This Week in The Journal

Opioid drugs and our brain’s endogenous opioids work primarily at mu-type opioid receptors ( R) to dampen pain signals. But because the R is expressed throughout the brain and body, R agonists can cause side effects ranging from constipation to addiction. The related delta-type opioid receptor ( R), in contrast, has more limited expression, but it is found in nociceptive sensory neurons, making it an attractive target to produce pain relief with lower abuse potential. Researchers have been stymied in this effort, however, because effective pain relief requires extremely high doses of R agonists for reasons that remain mysterious. Past studies have hinted that the receptor may be located inside sensory neurons with little availability at the surface. Shiwarski et al. delved into how receptor trafficking to the cell surface might be controlled in sensory neurons by focusing on the phosphatidylinositol 3 kinase (PI3K) and phosphatase and tensin (PTEN) pathways, which figure prominently in neuronal differentiation and trafficking. They hypothesized that the balance of activity between the two pathways might control R surface availability, with PI3K promoting membrane delivery and PTEN favoring intracellular retention. In heterologous PC12 cells expressing functional fluorescent R, receptors are found on the cell surface, but treatment with nerve growth factor led to intracellular accumulation of R. PTEN blockers prevented this accumulation and increased surface R. Similarly, PTEN inhibition in neurons cultured from mouse trigeminal ganglia caused redistribution of R to the cell surface. The Gi-coupled receptors were functional according to an assay that measured their inhibition of cAMP. To test whether PTEN increased availability of functional endogenous Rs, the team measured calcium current inhibition in response to a R agonist. While the magnitude of current inhibition remained steady, more trigeminal cells responded to the agonist following pretreatment with PTEN. In vivo, PTEN inhibition also increased trafficking of endogenous R to the cell surface in trigeminal neurons. Finally, in a mouse model of chronic inflammatory pain, PTEN inhibition reversed mechanical pain hypersensitivity that was prevented by a R-selective antagonist. The authors conclude that increasing R availability at the sensory neuron surface may be a viable strategy to target Rs for pain relief.