G protein-coupled receptor kinase 6 acts as a critical regulator of cytokine-induced hyperalgesia by promoting phosphatidylinositol 3-kinase and inhibiting p38 signaling.

Molecular Medicine
Niels EijkelkampAnnemieke Kavelaars

Abstract

The molecular mechanisms determining magnitude and duration of inflammatory pain are still unclear. We assessed the contribution of G protein-coupled receptor kinase (GRK)-6 to inflammatory hyperalgesia in mice. We showed that GRK6 is a critical regulator of severity and duration of cytokine-induced hyperalgesia. In GRK6⁻/⁻ mice, a significantly lower dose (100 times lower) of intraplantar interleukin (IL)-1β was sufficient to induce hyperalgesia compared with wild-type (WT) mice. In addition, IL-1β hyperalgesia lasted much longer in GRK6⁻/⁻ mice than in WT mice (8 d in GRK6⁻/⁻ versus 6 h in WT mice). Tumor necrosis factor (TNF)-α-induced hyperalgesia was also enhanced and prolonged in GRK6⁻/⁻ mice. In vitro, IL-1β-induced p38 phosphorylation in GRK6⁻/⁻ dorsal root ganglion (DRG) neurons was increased compared with WT neurons. In contrast, IL-1β only induced activation of the phosphatidylinositol (PI) 3-kinase/Akt pathway in WT neurons, but not in GRK6⁻/⁻ neurons. In vivo, p38 inhibition attenuated IL-1β- and TNF-α-induced hyperalgesia in both genotypes. Notably, however, whereas PI 3-kinase inhibition enhanced and prolonged hyperalgesia in WT mice, it did not have any effect in GRK6-deficient mice. The capacity of GRK6 to regu...Continue Reading

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Citations

Jun 27, 2012·Journal of Neuroinflammation·Hanneke L D M WillemenAnnemieke Kavelaars
Mar 15, 2015·International Journal of Molecular Sciences·Dianne Lorton, Denise L Bellinger
Aug 1, 2015·Genes and Immunity·N Packiriswamy, N Parameswaran
Jul 20, 2016·Journal of Neurogastroenterology and Motility·Mohammad H FarzaeiRoja Rahimi
Sep 25, 2017·Physiological Genomics·Taehyung LeeNarayanan Parameswaran
Feb 13, 2014·The Biochemical Journal·Hanneke L D M WillemenCristina Murga
Mar 28, 2013·High Blood Pressure & Cardiovascular Prevention : the Official Journal of the Italian Society of Hypertension·Gaetano SantulliGuido Iaccarino
Jun 25, 2021·Neuropathology and Applied Neurobiology·Thais Rafael GuimarãesAmantha Thathiah

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