Together, we define a critical role for PTEN in regulating the surface delivery and bioavailability of the δR, explain the low efficacy of δR agonists <i>in vivo</i>, and provide evidence that active δR relocation is a viable strategy to increase δR antinociception.<b>SIGNIFICANCE STATEMENT</b> Opioid analgesics, such as morphine, which target the μ opioid receptor (μR), have been the mainstay of pain management, but their use is highly limited by adverse effects and their variable efficacy in chronic pain.