TY - JOUR
T1 - Microglial/macrophage GRK2 determines duration of peripheral IL-1β-induced hyperalgesia
T2 - Contribution of spinal cord CX3CR1, p38 and IL-1 signaling
AU - Willemen, Hanneke L.D.M.
AU - Eijkelkamp, Niels
AU - Wang, Huijing
AU - Dantzer, Robert
AU - Dorn, Gerald W.
AU - Kelley, Keith W.
AU - Heijnen, Cobi J.
AU - Kavelaars, Annemieke
PY - 2010/9/1
Y1 - 2010/9/1
N2 - 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.
AB - 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.
KW - CX3CR1
KW - G protein-coupled receptor kinase 2
KW - IL-1β
KW - Inflammatory hyperalgesia
KW - Microglia
KW - p38
UR - http://www.scopus.com/inward/record.url?scp=77955574425&partnerID=8YFLogxK
U2 - 10.1016/j.pain.2010.06.015
DO - 10.1016/j.pain.2010.06.015
M3 - Article
C2 - 20609517
AN - SCOPUS:77955574425
SN - 0304-3959
VL - 150
SP - 550
EP - 560
JO - Pain
JF - Pain
IS - 3
ER -