Microglial/macrophage GRK2 determines duration of peripheral IL-1beta-induced hyperalgesia: contribution of spinal cord CX3CR1, p38 and IL-1 signaling

Pain. 2010 Sep;150(3):550-560. doi: 10.1016/j.pain.2010.06.015. Epub 2010 Jul 6.


Chronic pain associated with inflammation is a major clinical problem, but the underlying mechanisms are incompletely understood. Recently, we reported that GRK2(+/-) mice with a approximately 50% reduction of GRK2 develop prolonged hyperalgesia following a single intraplantar injection of the pro-inflammatory cytokine interleukin-1beta (IL-1beta). Here we show that spinal microglia/macrophage GRK2 is reduced during chronic inflammation-induced hyperalgesia. Next, we applied CRE-Lox technology to create mice with low GRK2 in microglia/macrophages/granulocytes (LysM-GRK2(f/+)), or sensory neurons or astrocytes. Only mice deficient in microglial/macrophage/granulocyte GRK2 display prolonged IL-1beta-induced hyperalgesia that lasts up to 8days. Two days after intraplantar IL-1beta, increased microglial/macrophage activity occurs in the lumbar but not thoracic spinal cord of GRK2-deficient mice. Intrathecal pre-treatment with minocycline, an inhibitor of microglia/macrophage activation, accelerates resolution of hyperalgesia independent of genotype and prevents transition to chronic hyperalgesia in GRK2(+/-) mice. Ongoing hyperalgesia in GRK2(+/-) mice is reversed by minocycline administration at days 1 and 2 after IL-1beta injection. Similarly, IL-1beta-induced hyperalgesia in LysM-GRK2(f/+) mice is attenuated by intrathecal administration of anti-CX3CR1 to abrogate fractalkine signaling, the p38 inhibitor SB239063 and the IL-1 antagonist IL-1ra. These data establish that chronic inflammatory hyperalgesia is associated with reduced GRK2 in microglia/macrophages and that low GRK2 in these cells is sufficient to markedly prolong hyperalgesia after a single intraplantar injection of IL-1beta. Ongoing hyperalgesia is maintained by spinal microglial/macrophage activity, fractalkine signaling, p38 activation and IL-1 signaling. We propose that chronic inflammation decreases spinal microglial/macrophage GRK2, which prevents silencing of microglia/macrophage activity and thereby contributes to prolonged hyperalgesia.

MeSH terms

  • Analysis of Variance
  • Animals
  • CX3C Chemokine Receptor 1
  • Carrageenan / adverse effects
  • Chemokine CX3CL1 / therapeutic use
  • Female
  • G-Protein-Coupled Receptor Kinase 2 / deficiency
  • G-Protein-Coupled Receptor Kinase 2 / metabolism*
  • Gene Expression Regulation / drug effects
  • Hyperalgesia / chemically induced
  • Hyperalgesia / drug therapy
  • Hyperalgesia / genetics
  • Hyperalgesia / pathology*
  • Inflammation / chemically induced
  • Inflammation / pathology
  • Interleukin-1 / metabolism*
  • Interleukin-1beta
  • Macrophages / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microglia / metabolism*
  • Minocycline / therapeutic use
  • Peroxidase / metabolism
  • Receptors, Chemokine / genetics
  • Receptors, Chemokine / metabolism*
  • Sensory Receptor Cells / drug effects
  • Sensory Receptor Cells / metabolism
  • Signal Transduction / drug effects
  • Spinal Cord / drug effects
  • Spinal Cord / metabolism*
  • p38 Mitogen-Activated Protein Kinases / metabolism*


  • CX3C Chemokine Receptor 1
  • Chemokine CX3CL1
  • Cx3cr1 protein, mouse
  • Interleukin-1
  • Interleukin-1beta
  • Receptors, Chemokine
  • Carrageenan
  • Peroxidase
  • GRK2 protein, mouse
  • G-Protein-Coupled Receptor Kinase 2
  • p38 Mitogen-Activated Protein Kinases
  • Minocycline