A PTEN-Regulated Checkpoint Controls Surface Delivery of [delta] Opioid Receptors

The [delta] opioid receptor ([delta]R) is a promising alternate target for pain management because [delta]R agonists show decreased abuse potential compared with current opioid analgesics that target the [mu] opioid receptor. A critical limitation in developing [delta]R as an analgesic target, however, is that [delta]R agonists show relatively low efficacy in vivo, requiring the use of high doses that often cause adverse effects, such as convulsions. Here we tested whether intracellular retention of [delta]R in sensory neurons contributes to this low [delta]R agonist efficacy in vivo by limiting surface [delta]R expression. Using direct visualization of [delta]R trafficking and localization, we define a phosphatase and tensin homolog (PTEN)-regulated checkpoint that retains [delta]R in the Golgi and decreases surface delivery in rat and mice sensory neurons. PTEN inhibition releases [delta]R from this checkpoint and stimulates delivery of exogenous and endogenous [delta]R to the neuronal surface both in vitro and in vivo. PTEN inhibition in vivo increases the percentage of TG neurons expressing [delta]R on the surface and allows efficient [delta]R-mediated antihyperalgesia in mice. Together, we define a critical role for PTEN in regulating the surface delivery and bioavailability of the [delta]R, explain the low efficacy of [delta]R agonists in vivo, and provide evidence that active [delta]R relocation is a viable strategy to increase [delta]R antinociception.