A “tail” of opioid receptor variants
Stephanie Puig, Howard B. Gutstein
Stephanie Puig, Howard B. Gutstein
Published March 20, 2017
Citation Information: J Clin Invest. 2017;127(4):1221-1224. https://doi.org/10.1172/JCI93582.
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A “tail” of opioid receptor variants

Abstract

Opioids are the gold-standard treatment for severe pain. However, potentially life-threatening side effects decrease the safety and effectiveness of these compounds. The addiction liability of these drugs has led to the current epidemic of opioid abuse in the US. Extensive research efforts have focused on trying to dissociate the analgesic properties of opioids from their undesirable side effects. Splice variants of the mu opioid receptor (MOR), which mediates opioid actions, have unique pharmacological properties and anatomic distributions that make them attractive candidates for therapeutic pain relief. In this issue of the JCI, Xu et al. show that specific C-terminal regions of the MOR can modulate side effects without altering analgesia. This discovery greatly improves our understanding of opioid side effects and suggests intriguing therapeutic approaches that could improve both the safety and long-term effectiveness of opioids.

Authors

Stephanie Puig, Howard B. Gutstein

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Figure 1

Mouse MOR (Oprm1) gene schematic structure and alternative splicing.

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Mouse MOR (Oprm1) gene schematic structure and alternative splicing. (A)...
(A) Oprm1 gene structure. Exons are indicated by color-coded boxes. Exons 1 (blue), 2 (yellow), and 3 (green) constitute the TM domains of the receptor. The mouse Oprm1 gene contains ten alternatively spliced exons (red boxes) downstream of exon 3 that generate different C-terminal tails. In this issue, Xu et al. report on their generation of mouse models (mE3M, mE4M, and mE7M) that express alternatively spliced variants with different C termini (25). Arrows indicate the location of the STOP codons that were inserted to generate each truncation. Consequences of specific C-terminal truncations on opioid-induced side effects are summarized in Table 1. (B) The three classes of MOR splice variants include the classical 7TM form as well as 6TM and 1TM versions. Color-coded structures match the color-coded exons in A. The red rectangles represent the alternatively spliced C-terminal tails of the receptor variants.