Balancing GRK2 and EPAC1 levels prevents and relieves chronic pain.
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 PKCε agonist ΨεRACK 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.
Huijing
H
Wang
Cobi J
CJ
Heijnen
Cindy T J
CT
van Velthoven
Hanneke L D M
HL
Willemen
Yoshihiro
Y
Ishikawa
Xinna
X
Zhang
Anil K
AK
Sood
Anne
A
Vroon
Niels
N
Eijkelkamp
Annemieke
A
Kavelaars
D000818:Animals; D002351:Carrageenan / Q000633:toxicity; D002417:Cattle; D059350:Chronic Pain / Q000209:etiology / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control*; D000242:Cyclic AMP / Q000502:physiology; D015232:Dinoprostone / Q000502:physiology; D005260:Female; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D005727:Ganglia, Spinal / Q000473:pathology; D005786:Gene Expression Regulation; D020868:Gene Silencing; D015316:Genetic Therapy; D020662:Guanine Nucleotide Exchange Factors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D006614:Hindlimb / Q000294:innervation; D006930:Hyperalgesia / Q000139:chemically induced / Q000235:genetics / Q000503:physiopathology* / Q000628:therapy; D007278:Injections, Spinal; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D009619:Nociceptors / Q000201:enzymology / Q000502:physiology; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage / Q000494:pharmacology; D009842:Oligopeptides / Q000633:toxicity; D011993:Recombinant Fusion Proteins / Q000235:genetics; D012584:Sciatic Nerve / Q000473:pathology; D015290:Second Messenger Systems; D011984:Sensory Receptor Cells / Q000201:enzymology / Q000502:physiology
C482601:Epac protein, mouse; D020662:Guanine Nucleotide Exchange Factors; C477271:His-Asp-Ala-Pro-Ile-Gly-Tyr-Asp; D016376:Oligonucleotides, Antisense; D009842:Oligopeptides; D011993:Recombinant Fusion Proteins; D002351:Carrageenan; D000242:Cyclic AMP; C496568:GRK2 protein, mouse; D054769:G-Protein-Coupled Receptor Kinase 2; D015232:Dinoprostone