Endomorphin analogs with analgesic actions mediated through exon 11 variants of the mu opioid receptor (MOR‐1) (659.10)

Multiple mu opioid receptors (MOR‐1) have been confirmed with the cloning of several mu splice variants. These variants are generated by distinct promoters associated with exon 1 and exon 11. Previously, our lab (Pan et al., 2009, PNAS) observed that the potency of morphine‐6β‐glucuronide, heroin, and fentanyl analgesia was significantly reduced in mice lacking truncated 6 transmembrane (6TM) exon 11 variants of MOR‐1. In contrast, morphine analgesia was intact. We now present evidence that the mu selective peptides endomorphin‐1 and endomorphin‐2 also require exon 11 variants for their analgesic actions supraspinally. An endomorphin‐2 analog, DAPP (dmt‐DAla‐Phe‐Phe‐NH2), produces analgesia via exon 11 variants of MOR‐1 as well. In vitro, approximately 50% of [125I]DAPP binding was lost in the brains of exon 11 knockout mice, whereas almost no specific binding was detected in triple knockout mice lacking MOR‐1 exon 1 variants, delta (DOR‐1), and kappa (KOR‐1). Consistent with our previous behavioral findings, morphine‐6β‐glucuronide, 6‐acetyl‐morphine, and fentanyl were less potent competitors of [125I]DAPP in the brains of exon 11 knockout mice compared to C57/B6 wild type mice. Overall, our findings provide further evidence for the functional role of truncated 6TM variants of MOR‐1. These results also suggest that mu analgesics, including peptides, can be subclassified based on their affinities to exon 11 associated splice variants. Grant Funding Source : NIDA DA02615, DA06142 and DA07242