GRK2: a novel cell-specific regulator of severity and duration of inflammatory pain.
Chronic pain associated with inflammation is a common clinical problem, and the underlying mechanisms have only begun to be unraveled. GRK2 regulates cellular signaling by promoting G-protein-coupled receptor (GPCR) desensitization and direct interaction with downstream kinases including p38. The aim of this study was to determine the contribution of GRK2 to regulation of inflammatory pain and to unravel the underlying mechanism. GRK2(+/-) mice with an approximately 50% reduction in GRK2 developed increased and markedly prolonged thermal hyperalgesia and mechanical allodynia after carrageenan-induced paw inflammation or after intraplantar injection of the GPCR-binding chemokine CCL3. The effect of reduced GRK2 in specific cells was investigated using Cre-Lox technology. Carrageenan- or CCL3-induced hyperalgesia was increased but not prolonged in mice with decreased GRK2 only in Na(v)1.8 nociceptors. In vitro, reduced neuronal GRK2 enhanced CCL3-induced TRPV1 sensitization. In vivo, CCL3-induced acute hyperalgesia in GRK2(+/-) mice was mediated via TRPV1. Reduced GRK2 in microglia/monocytes only was required and sufficient to transform acute carrageenan- or CCL3-induced hyperalgesia into chronic hyperalgesia. Chronic hyperalgesia in GRK2(+/-) mice was associated with ongoing microglial activation and increased phospho-p38 and tumor necrosis factor alpha (TNF-alpha) in the spinal cord. Inhibition of spinal cord microglial, p38, or TNF-alpha activity by intrathecal administration of specific inhibitors reversed ongoing hyperalgesia in GRK2(+/-) mice. Microglia/macrophage GRK2 expression was reduced in the lumbar ipsilateral spinal cord during neuropathic pain, underlining the pathophysiological relevance of microglial GRK2. Thus, we identified completely novel cell-specific roles of GRK2 in regulating acute and chronic inflammatory hyperalgesia.
Laboratory of Psychoneuroimmunology, University Medical Center Utrecht, 3584 EA Utrecht, The Netherlands.
Niels
N
Eijkelkamp
Cobi J
CJ
Heijnen
Hanneke L D M
HL
Willemen
Ronald
R
Deumens
Elbert A J
EA
Joosten
Wendy
W
Kleibeuker
Ilona J M
IJ
den Hartog
Cindy T J
CT
van Velthoven
Cora
C
Nijboer
Mohammed A
MA
Nassar
Gerald W
GW
Dorn
John N
JN
Wood
Annemieke
A
Kavelaars
D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D002478:Cells, Cultured; D054405:Chemokine CCL3 / Q000494:pharmacology / Q000502:physiology; D005260:Female; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000235:genetics / Q000502:physiology*; D006930:Hyperalgesia / Q000201:enzymology / Q000503:physiopathology; D007249:Inflammation / Q000201:enzymology / Q000503:physiopathology; D008264:Macrophages / Q000201:enzymology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000201:enzymology; D010146:Pain / Q000201:enzymology* / Q000276:immunology / Q000503:physiopathology*; D010523:Peripheral Nervous System Diseases / Q000201:enzymology / Q000276:immunology / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011984:Sensory Receptor Cells / Q000201:enzymology; D013116:Spinal Cord / Q000201:enzymology; D050916:TRPV Cation Channels / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology
D054405:Chemokine CCL3; D050916:TRPV Cation Channels; D014409:Tumor Necrosis Factor-alpha; C496568:GRK2 protein, mouse; C496569:Grk2 protein, rat; D054769:G-Protein-Coupled Receptor Kinase 2; D048051:p38 Mitogen-Activated Protein Kinases