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

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 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.

• Authors: Hanneke L D M Willemen, Niels Eijkelkamp, Huijing Wang, Robert Dantzer, Gerald W Dorn 2nd, Keith W Kelley, Cobi J Heijnen, Annemieke Kavelaars
• Journal: Pain (Pain) Vol. 150 Issue 3 Pg. 550-560 (Sep 2010) ISSN: 1872-6623 [Electronic] United States
• PMID: 20609517 (Publication Type: Journal Article)
• Copyright: Copyright (c) 2010 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

Chemical References

• 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

Topics

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