Balancing GRK2 and EPAC1 levels prevents and relieves chronic pain

Abstract

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 PGE 2 -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 PGE 2 -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 PGE 2 -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.

Critical role for Epac1 in inflammatory pain controlled by GRK2-mediated phosphorylation of Epac1

“…Earlier studies by us and others have shown that Epac1 protein levels in the DRG are increased in the CFA model of chronic inflammatory pain, whereas GRK2 levels are decreased (16,17,(30)(31)(32). In addition, we presented evidence that Epac1-dependent pain signaling is inhibited by GRK2, but the mechanism remained to be determined (17).…”

“…In addition, we presented evidence that Epac1-dependent pain signaling is inhibited by GRK2, but the mechanism remained to be determined (17). Here, we identify GRK2, to our knowledge, as the first kinase known to directly phosphorylate Epac1, identify the site of phosphorylation, and demonstrate that this phosphorylation event inhibits Epac1-to-Rap1 signaling.…”

“…In vitro it has been shown that activated Rap signals to, e.g., Akt (13), PLC-e (14), PKC, and MAPKs (15). Our recently published work showed that the serine-threonine kinase G protein-coupled receptor kinase 2 (GRK2) inhibits Epac1-mediated pain signaling (16,17). Specifically, we showed that chronic inflammatory pain is associated with a decrease in GRK2 levels in pain-sensing neurons and that either increasing GRK2 protein levels or reducing Epac1 levels prevents chronic pain (17).…”

“…Our recently published work showed that the serine-threonine kinase G protein-coupled receptor kinase 2 (GRK2) inhibits Epac1-mediated pain signaling (16,17). Specifically, we showed that chronic inflammatory pain is associated with a decrease in GRK2 levels in pain-sensing neurons and that either increasing GRK2 protein levels or reducing Epac1 levels prevents chronic pain (17). However, the mechanism via which GRK2 controls Epac1-mediated pain signaling remained to be identified.…”

G Protein-Coupled Receptor Kinases in the Inflammatory Response and Signaling

“…GRK2 heterozygous mice suffer from chronic hyperalgesia due to continued microglial activation via p38-dependent TNFα production (Eijkelkamp, Heijnen, et al, 2010; Willemen et al, 2010) and prolonged activation of prostaglandin E2-mediated pathway. This prolonged activation is mediated through interactions with EPAC1 (exchange protein directly activated cAMP) and activation of protein kinase Cε- and ERK-dependent pathways (Eijkelkamp, Wang, et al, 2010; H. Wang et al, 2013).…”