GRK2 Constitutively Governs Peripheral Delta Opioid Receptor Activity

Cell Rep. 2016 Sep 6;16(10):2686-2698. doi: 10.1016/j.celrep.2016.07.084. Epub 2016 Aug 25.


Opioids remain the standard for analgesic care; however, adverse effects of systemic treatments contraindicate long-term administration. While most clinical opioids target mu opioid receptors (MOR), those that target the delta class (DOR) also demonstrate analgesic efficacy. Furthermore, peripherally restrictive opioids represent an attractive direction for analgesia. However, opioid receptors including DOR are analgesically incompetent in the absence of inflammation. Here, we report that G protein-coupled receptor kinase 2 (GRK2) naively associates with plasma membrane DOR in peripheral sensory neurons to inhibit analgesic agonist efficacy. This interaction prevents optimal Gβ subunit association with the receptor, thereby reducing DOR activity. Importantly, bradykinin stimulates GRK2 movement away from DOR and onto Raf kinase inhibitory protein (RKIP). protein kinase C (PKC)-dependent RKIP phosphorylation induces GRK2 sequestration, restoring DOR functionality in sensory neurons. Together, these results expand the known function of GRK2, identifying a non-internalizing role to maintain peripheral DOR in an analgesically incompetent state.

MeSH terms

  • Analgesics, Opioid / pharmacology
  • Animals
  • Bradykinin / pharmacology
  • G-Protein-Coupled Receptor Kinase 2 / metabolism*
  • GTP-Binding Proteins / metabolism
  • Male
  • Nociception / drug effects
  • Phosphatidylethanolamine Binding Protein / metabolism
  • Protein Kinase C / metabolism
  • Rats, Sprague-Dawley
  • Receptors, Opioid, delta / metabolism*
  • Sensory Receptor Cells / drug effects
  • Sensory Receptor Cells / metabolism
  • Signal Transduction / drug effects
  • Type C Phospholipases / metabolism


  • Analgesics, Opioid
  • PEBP1 protein, rat
  • Phosphatidylethanolamine Binding Protein
  • Receptors, Opioid, delta
  • Protein Kinase C
  • G-Protein-Coupled Receptor Kinase 2
  • Type C Phospholipases
  • GTP-Binding Proteins
  • Bradykinin