title: G protein-coupled receptor kinase 6 acts as a critical regulator of cytokine-induced hyperalgesia by promoting phosphatidylinositol 3-kinase and inhibiting p38 signaling.
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 regulate pain responses was also apparent in carrageenan-induced hyperalgesia, since thermal and mechanical hypersensitivity was significantly prolonged in GRK6⁻/⁻ mice. Finally, GRK6 expression was reduced in DRGs of mice with chronic neuropathic or inflammatory pain. Collectively, these findings underline the potential role of GRK6 in pathological pain. We propose the novel concept that GRK6 acts as a kinase that constrains neuronal responsiveness to IL-1β and TNF-α and cytokine-induced hyperalgesia via biased cytokine-induced p38 and PI 3-kinase/Akt activation.
authors.affiliation: Laboratory of Neuroimmunology and Developmental Origins of Disease-NIDOD, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Niels
authors.initials: N
authors.lastname: Eijkelkamp
authors.forename: Cobi J
authors.initials: CJ
authors.lastname: Heijnen
authors.forename: Anibal Garza
authors.initials: AG
authors.lastname: Carbajal
authors.forename: Hanneke L D M
authors.initials: HL
authors.lastname: Willemen
authors.forename: Huijing
authors.initials: H
authors.lastname: Wang
authors.forename: Michael S
authors.initials: MS
authors.lastname: Minett
authors.forename: John N
authors.initials: JN
authors.lastname: Wood
authors.forename: Manfred
authors.initials: M
authors.lastname: Schedlowski
authors.forename: Robert
authors.initials: R
authors.lastname: Dantzer
authors.forename: Keith W
authors.initials: KW
authors.lastname: Kelley
authors.forename: Annemieke
authors.initials: A
authors.lastname: Kavelaars
mesh_terms: D000818:Animals; D016207:Cytokines / Q000008:administration & dosage / Q000633:toxicity*; D015232:Dinoprostone / Q000008:administration & dosage; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism; D005260:Female; D054768:G-Protein-Coupled Receptor Kinases / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D006930:Hyperalgesia / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D053583:Interleukin-1beta / Q000008:administration & dosage; D051379:Mice; D018345:Mice, Knockout; D009437:Neuralgia / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D016207:Cytokines; D053583:Interleukin-1beta; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D019869:Phosphatidylinositol 3-Kinases; D054768:G-Protein-Coupled Receptor Kinases; C089176:G-protein-coupled receptor kinase 6; D048051:p38 Mitogen-Activated Protein Kinases; D015232:Dinoprostone