Abstract
Chronic pain is an incapacitating condition that arises from diverse origins, including inflammatory disorders, nerve damage, chemotherapy, and diabetes, implicating numerous signaling mechanisms. The pain response involves multiple cell types including neurons, microglia, and astrocytes. Recently our group and others have elucidated a crucial role for G protein coupled receptor kinase 2 (GRK2) in the development and maintenance of chronic pain using mice with global and cell specific deletion of GRK2 in vivo. The studies summarized here indicate that GRK2 controls multiple pathways in order to regulate severity and duration of pain in a cell-specific manner. For instance, reduced GRK2 in nociceptive neurons leads to increased G protein coupled receptor signaling and increased pain in response to a chemokine. Low GRK2 in nociceptors leads to transition to chronic pain by promoting biased cAMP signaling to Epac/PKCĪµ/ERK- mediated pathway. Via mechanisms that remain to be elucidated, low monocyte GRK2 leads to IL-10 deficiency and prolonged inflammatory pain. The clinical relevance of these findings is discussed in the light of the observed decrease of GRK2 in nociceptors, glia and leukocytes in response to nerve injury in rodents and in patients and rodents with inflammatory conditions such as arthritis or multiple sclerosis.
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Abbreviations
- 6-Bnz-cAMP:
-
N6-Benzoyladenosine cAMP
- 8-Br-cAMP:
-
8-Bromoadenosine cAMP
- 8-pCPT:
-
8-(4-Chlorophenylthio)-2ā²-O-methyladenosine cAMP
- asODN:
-
Antisense oligodeoxynucleotide
- cAMP:
-
Cyclic adenosine monophosphate
- CCL2/3:
-
Chemokine (C-C motif) ligand 2/3
- CCR1/5:
-
CC-chemokine receptor 1/5
- cdk1:
-
Cyclin-dependent kinase 1
- CFA:
-
Complete Freundās adjuvant
- DRG:
-
Dorsal root ganglion
- Epac:
-
Exchange protein directly activated by cAMP
- EPI:
-
Epinephrine
- ERK:
-
Extracellular signal-regulated kinase
- GDNF:
-
Glial cell-derived neurotrophic factor
- GLAST:
-
Glutamate aspartate transporter
- GPCR:
-
G-protein-coupled receptor
- GRK:
-
G-protein-coupled receptor kinase
- HI:
-
Hypoxicāischemic
- IFNĪ³:
-
Interferon Ī³
- IL-1R:
-
Interleukin 1 receptor
- IL-1Ī²:
-
Interleukin-1Ī²
- LPS:
-
Lipopolysaccharide
- LysM:
-
Lysozyme M
- MAPK:
-
Mitogen-activated protein kinase
- miRNA:
-
MicroRNA
- MS:
-
Multiple sclerosis
- mTOR:
-
Mechanistic target of rapamycin
- NGF:
-
Nerve growth factor
- PBMC:
-
Peripheral blood mononuclear cells
- PGE2:
-
Prostaglandin E2
- PKA/C:
-
Protein kinase A or C
- RA:
-
Rheumatoid arthritis
- ROS:
-
Reactive oxygen species
- SNS:
-
Small sensory neuron
- TAM:
-
Tamoxifen
- TNFĪ±:
-
Tumor necrosis factor Ī±
- TRPV1:
-
Transient receptor potential cation channel V1
- WT:
-
Wild type
- Ī±/Ī²AR:
-
Ī± or Ī² adrenergic receptor
- ĪØRACK:
-
PKCĪµ activator
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Acknowledgements
The work of Drs. Kavelaars and Heijnen is supported by grants NS 073939, NS 074999, CA 183736, and CA 193522 from the National Institutes of Health and a STAR grant from the University of Texas System.
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Baameur, F., Singhmar, P., Heijnen, C.J., Kavelaars, A. (2016). Critical Role of GRK2 in the Prevention of Chronic Pain. In: Gurevich, V., Gurevich, E., Tesmer, J. (eds) G Protein-Coupled Receptor Kinases. Methods in Pharmacology and Toxicology. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-3798-1_9
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