Low GRK2 Underlies Hyperalgesic Priming by Glial Cell-Derived Neurotrophic Factor.

Hui-Jing Wang,Annemieke Kavelaars,Han-Xin Gu,Niels Eijkelkamp,Cobi J Heijnen

doi:10.3389/fphar.2018.00592

Abstract

Background: We recently identified the balance between the level of G protein coupled receptor kinase 2 (GRK2) and Epac1 in nociceptors as a key factor in the transition from acute to chronic pain that occurs in mice ‘primed’ by an inflammatory stimulus. Here, we examined the contribution of GRK2 and Epac-signaling to growth factor-induced hyperalgesic priming.Methods: Mice were primed by intraplantar injection with glial cell-derived neurotrophic factor (GDNF). Mechanical allodynia in response to PGE2 was followed over time in primed and non-primed animals. GRK2 protein levels in dorsal root ganglion (DRG) neurons were quantified by immunohistochemistry. The effect of herpes simplex virus (HSV)-GRK2 amplicons to restore GRK2 levels or of an Epac inhibitor on PGE2 allodynia in primed mice was examined.Results: Glial cell-derived neurotrophic factor-induced hyperalgesia disappeared within 12 days. The hyperalgesic response to a subsequent intraplantar injection of PGE2 was prolonged from <24 h in control mice to more than 72 h in GDNF-primed mice. In male and female primed mice, PGE2 hyperalgesia was inhibited by oral administration of the Epac inhibitor ESI-09, while the drug had no effect in control mice. Mice primed with GDNF had reduced levels of GRK2 in IB4(+) small DRG neurons, but normal GRK2 levels in IB4(-) DRG neurons. Intraplantar administration of HSV-GRK2 amplicons to increase GRK2 protein levels prevented the prolongation of PGE2-induced hyperalgesia in GDNF-primed mice.Conclusion: Low GRK2 in nociceptors is critical to develop a primed state in response to GDNF and leads to engagement of Epac signaling and transition to chronic PGE2-induced hyperalgesia. Increasing GRK2 protein or inhibiting Epac signaling may represent new avenues for preventing transition to a chronic pain state.

Highlights

The mechanisms underlying the development of persistent pain are poorly understood and this limits identification of novel therapeutic strategies to combat chronic pain
In the carrageenan model of hyperalgesic priming in female mice, we showed that normalization of nociceptor G protein-coupled receptor kinase 2 (GRK2) in primed mice by viral-based gene transfer or reducing Epac1 by intrathecal administration of anti-sense oligonucleotides prevented the prolongation of PGE2-induced allodynia (Wang et al, 2013)
When the mice subsequently received an injection of PGE2 at day 14 after GDNF injection, PGE2-induced mechanical hyperalgesia lasted more than 72 h in both sexes

Summary

Introduction

The mechanisms underlying the development of persistent pain are poorly understood and this limits identification of novel therapeutic strategies to combat chronic pain. We showed that hyperalgesic priming in response to the inflammatory stimulus carrageenan is caused by a persistent reduction in the level of G protein-coupled receptor kinase 2 (GRK2) in nociceptors (Wang et al, 2013). Mice with a global ∼50% reduction in GRK2 develop prolonged and /or increased pain behavior in response to carrageenan, PGE2, epinephrine, IL-1β, and CCL3 (Eijkelkamp et al, 2010b; Willemen et al, 2010; Wang et al, 2011). We recently identified the balance between the level of G protein coupled receptor kinase 2 (GRK2) and Epac in nociceptors as a key factor in the transition from acute to chronic pain that occurs in mice ‘primed’ by an inflammatory stimulus. We examined the contribution of GRK2 and Epac-signaling to growth factor-induced hyperalgesic priming

Methods

Results

Discussion

Conclusion