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

Hanneke L.D.M. Willemen, Niels Eijkelkamp, Huijing Wang, Robert Dantzer, Gerald W. Dorn, Keith W. Kelley, Cobi J. Heijnen, Annemieke Kavelaars

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67 Scopus citations

Abstract

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 ∼50% reduction of GRK2 develop prolonged hyperalgesia following a single intraplantar injection of the pro-inflammatory cytokine interleukin-1β (IL-1β). 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-GRK2f/+), or sensory neurons or astrocytes. Only mice deficient in microglial/macrophage/granulocyte GRK2 display prolonged IL-1β-induced hyperalgesia that lasts up to 8 days. Two days after intraplantar IL-1β, 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-1β injection. Similarly, IL-1β-induced hyperalgesia in LysM-GRK2f/+ 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-1β. 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.

Original languageEnglish
Pages (from-to)550-560
Number of pages11
JournalPain
Volume150
Issue number3
DOIs
StatePublished - Sep 1 2010

Keywords

  • CX3CR1
  • G protein-coupled receptor kinase 2
  • IL-1β
  • Inflammatory hyperalgesia
  • Microglia
  • p38

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    Willemen, H. L. D. M., Eijkelkamp, N., Wang, H., Dantzer, R., Dorn, G. W., Kelley, K. W., Heijnen, C. J., & Kavelaars, A. (2010). Microglial/macrophage GRK2 determines duration of peripheral IL-1β-induced hyperalgesia: Contribution of spinal cord CX3CR1, p38 and IL-1 signaling. Pain, 150(3), 550-560. https://doi.org/10.1016/j.pain.2010.06.015