1 research outputs found
Tetrapeptide Endomorphin Analogs Require Both Full Length and Truncated Splice Variants of the Mu Opioid Receptor Gene <i>Oprm1</i> for Analgesia
The mu opioid receptor gene undergoes
extensive alternative splicing.
Mu opioids can be divided into three classes based on the role of
different groups of splice variants. Morphine and methadone require
only full length seven transmembrane (7TM) variants for analgesia,
whereas IBNtxA (3′-iodobenzyol-6β-naltrexamide) needs
only truncated 6TM variants. A set of endomorphin analogs fall into
a third group that requires both 6TM and 7TM splice variants. Unlike
morphine, endomorphin 1 and 2, DAPP (Dmt,d-Ala-Phe-Phe-NH<sub>2</sub>), and IDAPP (3′-iodo-Dmt-d-Ala-Phe-Phe-NH<sub>2</sub>) analgesia was lost in an exon 11 knockout mouse lacking
6TM variants. Restoring 6TM variant expression in a knockout mouse
lacking both 6TM and 7TM variants failed to rescue DAPP or IDAPP analgesia.
However, re-establishing 6TM expression in an exon 11 knockout mouse
that still expressed 7TM variants did rescue the response, consistent
with the need for both 6TM and 7TM variants. In receptor binding assays, <sup>125</sup>I-IDAPP labeled more sites (<i>B</i><sub>max</sub>) than <sup>3</sup>H-DAMGO ([d-Ala<sup>2</sup>,N-MePhe<sup>4</sup>,GlyÂ(ol)<sup>5</sup>]-enkephalin) in wild-type mice. In exon
11 knockout mice, <sup>125</sup>I-IDAPP binding was lowered to levels
similar to <sup>3</sup>H-DAMGO, which remained relatively unchanged
compared to wild-type mice. <sup>125</sup>I-IDAPP binding was totally
lost in an exon 1/exon 11 knockout model lacking all <i>Oprm1</i> variant expression, confirming that the drug was not cross labeling
non-mu opioid receptors. These findings suggested that <sup>125</sup>I-IDAPP labeled two populations of mu binding sites in wild-type
mice, one corresponding to 7TM variants and the second dependent upon
6TM variants. Together, these data indicate that endomorphin analogs
represent a unique, genetically defined, and distinct class of mu
opioid analgesic