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

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

doi:10.1016/j.pain.2010.06.015

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Volume 150, Issue 3 , Pages 550-560, September 2010

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
- Laboratory of Neuroimmunology and Developmental Origins of Disease (NIDOD), University Medical Center Utrecht, 3584 EA Utrecht, The Netherlands
- These authors contributed equally to this work.
Niels Eijkelkamp
- Laboratory of Neuroimmunology and Developmental Origins of Disease (NIDOD), University Medical Center Utrecht, 3584 EA Utrecht, The Netherlands
- Integrative Immunology and Behavior Program, College of ACES and College of Medicine, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
- These authors contributed equally to this work.
Huijing Wang
- Laboratory of Neuroimmunology and Developmental Origins of Disease (NIDOD), University Medical Center Utrecht, 3584 EA Utrecht, The Netherlands
Robert Dantzer
- Integrative Immunology and Behavior Program, College of ACES and College of Medicine, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
Gerald W. Dorn II
- Center for Pharmacogenomics, Washington University, St. Louis, MI 63110, USA
Keith W. Kelley
- Integrative Immunology and Behavior Program, College of ACES and College of Medicine, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
Cobi J. Heijnen
- Laboratory of Neuroimmunology and Developmental Origins of Disease (NIDOD), University Medical Center Utrecht, 3584 EA Utrecht, The Netherlands
- Integrative Immunology and Behavior Program, College of ACES and College of Medicine, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
Annemieke Kavelaars
- Laboratory of Neuroimmunology and Developmental Origins of Disease (NIDOD), University Medical Center Utrecht, 3584 EA Utrecht, The Netherlands
- Integrative Immunology and Behavior Program, College of ACES and College of Medicine, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
- Corresponding author at: Laboratory for Neuroimmunology and Developmental Origins of Disease, University Medical Center Utrecht, Lundlaan 6, Office KC 03.068.0, 3584 EA Utrecht, The Netherlands. Tel.: +31 88 755 4359; fax: +31 88 755 5311.

Received 19 January 2010; received in revised form 17 May 2010; accepted 15 June 2010. published online 07 July 2010.

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-GRK2^f/+), or sensory neurons or astrocytes. Only mice deficient in microglial/macrophage/granulocyte GRK2 display prolonged IL-1β-induced hyperalgesia that lasts up to 8days. 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-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-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.