A PTEN-regulated checkpoint controls surface delivery of σ opioid receptors

The σ opioid receptor (σR) is a promising alternate target for pain management because σR agonists show decreased abuse potential compared with current opioid analgesics that target theµ opioid receptor. A critical limitation in developing σR as an analgesic target, however, is that σR 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 ofσRin sensory neurons contributes to this lowσRagonist efficacy in vivo by limiting surfaceσR expression. Using direct visualization ofσR trafficking and localization, we define a phosphatase and tensin homolog (PTEN)-regulated checkpoint that retains σR in the Golgi and decreases surface delivery in rat and mice sensory neurons. PTEN inhibition releases σR from this checkpoint and stimulates delivery of exogenous and endogenous σR to the neuronal surface both in vitro and in vivo. PTEN inhibition in vivo increases the percentage of TG neurons expressingσR on the surface and allows efficientσR-mediated antihyperalgesia in mice. Together, we define a critical role for PTEN in regulating the surface delivery and bioavailability of the σR, explain the low efficacy ofσR agonists in vivo, and provide evidence that activeσR relocation is a viable strategy to increaseσR antinociception.