Elucidation of mu-opioid gene structure: How genetics can help predict therapeutic response to opioids

摘要

Opioid drugs are among the most commonly used and effective human analgesics. To date, the clinical benefits of opioid analgesics have not been fully realized due to substantial individual variations in the responses to opioids, insufficient drug dosing, and a high rate (up to 66%) of adverse events. As such, there is a substantial need to identify the genetic and molecular biological mechanisms that mediate individual responses to opioid therapy. Recent discoveries show that genetic variations in the mu-opioid receptor (0PRM1) gene locus play an essential role in inter-individual responses. The majority of genetic association studies have focused on the A118G polymorphism, which codes for a non-synonymous change in OPRM1 exon 1. In addition to the All 8G polymorphism, another functional SNP (rs563649), which is located within an alternatively-spliced 0PRM1 isoform (MOR-1K), has been identified. The MOR-1K alternatively-spliced variant codes for 6TM 0PRM1 isoforms that display excitatory rather than the inhibitory cellular effects, which are characteristic of the canonical 7TM isoforms. Thus, stimulation of the 6TM isoforms may engage the molecular mechanisms mediating opioid-dependent hyperalgesia, tolerance and dependence. Future clinical and basic studies that seek to identify the functional genetic variants within 0PRM1 locus, and associated molecular mechanisms, will result in a better understanding of individual responses to opioid therapy and ultimately to the development new pharmacotherapeutics and diagnostic tools.