title: Contribution of platelet P2Y12receptors to chronic Complete Freund's adjuvant-induced inflammatory pain.
abstract: Essentials The role of platelet P2Y12receptors in the regulation of chronic inflammatory pain is unknown. Complete Freund's Adjuvant (CFA)-induced chronic inflammatory pain model was used in mice. Gene deficiency and antagonists of P2Y12receptors attenuate hyperalgesia and local inflammation. Platelet P2Y12receptors contribute to these effects in the chronic phase of inflammation.
  
  
  
  Background P2Y12receptor antagonists are widely used in clinical practice to inhibit platelet aggregation. P2Y12receptors are also known to regulate different forms of pain as well as local and systemic inflammation. However, it is not known whether platelet P2Y12receptors contribute to these effects. Objectives To explore the contribution of platelet P2Y12receptors to chronic inflammatory pain in mice. Methods Complete Freund's adjuvant (CFA)-induced chronic inflammatory pain was induced in wild-type and P2ry12 gene-deficient (P2ry12-/-) mice, and the potent, direct-acting and reversible P2Y12receptor antagonists PSB-0739 and cangrelor were used. Results CFA-induced mechanical hyperalgesia was significantly decreased in P2ry12-/-mice for up to 14 days, and increased neutrophil myeloperoxidase activity and tumor necrosis factor (TNF)-α and CXCL1 (KC) levels in the hind paws were also attenuated in the acute inflammation phase. At day 14, increased interleukin (IL)-1β, IL-6, TNF-α and KC levels were attenuated in P2ry12-/-mice. PSB-0739 and cangrelor reversed hyperalgesia in wild-type mice but had no effect in P2ry12-/-mice, and PSB-0739 was also effective when applied locally. The effects of both local and systemic PSB-0739 were prevented by A-803467, a selective NaV1.8 channel antagonist, suggesting the involvement of NaV1.8 channels in the antihyperalgesic effect. Platelet depletion by anti-mouse CD41 antibody decreased hyperalgesia and attenuated the proinflammatory cytokine response in wild-type but not in P2ry12-/-mice on day 14. Conclusions In conclusion, P2Y12receptors regulate CFA-induced hyperalgesia and the local inflammatory response, and platelet P2Y12receptors contribute to these effects in the chronic inflammation phase.
authors.affiliation: Laboratory of Molecular Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary.|János Szentágothai School of Neurosciences, Semmelweis University School of PhD Studies, Budapest, Hungary.
authors.forename: K
authors.initials: K
authors.lastname: Bekő
authors.affiliation: Laboratory of Molecular Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary.|János Szentágothai School of Neurosciences, Semmelweis University School of PhD Studies, Budapest, Hungary.
authors.forename: B
authors.initials: B
authors.lastname: Koványi
authors.affiliation: Laboratory of Molecular Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary.|János Szentágothai School of Neurosciences, Semmelweis University School of PhD Studies, Budapest, Hungary.
authors.forename: F
authors.initials: F
authors.lastname: Gölöncsér
authors.affiliation: Laboratory of Molecular Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary.|János Szentágothai School of Neurosciences, Semmelweis University School of PhD Studies, Budapest, Hungary.
authors.forename: G
authors.initials: G
authors.lastname: Horváth
authors.affiliation: Laboratory of Neuroimmunology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary.
authors.forename: Á
authors.initials: Á
authors.lastname: Dénes
authors.affiliation: Laboratory of Neuroimmunology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary.
authors.forename: Z
authors.initials: Z
authors.lastname: Környei
authors.affiliation: Department of Pharmacology and Pharmacotherapy, Center for Neuroscience, and Molecular Pharmacology, Research Team, János Szentágothai Research Center, University of Pécs, University of Pécs Medical School, Pécs, Hungary.
authors.forename: B
authors.initials: B
authors.lastname: Botz
authors.affiliation: Department of Pharmacology and Pharmacotherapy, Center for Neuroscience, and Molecular Pharmacology, Research Team, János Szentágothai Research Center, University of Pécs, University of Pécs Medical School, Pécs, Hungary.|MTA-PTE NAP B Chronic Pain Research Group, University of Pécs, Pécs, Hungary.
authors.forename: Z
authors.initials: Z
authors.lastname: Helyes
authors.affiliation: Pharmaceutical Institute, PharmaCenter Bonn, University of Bonn, Bonn, Germany.
authors.forename: C E
authors.initials: CE
authors.lastname: Müller
authors.affiliation: Laboratory of Molecular Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary.
authors.forename: B
authors.initials: B
authors.lastname: Sperlágh
mesh_terms: D000249:Adenosine Monophosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D000814:Aniline Compounds / Q000737:chemistry; D000818:Animals; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D054360:Chemokine CXCL1 / Q000378:metabolism; D059350:Chronic Pain / Q000139:chemically induced*; D016207:Cytokines / Q000378:metabolism; D005620:Freund's Adjuvant / Q000737:chemistry*; D005663:Furans / Q000737:chemistry; D006930:Hyperalgesia; D007249:Inflammation / Q000139:chemically induced*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010146:Pain; D058925:Receptors, Purinergic P2Y12 / Q000737:chemistry*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: C520740:A 803467; D000814:Aniline Compounds; D054360:Chemokine CXCL1; C475895:Cxcl1 protein, mouse; D016207:Cytokines; D005663:Furans; C548577:P2ry12 protein, mouse; D058925:Receptors, Purinergic P2Y12; D014409:Tumor Necrosis Factor-alpha; D000249:Adenosine Monophosphate; C117446:cangrelor; D005620:Freund's Adjuvant
keywords: P2Y12 purinoceptor; cytokines; inflammation; pain; platelet activation