title: GRK2 in sensory neurons regulates epinephrine-induced signalling and duration of mechanical hyperalgesia.
abstract: Epinephrine (EPI) contributes to hyperalgesia in inflammatory and stress conditions. EPI signals via adrenoceptors, which are regulated by G protein-coupled receptor kinase 2 (GRK2). We previously reported that GRK2 is decreased in nociceptors during chronic inflammation. Herein, we investigated whether GRK2 modulates EPI-induced mechanical and thermal hyperalgesia by using GRK2(+/-) mice, which express 50% of the GRK2 protein. We demonstrate for the first time that EPI-induced mechanical as well as thermal hyperalgesia is prolonged to approximately 21 days in GRK2(+/-) mice, whereas it lasts only 3 to 4 days in wild-type mice. Using cell- specific GRK2-deficient mice, we further show that a low level of GRK2 in primary sensory neurons is critical for this prolongation of EPI-induced hyperalgesia. Low GRK2 in microglia had only a small effect on EPI-induced hyperalgesia. Low GRK2 in astrocytes did not alter EPI-induced hyperalgesia. EPI-induced hyperalgesia was prolonged similarly in mice with tamoxifen-induced homozygous or heterozygous deletion of GRK2. In terms of EPI signalling pathways, the protein kinase A (PKA) inhibitor H-89 inhibited EPI-induced mechanical hyperalgesia in wild-type mice, whereas H-89 had no effect in mice with low GRK2 in sensory neurons (SNS-GRK2(+/-) mice). Conversely, intraplantar injection of the protein kinase Cε PKCε inhibitor TAT-PKC(εv1-2) inhibited hyperalgesia in sensory neuron specific (SNS)-GRK2(+/-) mice and not in wild-type mice. These results indicate that low GRK2 in primary sensory neurons switches EPI-induced signalling from a protein kinase A-dependent toward a PKCε-dependent pathway that ultimately mediates prolonged EPI-induced hyperalgesia.
authors.affiliation: Laboratory of Neuroimmunology and Developmental Origins of Disease, University Medical Center Utrecht, 3584 EA Utrecht, The Netherlands Department of Pharmacology, Shanghai Medical College, Fudan University, 200032 Shanghai, PR China Molecular Nociception Group, University College London, London WC1E 6BT, UK Institute of Medical Psychology and Immunobiology, University Hospital Essen, University Duisburg-Essen, Essen, Germany Integrative Immunology and Behavior Program, College of Medicine and College of ACES, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
authors.forename: Huijing
authors.initials: H
authors.lastname: Wang
authors.forename: Cobi J
authors.initials: CJ
authors.lastname: Heijnen
authors.forename: Niels
authors.initials: N
authors.lastname: Eijkelkamp
authors.forename: Anibal Garza
authors.initials: AG
authors.lastname: Carbajal
authors.forename: Manfred
authors.initials: M
authors.lastname: Schedlowski
authors.forename: Keith W
authors.initials: KW
authors.lastname: Kelley
authors.forename: Robert
authors.initials: R
authors.lastname: Dantzer
authors.forename: Annemieke
authors.initials: A
authors.lastname: Kavelaars
mesh_terms: D000317:Adrenergic alpha-Antagonists / Q000627:therapeutic use; D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use; D000818:Animals; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004837:Epinephrine / Q000633:toxicity*; D005260:Female; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000172:deficiency / Q000378:metabolism*; D005727:Ganglia, Spinal / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006930:Hyperalgesia / Q000139:chemically induced* / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects*; D010646:Phentolamine / Q000627:therapeutic use; D011412:Propanolamines / Q000627:therapeutic use; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics
chemical_list: D000317:Adrenergic alpha-Antagonists; D000319:Adrenergic beta-Antagonists; D004791:Enzyme Inhibitors; D011412:Propanolamines; C026777:ICI 118551; C496568:GRK2 protein, mouse; D054769:G-Protein-Coupled Receptor Kinase 2; D004837:Epinephrine; D010646:Phentolamine