The chemokine Bv8/prokineticin 2 is up-regulated in inflammatory granulocytes and modulates inflammatory pain.
Neutrophil migration into injured tissues is invariably accompanied by pain. Bv8/prokineticin 2 (PK2), a chemokine characterized by a unique structural motif comprising five disulfide bonds, is highly expressed in inflamed tissues associated to infiltrating cells. Here, we demonstrate the fundamental role of granulocyte-derived PK2 (GrPK2) in initiating inflammatory pain and driving peripheral sensitization. In animal models of complete Freund's adjuvant-induced paw inflammation the development and duration of pain temporally correlated with the expression levels of PK2 in the inflamed sites. Such an increase in PK2 mRNA depends mainly on a marked up-regulation of PK2 gene transcription in granulocytes. A substantially lower up-regulation was also detected in macrophages. From a pool of peritoneal granulocytes, elicited in rats by oyster glycogen, we purified the GrPK2 protein, which displayed high affinity for the prokineticin receptors (PKRs) and, when injected into the rat paw, induced hypersensitivity to noxious stimuli as the amphibian prokineticin Bv8 did. Mice lacking PKR1 or PKR2 developed significantly less inflammation-induced hyperalgesia in comparison with WT mice, confirming the involvement of both PKRs in inflammatory pain. The inflammation-induced up-regulation of PK2 was significantly less in pkr1 null mice than in WT and pkr2 null mice, demonstrating a role of PKR1 in setting PK2 levels during inflammation. Pretreatment with a nonpeptide PKR antagonist, which preferentially binds PKR1, dose-dependently reduced and eventually abolished both prokineticin-induced hypernociception and inflammatory hyperalgesia. Inhibiting PK2 formation or antagonizing PKRs may represent another therapeutic approach for controlling inflammatory pain.
Giannini
Elisa
E
Department of Physiology and Pharmacology Vittorio Erspamer, Sapienza University of Rome, I-00185 Rome, Italy.
Lattanzi
Roberta
R
Nicotra
Annalisa
A
Campese
Antonio F
AF
Grazioli
Paola
P
Screpanti
Isabella
I
Balboni
Gianfranco
G
Salvadori
Severo
S
Sacerdote
Paola
P
Negri
Lucia
L
D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D005620:Freund's Adjuvant; D005768:Gastrointestinal Hormones / Q000235:genetics*; D006098:Granulocytes / Q000378:metabolism*; D006930:Hyperalgesia / Q000503:physiopathology / Q000517:prevention & control; D017403:In Situ Hybridization; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics / Q000503:physiopathology*; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009479:Neuropeptides / Q000235:genetics*; D009504:Neutrophils / Q000378:metabolism; D010146:Pain / Q000503:physiopathology* / Q000517:prevention & control; D010147:Pain Measurement; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014227:Triazines / Q000494:pharmacology; D015854:Up-Regulation / Q000235:genetics
D005768:Gastrointestinal Hormones; D009479:Neuropeptides; C525015:PKR1 protein, mouse; C525016:PKR2 protein, mouse; C486586:Prok2 protein, mouse; D043562:Receptors, G-Protein-Coupled; D014227:Triazines; D005620:Freund's Adjuvant