دورية أكاديمية
GRK2: a novel cell-specific regulator of severity and duration of inflammatory pain.
| العنوان: | GRK2: a novel cell-specific regulator of severity and duration of inflammatory pain. |
|---|---|
| المؤلفون: | Eijkelkamp N; Laboratory of Psychoneuroimmunology, University Medical Center Utrecht, 3584 EA Utrecht, The Netherlands., Heijnen CJ, Willemen HL, Deumens R, Joosten EA, Kleibeuker W, den Hartog IJ, van Velthoven CT, Nijboer C, Nassar MA, Dorn GW 2nd, Wood JN, Kavelaars A |
| المصدر: | The Journal of neuroscience : the official journal of the Society for Neuroscience [J Neurosci] 2010 Feb 10; Vol. 30 (6), pp. 2138-49. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: Society for Neuroscience Country of Publication: United States NLM ID: 8102140 Publication Model: Print Cited Medium: Internet ISSN: 1529-2401 (Electronic) Linking ISSN: 02706474 NLM ISO Abbreviation: J Neurosci Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Washington, DC : Society for Neuroscience Original Publication: [Baltimore, Md.] : The Society, c1981- |
| مواضيع طبية MeSH: | G-Protein-Coupled Receptor Kinase 2/*physiology , Pain/*enzymology , Pain/*physiopathology, Animals ; Astrocytes/metabolism ; Cells, Cultured ; Chemokine CCL3/pharmacology ; Chemokine CCL3/physiology ; Female ; G-Protein-Coupled Receptor Kinase 2/genetics ; Hyperalgesia/enzymology ; Hyperalgesia/physiopathology ; Inflammation/enzymology ; Inflammation/physiopathology ; Macrophages/enzymology ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Microglia/enzymology ; Pain/immunology ; Peripheral Nervous System Diseases/enzymology ; Peripheral Nervous System Diseases/immunology ; Peripheral Nervous System Diseases/physiopathology ; Rats ; Rats, Sprague-Dawley ; Sensory Receptor Cells/enzymology ; Spinal Cord/enzymology ; TRPV Cation Channels/physiology ; Tumor Necrosis Factor-alpha/physiology ; p38 Mitogen-Activated Protein Kinases/physiology |
| مستخلص: | Chronic pain associated with inflammation is a common clinical problem, and the underlying mechanisms have only begun to be unraveled. GRK2 regulates cellular signaling by promoting G-protein-coupled receptor (GPCR) desensitization and direct interaction with downstream kinases including p38. The aim of this study was to determine the contribution of GRK2 to regulation of inflammatory pain and to unravel the underlying mechanism. GRK2(+/-) mice with an approximately 50% reduction in GRK2 developed increased and markedly prolonged thermal hyperalgesia and mechanical allodynia after carrageenan-induced paw inflammation or after intraplantar injection of the GPCR-binding chemokine CCL3. The effect of reduced GRK2 in specific cells was investigated using Cre-Lox technology. Carrageenan- or CCL3-induced hyperalgesia was increased but not prolonged in mice with decreased GRK2 only in Na(v)1.8 nociceptors. In vitro, reduced neuronal GRK2 enhanced CCL3-induced TRPV1 sensitization. In vivo, CCL3-induced acute hyperalgesia in GRK2(+/-) mice was mediated via TRPV1. Reduced GRK2 in microglia/monocytes only was required and sufficient to transform acute carrageenan- or CCL3-induced hyperalgesia into chronic hyperalgesia. Chronic hyperalgesia in GRK2(+/-) mice was associated with ongoing microglial activation and increased phospho-p38 and tumor necrosis factor alpha (TNF-alpha) in the spinal cord. Inhibition of spinal cord microglial, p38, or TNF-alpha activity by intrathecal administration of specific inhibitors reversed ongoing hyperalgesia in GRK2(+/-) mice. Microglia/macrophage GRK2 expression was reduced in the lumbar ipsilateral spinal cord during neuropathic pain, underlining the pathophysiological relevance of microglial GRK2. Thus, we identified completely novel cell-specific roles of GRK2 in regulating acute and chronic inflammatory hyperalgesia. |
