variants for analgesia and a significant portion of binding.