Anatomical and functional correlation of the endomorphins with mu opioid receptor splice variants

The present study characterizes the relationship between the endogenous mu opioid peptides endomorphin‐1 (EM‐1) and endomorphin‐2 (EM‐2) and several splice variants of the cloned mu opioid receptor (MOR‐1) encoded by the mu opioid receptor gene (Oprm). Confocal laser microscopy revealed that fibers containing EM‐2‐like immunoreactivity (‐LI) were distributed in close apposition to fibers showing MOR‐1‐LI (exon 4‐LI) and to MOR‐1C‐LI (exons 7/8/9‐LI) in the superficial laminae of the lumbar spinal cord. We also observed colocalization of EM‐2‐LI and MOR‐1‐LI in a few fibers of lamina II, and colocalization of EM‐2‐LI and MOR‐1C‐LI in laminae I–II, and V–VI. To assess the functional relevance of the MOR‐1 variants in endomorphin analgesia, we examined the effects of antisense treatments that targeted individual exons within the Oprm1 gene on EM‐1 and EM‐2 analgesia in the tail flick test. This antisense mapping study implied mu opioid receptor mechanisms for the endomorphins are distinct from those of morphine or morphine‐6β‐glucuronide (M6G).