| References: | Gut. 2007 Jun;56(6):847-54. (PMID: 17229795) Brain Res Rev. 2006 Aug;51(2):240-64. (PMID: 16388853) Recept Channels. 1997;5(3-4):193-9. (PMID: 9606723) J Neurochem. 2007 Nov;103(4):1319-33. (PMID: 17714453) J Leukoc Biol. 2006 May;79(5):1022-32. (PMID: 16522746) Mol Pain. 2007 Nov 01;3:33. (PMID: 17974036) Proc Natl Acad Sci U S A. 2005 Feb 1;102(5):1755-60. (PMID: 15665080) Adv Exp Med Biol. 2003;521:1-21. (PMID: 12617561) Biochim Biophys Acta. 2007 Apr;1768(4):913-22. (PMID: 17084806) Science. 2008 Aug 1;321(5889):702-5. (PMID: 18669863) Curr Biol. 2006 Oct 24;16(20):2042-7. (PMID: 17055984) Circ Res. 2006 Oct 27;99(9):996-1003. (PMID: 17008600) J Immunol. 2001 Feb 1;166(3):1635-40. (PMID: 11160205) Brain Behav Immun. 2008 Feb;22(2):200-8. (PMID: 17869478) J Leukoc Biol. 2008 Apr;83(4):824-32. (PMID: 18203872) J Immunol. 2005 Apr 1;174(7):4400-6. (PMID: 15778405) Trends Endocrinol Metab. 2006 May-Jun;17(4):159-65. (PMID: 16595179) Pain. 2001 Feb 1;90(1-2):1-6. (PMID: 11166964) J Biol Chem. 1999 Mar 26;274(13):8875-85. (PMID: 10085131) Brain Res Rev. 2009 Apr;60(1):135-48. (PMID: 19150373) J Neuroimmunol. 2003 Apr;137(1-2):79-86. (PMID: 12667650) Neuron. 2007 Aug 2;55(3):365-76. (PMID: 17678851) J Neurosci. 2001 Jul 15;21(14):5027-35. (PMID: 11438578) Neurosci Lett. 2007 Oct 29;427(1):50-4. (PMID: 17923327) FASEB J. 1999 Apr;13(6):715-25. (PMID: 10094932) J Neurosci. 2001 Apr 15;21(8):2580-8. (PMID: 11306611) J Neurochem. 2008 Feb;104(4):979-92. (PMID: 17971124) J Neurophysiol. 1999 Nov;82(5):2649-56. (PMID: 10561434) Pain. 1988 Jan;32(1):77-88. (PMID: 3340425) J Neurosci. 2008 Mar 26;28(13):3324-32. (PMID: 18367599) Nat Rev Neurosci. 2005 Jul;6(7):521-32. (PMID: 15995723) Nat Rev Drug Discov. 2003 Dec;2(12):973-85. (PMID: 14654796) Pain. 2005 Jan;113(1-2):27-36. (PMID: 15621361) Eur J Neurosci. 2007 Mar;25(6):1696-704. (PMID: 17408432) Neurosci Lett. 2005 May 13;379(3):209-13. (PMID: 15843065) Nat Neurosci. 2007 Nov;10(11):1361-8. (PMID: 17965656) Nat Rev Neurosci. 2009 Jan;10(1):23-36. (PMID: 19096368) Nature. 1996 Jan 18;379(6562):257-62. (PMID: 8538791) J Pharmacol Exp Ther. 2003 Aug;306(2):624-30. (PMID: 12734393) Eur J Pharmacol. 1980 Oct 17;67(2-3):313-6. (PMID: 6893963) Transgenic Res. 1999 Aug;8(4):265-77. (PMID: 10621974) J Neurosci. 2006 Apr 5;26(14):3864-74. (PMID: 16597741) Proc Natl Acad Sci U S A. 2005 Mar 22;102(12):4536-41. (PMID: 15764707) J Leukoc Biol. 2004 May;75(5):901-9. (PMID: 14761932) Proc Natl Acad Sci U S A. 1996 Nov 12;93(23):12974-9. (PMID: 8917529) Circulation. 2000 May 2;101(17):2083-9. (PMID: 10790351) Neuron. 2009 Oct 15;64(1):46-54. (PMID: 19840548) |
| معلومات مُعتمدة: | R01 HL059888-12 United States HL NHLBI NIH HHS; R01 HL059888-06 United States HL NHLBI NIH HHS; R01 HL059888-03 United States HL NHLBI NIH HHS; R01 HL087871-02 United States HL NHLBI NIH HHS; R01 HL059888-01A1 United States HL NHLBI NIH HHS; R01 HL059888-11 United States HL NHLBI NIH HHS; R01 HL080008-02 United States HL NHLBI NIH HHS; R01 HL059888-09A1 United States HL NHLBI NIH HHS; BB/F000227/1 United Kingdom BB_ Biotechnology and Biological Sciences Research Council; R01 HL087871-06 United States HL NHLBI NIH HHS; R01 HL080008-05 United States HL NHLBI NIH HHS; R01 HL087871-05 United States HL NHLBI NIH HHS; R01 HL080008 United States HL NHLBI NIH HHS; R01 HL080008-06 United States HL NHLBI NIH HHS; R01 HL059888-08 United States HL NHLBI NIH HHS; R01 HL087871-04 United States HL NHLBI NIH HHS; R01 HL059888-09A1W1 United States HL NHLBI NIH HHS; R01 HL059888-02 United States HL NHLBI NIH HHS; R01 HL059888-07 United States HL NHLBI NIH HHS; R01 HL059888 United States HL NHLBI NIH HHS; R01 HL080008-03 United States HL NHLBI NIH HHS; R01 HL087871-01 United States HL NHLBI NIH HHS; G0901905 United Kingdom MRC_ Medical Research Council; R01 HL080008-04 United States HL NHLBI NIH HHS; R01 HL059888-10 United States HL NHLBI NIH HHS; R01 HL059888-05 United States HL NHLBI NIH HHS; R01 HL087871 United States HL NHLBI NIH HHS; R01 HL080008-01A1 United States HL NHLBI NIH HHS; R01 HL087871-03 United States HL NHLBI NIH HHS; R01 HL059888-04 United States HL NHLBI NIH HHS |
| المشرفين على المادة: | 0 (Chemokine CCL3) 0 (TRPV Cation Channels) 0 (Tumor Necrosis Factor-alpha) EC 2.7.11.15 (GRK2 protein, mouse) EC 2.7.11.15 (Grk2 protein, rat) EC 2.7.11.16 (G-Protein-Coupled Receptor Kinase 2) EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases) |
| تواريخ الأحداث: | Date Created: 20100212 Date Completed: 20100305 Latest Revision: 20211020 |
| رمز التحديث: | 20240628 |
| مُعرف محوري في PubMed: | PMC3129713 |
| DOI: | 10.1523/JNEUROSCI.5752-09.2010 |
| PMID: | 20147541 |
| قاعدة البيانات: | MEDLINE |
كن أول من يترك تعليقا!