title: 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.affiliation: 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 Center for Pharmacogenomics, Washington University, St. Louis, MI 63110, USA.
authors.forename: Hanneke L D M
authors.initials: HLDM
authors.lastname: Willemen
authors.forename: Niels
authors.initials: N
authors.lastname: Eijkelkamp
authors.forename: Huijing
authors.initials: H
authors.lastname: Wang
authors.forename: Robert
authors.initials: R
authors.lastname: Dantzer
authors.forename: Gerald W
authors.initials: GW
authors.lastname: Dorn
authors.forename: Keith W
authors.initials: KW
authors.lastname: Kelley
authors.forename: Cobi J
authors.initials: CJ
authors.lastname: Heijnen
authors.forename: Annemieke
authors.initials: A
authors.lastname: Kavelaars
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000073883:CX3C Chemokine Receptor 1; D002351:Carrageenan / Q000009:adverse effects; D054428:Chemokine CX3CL1 / Q000627:therapeutic use; D005260:Female; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000172:deficiency / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D007249:Inflammation / Q000139:chemically induced / Q000473:pathology; D007375:Interleukin-1 / Q000378:metabolism*; D053583:Interleukin-1beta; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism*; D008911:Minocycline / Q000627:therapeutic use; D009195:Peroxidase / Q000378:metabolism; D019707:Receptors, Chemokine / Q000235:genetics / Q000378:metabolism*; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D000073883:CX3C Chemokine Receptor 1; D054428:Chemokine CX3CL1; C471885:Cx3cr1 protein, mouse; D007375:Interleukin-1; D053583:Interleukin-1beta; D019707:Receptors, Chemokine; D002351:Carrageenan; D009195:Peroxidase; C496568:GRK2 protein, mouse; D054769:G-Protein-Coupled Receptor Kinase 2; D048051:p38 Mitogen-Activated Protein Kinases; D008911:Minocycline