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The chemokine Bv8/prokineticin 2 is up-regulated\ud in inflammatory granulocytes and modulates\ud inflammatory pain

By E. Giannini, R. Lattanzi, A. Nicotra, A. F. Campese, P. Grazioli, I. Screpanti, G. Balboni, S. Salvadori, P. Sacerdote and L. Negri.


Neutrophil migration into injured tissues is invariably accompanied\ud by pain. Bv8/prokineticin 2 (PK2), a chemokine characterized by a\ud unique structural motif comprising five disulfide bonds, is highly\ud expressed in inflamed tissues associated to infiltrating cells. Here,\ud we demonstrate the fundamental role of granulocyte-derived PK2\ud (GrPK2) in initiating inflammatory pain and driving peripheral\ud sensitization. In animal models of complete Freund’s adjuvantinduced\ud paw inflammation the development and duration of pain\ud temporally correlated with the expression levels of PK2 in the\ud inflamed sites. Such an increase in PK2 mRNA depends mainly on\ud a marked up-regulation of PK2 gene transcription in granulocytes.\ud A substantially lower up-regulation was also detected in macrophages.\ud From a pool of peritoneal granulocytes, elicited in rats by\ud oyster glycogen, we purified the GrPK2 protein, which displayed\ud high affinity for the prokineticin receptors (PKRs) and, when\ud injected into the rat paw, induced hypersensitivity to noxious\ud stimuli as the amphibian prokineticin Bv8 did. Mice lacking PKR1 or\ud PKR2 developed significantly less inflammation-induced hyperalgesia\ud in comparison with WT mice, confirming the involvement of\ud both PKRs in inflammatory pain. The inflammation-induced upregulation\ud of PK2 was significantly less in pkr1 null mice than in WT\ud and pkr2 null mice, demonstrating a role of PKR1 in setting PK2\ud levels during inflammation. Pretreatment with a nonpeptide PKR\ud antagonist, which preferentially binds PKR1, dose-dependently\ud reduced and eventually abolished both prokineticin-induced hypernociception\ud and inflammatory hyperalgesia. Inhibiting PK2 formation\ud or antagonizing PKRs may represent another therapeutic\ud approach for controlling inflammatory pain

Topics: hypernociception, inflammation, prokineticin receptors.
Year: 2009
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