Central P2Y12 receptor blockade alleviates inflammatory and neuropathic pain and cytokine production in rodents

NEUROBIOLOGY OF DISEASE

卷:70

Article

Horvath, Gergely^1,2  Goeloencser, Flora^1,2  Csoelle, Cecilia^1,2  Kiraly, Kornel³  Ando, Romeo D.¹  Baranyi, Maria¹  Kovanyi, Bence^1,2  Mate, Zoltan⁴  Hoffmann, Kristina⁵  Algaier, Irina⁵  Baqi, Younis^6,7  Mueller, Christa E.⁷  Von Kuegelgen, Ivar⁵  Sperlagh, Beata¹ 

[1] Hungarian Acad Sci, Inst Expt Med, Mol Pharmacol Lab, H-1083 Budapest, Hungary

[2] Semmelweis Univ, Sch PhD Studies, Janos Szentagothai Sch Neurosci, H-1089 Budapest, Hungary

[3] Semmelweis Univ, Fac Med, Dept Pharmacol & Pharmacotherapy, H-1089 Budapest, Hungary

[4] Hungarian Acad Sci, Inst Expt Med, Med Gene Technol Unit, H-1083 Budapest, Hungary

[5] Univ Bonn, Dept Pharmacol & Toxicol, D-53105 Bonn, Germany

[6] Sultan Qaboos Univ, Fac Sci, Dept Chem, Muscat, Oman

[7] Univ Bonn, Inst Pharmaceut, PharmaCtr Bonn, D-53119 Bonn, Germany

关键词: P2Y(12) receptor;    Purine receptor;    Inflammatory pain;    Neuropathic pain;    Spinal cord;    Interleukin-1 beta;   

DOI  :  10.1016/j.nbd.2014.06.011

来源: Elsevier

【 摘 要 】

In this study the role of P2Y(12) receptors (P2Y(12)R) was explored in rodent models of inflammatory and neuropathic pain and in acute thermal nociception. In correlation with their activity to block the recombinant human P2Y(12)R, the majority of P2Y(12)R antagonists alleviated mechanical hyperalgesia dose-dependently, following intraplantar CFA injection, and after partial ligation of the sciatic nerve in rats. They also caused an increase in thermal nociceptive threshold in the hot plate test. Among the six P2Y(12)R antagonists evaluated in the pain studies, the selective P2Y(12) receptor antagonist PSB-0739 was most potent upon intrathecal application. P2Y(12)R mRNA and IL-1 beta protein were time-dependently overexpressed in the rat hind paw and lumbar spinal cord following intraplantar CFA injection. This was accompanied by the upregulation of TNF-alpha, IL-6 and IL-10 in the hind paw. PSB-0739 (0.3 mg/kg i.t.) attenuated CFA-induced expression of cytokines in the hind paw and of IL-beta in the spinal cord. Subdiaphragmatic vagotomy and the alpha 7 nicotinic acetylcholine receptor antagonist MLA occluded the effect of PSB-0739 (i.t.) on pain behavior and peripheral cytokine induction. Denervation of sympathetic nerves by 6-OHDA pretreatment did not affect the action of PSB-0739. PSB-0739, in an analgesic dose, did not influence motor coordination and platelet aggregation. Genetic deletion of the P2Y(12)R in mice reproduced the effect of P2Y(12)R antagonists on mechanical hyperalgesia in inflammatory and neuropathic pain models, on acute thermal nociception and on the induction of spinal IL-1 beta. Here we report the robust involvement of the P2Y(12)R in inflammatory pain. The anti-hyperalgesic effect of P2Y(12)R antagonism could be mediated by the inhibition of both central and peripheral cytokine production and involves alpha 7-receptor mediated efferent pathways. (C) 2014 The Authors. Published by Elsevier Inc.

【 授权许可】

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