A new splice of life for the μ-opioid receptor

Abstract

μ-Opioid agonists mediate their analgesic effect through GPCRs that are generated via alternate splicing of the Oprm1 transcript. While the majority of μ-opioids interact with receptors comprising the canonical 7 transmembrane (7TM) domain, a recently identified class of μ-opioids appears to require a 6TM domain variant. In this issue of the JCI, Lu and colleagues provide an in vivo proof-of-concept demonstration that a 6TM isoform of the μ-opioid receptor can support functional analgesia in Oprm1-deficent animals. The 6TM isoform was pharmacologically distinct from the canonical 7TM μ-opioid receptor, and 6TM agonists had a reduced side effect profile, which confers a strong therapeutic advantage over standard opioid analgesics. The observations of Lu et al. extend the reach of opioid-receptor neurobiology and pharmacology into a new era of analgesic discovery. This advance emerges from a series of fundamental research analyses in which elements of the endogenous opioid system were frequently in the vanguard.

Figure 1. RNA-Seq analysis of mouse Oprm1 exons in Trpv1 lineage DRG.

In the mouse DRG, cells expressing RFP under the Trpv1 promoter were separated by FACS and analyzed by RNA-Seq (37). Exons 1, 2, 3, and 4 were clearly identified (colored boxes) with approximately equal reads/kilobase of transcript/million bases sequenced (RPKM), although exon 4 shows a slightly increased RPKM, likely due to additional sequence present at the 3′ end of this exon. Measurements of junctional reads containing sequences from more than one exon provide quantitative assessments of mRNA splicing. Junctional reads were detected between each of the major exons, spanning the introns between them (dashed lines). Additional splicing of Oprm1 was not robustly detected. Notably, the 5′ exon 11 was detected with 5 reads (not shown); however, this is below what can be reliably measured by RNA-Seq.