Balancing GRK2 and EPAC1 levels prevents and relieves chronic pain
| Autor: | Anil K. Sood, Anne Vroon, Huijing Wang, Yoshihiro Ishikawa, Annemieke Kavelaars, Cindy T. J. van Velthoven, Hanneke L.D.M. Willemen, Niels Eijkelkamp, Xinna Zhang, Cobi Jacoba Johanna Heijnen |
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| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
Agonist
G-Protein-Coupled Receptor Kinase 2 Sensory Receptor Cells medicine.drug_class Recombinant Fusion Proteins Priming (immunology) Pharmacology Carrageenan Second Messenger Systems Dinoprostone Mice Dorsal root ganglion Ganglia Spinal medicine Cyclic AMP Gene silencing Animals Guanine Nucleotide Exchange Factors Gene Silencing Injections Spinal biology business.industry Beta adrenergic receptor kinase Chronic pain Nociceptors General Medicine Genetic Therapy Oligonucleotides Antisense medicine.disease Sciatic Nerve Hindlimb Mice Inbred C57BL medicine.anatomical_structure Gene Expression Regulation Hyperalgesia Anesthesia Models Animal Nociceptor biology.protein Cattle Female medicine.symptom Chronic Pain business Oligopeptides Research Article |
| Popis: | Chronic pain is a major clinical problem, yet the mechanisms underlying the transition from acute to chronic pain remain poorly understood. In mice, reduced expression of GPCR kinase 2 (GRK2) in nociceptors promotes cAMP signaling to the guanine nucleotide exchange factor EPAC1 and prolongs the PGE2-induced increase in pain sensitivity (hyperalgesia). Here we hypothesized that reduction of GRK2 or increased EPAC1 in dorsal root ganglion (DRG) neurons would promote the transition to chronic pain. We used 2 mouse models of hyperalgesic priming in which the transition from acute to chronic PGE2-induced hyperalgesia occurs. Hyperalgesic priming with carrageenan induced a sustained decrease in nociceptor GRK2, whereas priming with the PKCe agonist ΨeRACK increased DRG EPAC1. When either GRK2 was increased in vivo by viral-based gene transfer or EPAC1 was decreased in vivo, as was the case for mice heterozygous for Epac1 or mice treated with Epac1 antisense oligodeoxynucleotides, chronic PGE2-induced hyperalgesia development was prevented in the 2 priming models. Using the CFA model of chronic inflammatory pain, we found that increasing GRK2 or decreasing EPAC1 inhibited chronic hyperalgesia. Our data suggest that therapies targeted at balancing nociceptor GRK2 and EPAC1 levels have promise for the prevention and treatment of chronic pain. |
| Databáze: | OpenAIRE |
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