Contribution of platelet P2Y12 receptors to chronic Complete Freund's adjuvant-induced inflammatory pain

K. Bekő, B. Koványi, F. Gölöncsér, G. Horváth, Dénes, Z. Környei, B. Botz, Z. Helyes, C. E. Müller, B. Sperlágh

Research output: Contribution to journalArticle

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Abstract

Essentials The role of platelet P2Y12 receptors 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 P2Y12 receptors attenuate hyperalgesia and local inflammation. Platelet P2Y12 receptors contribute to these effects in the chronic phase of inflammation. Summary: Background P2Y12 receptor antagonists are widely used in clinical practice to inhibit platelet aggregation. P2Y12 receptors are also known to regulate different forms of pain as well as local and systemic inflammation. However, it is not known whether platelet P2Y12 receptors contribute to these effects. Objectives To explore the contribution of platelet P2Y12 receptors 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 P2Y12 receptor 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, P2Y12 receptors regulate CFA-induced hyperalgesia and the local inflammatory response, and platelet P2Y12 receptors contribute to these effects in the chronic inflammation phase.

Original languageEnglish
Pages (from-to)1223-1235
Number of pages13
JournalJournal of Thrombosis and Haemostasis
Volume15
Issue number6
DOIs
Publication statusPublished - Jun 1 2017

Fingerprint

Freund's Adjuvant
Blood Platelets
Pain
Hyperalgesia
Purinergic P2Y Receptor Antagonists
Chronic Pain
Inflammation
Tumor Necrosis Factor-alpha
Interleukin-1
Platelet Aggregation
Peroxidase
Genes
Interleukin-6
Neutrophils
Cytokines
Antibodies

Keywords

  • cytokines
  • inflammation
  • P2Y purinoceptor
  • pain
  • platelet activation

ASJC Scopus subject areas

  • Hematology

Cite this

Contribution of platelet P2Y12 receptors to chronic Complete Freund's adjuvant-induced inflammatory pain. / Bekő, K.; Koványi, B.; Gölöncsér, F.; Horváth, G.; Dénes; Környei, Z.; Botz, B.; Helyes, Z.; Müller, C. E.; Sperlágh, B.

In: Journal of Thrombosis and Haemostasis, Vol. 15, No. 6, 01.06.2017, p. 1223-1235.

Research output: Contribution to journalArticle

Bekő, K, Koványi, B, Gölöncsér, F, Horváth, G, Dénes, Környei, Z, Botz, B, Helyes, Z, Müller, CE & Sperlágh, B 2017, 'Contribution of platelet P2Y12 receptors to chronic Complete Freund's adjuvant-induced inflammatory pain', Journal of Thrombosis and Haemostasis, vol. 15, no. 6, pp. 1223-1235. https://doi.org/10.1111/jth.13684
Bekő, K. ; Koványi, B. ; Gölöncsér, F. ; Horváth, G. ; Dénes ; Környei, Z. ; Botz, B. ; Helyes, Z. ; Müller, C. E. ; Sperlágh, B. / Contribution of platelet P2Y12 receptors to chronic Complete Freund's adjuvant-induced inflammatory pain. In: Journal of Thrombosis and Haemostasis. 2017 ; Vol. 15, No. 6. pp. 1223-1235.
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abstract = "Essentials The role of platelet P2Y12 receptors 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 P2Y12 receptors attenuate hyperalgesia and local inflammation. Platelet P2Y12 receptors contribute to these effects in the chronic phase of inflammation. Summary: Background P2Y12 receptor antagonists are widely used in clinical practice to inhibit platelet aggregation. P2Y12 receptors are also known to regulate different forms of pain as well as local and systemic inflammation. However, it is not known whether platelet P2Y12 receptors contribute to these effects. Objectives To explore the contribution of platelet P2Y12 receptors 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 P2Y12 receptor 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, P2Y12 receptors regulate CFA-induced hyperalgesia and the local inflammatory response, and platelet P2Y12 receptors contribute to these effects in the chronic inflammation phase.",
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AU - Gölöncsér, F.

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AU - Dénes,

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N2 - Essentials The role of platelet P2Y12 receptors 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 P2Y12 receptors attenuate hyperalgesia and local inflammation. Platelet P2Y12 receptors contribute to these effects in the chronic phase of inflammation. Summary: Background P2Y12 receptor antagonists are widely used in clinical practice to inhibit platelet aggregation. P2Y12 receptors are also known to regulate different forms of pain as well as local and systemic inflammation. However, it is not known whether platelet P2Y12 receptors contribute to these effects. Objectives To explore the contribution of platelet P2Y12 receptors 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 P2Y12 receptor 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, P2Y12 receptors regulate CFA-induced hyperalgesia and the local inflammatory response, and platelet P2Y12 receptors contribute to these effects in the chronic inflammation phase.

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