GRK2 in sensory neurons regulates epinephrine-induced signalling and duration of mechanical hyperalgesia

Pain. 2011 Jul;152(7):1649-1658. doi: 10.1016/j.pain.2011.03.010. Epub 2011 Apr 22.


Epinephrine (EPI) contributes to hyperalgesia in inflammatory and stress conditions. EPI signals via adrenoceptors, which are regulated by G protein-coupled receptor kinase 2 (GRK2). We previously reported that GRK2 is decreased in nociceptors during chronic inflammation. Herein, we investigated whether GRK2 modulates EPI-induced mechanical and thermal hyperalgesia by using GRK2(+/-) mice, which express 50% of the GRK2 protein. We demonstrate for the first time that EPI-induced mechanical as well as thermal hyperalgesia is prolonged to approximately 21 days in GRK2(+/-) mice, whereas it lasts only 3 to 4 days in wild-type mice. Using cell- specific GRK2-deficient mice, we further show that a low level of GRK2 in primary sensory neurons is critical for this prolongation of EPI-induced hyperalgesia. Low GRK2 in microglia had only a small effect on EPI-induced hyperalgesia. Low GRK2 in astrocytes did not alter EPI-induced hyperalgesia. EPI-induced hyperalgesia was prolonged similarly in mice with tamoxifen-induced homozygous or heterozygous deletion of GRK2. In terms of EPI signalling pathways, the protein kinase A (PKA) inhibitor H-89 inhibited EPI-induced mechanical hyperalgesia in wild-type mice, whereas H-89 had no effect in mice with low GRK2 in sensory neurons (SNS-GRK2(+/-) mice). Conversely, intraplantar injection of the protein kinase Cε PKCε inhibitor TAT-PKC(εv1-2) inhibited hyperalgesia in sensory neuron specific (SNS)-GRK2(+/-) mice and not in wild-type mice. These results indicate that low GRK2 in primary sensory neurons switches EPI-induced signalling from a protein kinase A-dependent toward a PKCε-dependent pathway that ultimately mediates prolonged EPI-induced hyperalgesia.

MeSH terms

  • Adrenergic alpha-Antagonists / therapeutic use
  • Adrenergic beta-Antagonists / therapeutic use
  • Animals
  • Disease Models, Animal
  • Enzyme Inhibitors / pharmacology
  • Epinephrine / toxicity*
  • Female
  • G-Protein-Coupled Receptor Kinase 2 / deficiency
  • G-Protein-Coupled Receptor Kinase 2 / metabolism*
  • Ganglia, Spinal / pathology
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / genetics
  • Hyperalgesia / chemically induced*
  • Hyperalgesia / drug therapy
  • Hyperalgesia / genetics
  • Hyperalgesia / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neuroglia / drug effects
  • Neuroglia / metabolism
  • Pain Measurement
  • Pain Threshold / drug effects*
  • Phentolamine / therapeutic use
  • Propanolamines / therapeutic use
  • Sensory Receptor Cells / drug effects
  • Sensory Receptor Cells / metabolism*
  • Signal Transduction / drug effects*
  • Signal Transduction / genetics


  • Adrenergic alpha-Antagonists
  • Adrenergic beta-Antagonists
  • Enzyme Inhibitors
  • Propanolamines
  • ICI 118551
  • GRK2 protein, mouse
  • G-Protein-Coupled Receptor Kinase 2
  • Epinephrine
  • Phentolamine