title: G protein-coupled receptor kinase 6 controls post-inflammatory visceral hyperalgesia.
abstract: Post-inflammatory pain is a poorly understood phenomenon. G protein-coupled receptors are involved in regulating pain signaling in the context of inflammation. G protein-coupled receptor kinases (GRK) modulate signaling through these receptors. We investigated whether GRK6 contributes to post-inflammatory visceral hyperalgesia. Colitis was induced in female mice by 1% dextran sodium sulphate in drinking water for 7 days. Disease score, colon length, and colonic cytokines were determined. On day 49, when animals had recovered from colitis, we induced visceral pain by intracolonic capsaicin instillation. Behavioral responses to capsaicin were monitored for 20 min. Referred hyperalgesia was measured using von Frey hairs. Spinal cord c-Fos was visualized by immunohistochemistry. In contrast to our earlier observations in male GRK6-/- and wild type (WT) mice, we did not detect differences in the course of colitis or in expression of colonic cytokines between female GRK6-/- and WT mice. After recovery from colitis, capsaicin-induced behavioral pain responses and spinal cord c-Fos expression were more pronounced in female GRK6-/- than WT mice. Naive GRK6-/- and WT animals did not differ in pain and c-Fos responses to capsaicin. Capsaicin-induced referred hyperalgesia post-colitis was increased in GRK6-/- compared to WT mice. However, referred hyperalgesia post-colitis was not affected by ablation of GRK6. Furthermore, in vitro IL-1beta sensitized the capsaicin receptor TRPV1 and this process was inhibited by over-expression of GRK6. We describe the novel concept that GRK6 inhibits post-inflammatory visceral hyperalgesia but does not contribute to visceral pain in naive animals. We propose that GRK6 regulates inflammation-induced sensitization of TRPV1.
authors.affiliation: Laboratory of Psychoneuroimmunology, University Medical Center Utrecht, Room KC 03.068.0, Lundlaan 6, 3584 EA Utrecht, The Netherlands.
authors.forename: Niels
authors.initials: N
authors.lastname: Eijkelkamp
authors.forename: Cobi J
authors.initials: CJ
authors.lastname: Heijnen
authors.forename: Sigrid
authors.initials: S
authors.lastname: Elsenbruch
authors.forename: Gerald
authors.initials: G
authors.lastname: Holtmann
authors.forename: Manfred
authors.initials: M
authors.lastname: Schedlowski
authors.forename: Annemieke
authors.initials: A
authors.lastname: Kavelaars
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D002211:Capsaicin; D002460:Cell Line; D003092:Colitis / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D016207:Cytokines / Q000378:metabolism; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D005260:Female; D054768:G-Protein-Coupled Receptor Kinases / Q000378:metabolism*; D006930:Hyperalgesia / Q000139:chemically induced / Q000378:metabolism*; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D010146:Pain / Q000378:metabolism* / Q000503:physiopathology; D010147:Pain Measurement / Q000379:methods; D017288:Pain Threshold; D009195:Peroxidase / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D017833:Visceral Afferents / Q000378:metabolism
chemical_list: D016207:Cytokines; D016760:Proto-Oncogene Proteins c-fos; D016264:Dextran Sulfate; D009195:Peroxidase; D054768:G-Protein-Coupled Receptor Kinases; C089176:G-protein-coupled receptor kinase 6; D002211:Capsaicin