2. Academic Validation
  3. Central P2Y12 receptor blockade alleviates inflammatory and neuropathic pain and cytokine production in rodents

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

  • Neurobiol Dis. 2014 Oct;70:162-78. doi: 10.1016/j.nbd.2014.06.011.
Gergely Horváth 1,  Flóra Gölöncsér 1,  Cecilia Csölle 1,  Kornél Király 2,  Rómeó D Andó 3,  Mária Baranyi 3,  Bence Koványi 1,  Zoltán Máté 4,  Kristina Hoffmann 5,  Irina Algaier 5,  Younis Baqi 6,  Christa E Müller 7,  Ivar Von Kügelgen 5,  Beáta Sperlágh 8
Affiliations

Affiliations

  • 1 Laboratory of Molecular Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences, H-1083 Budapest, Szigony u. 43, Hungary; János Szentágothai School of Neurosciences, Semmelweis University School of Ph.D Studies, Budapest, Hungary.
  • 2 Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University, H-1089 Budapest, Hungary.
  • 3 Laboratory of Molecular Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences, H-1083 Budapest, Szigony u. 43, Hungary.
  • 4 Medical Gene Technology Unit, Institute of Experimental Medicine, Hungarian Academy of Sciences, H-1083 Budapest, Szigony u. 43, Hungary.
  • 5 Department of Pharmacology and Toxicology, University of Bonn, D-53105 Bonn, Germany.
  • 6 Department of Chemistry, Faculty of Science, Sultan Qaboos University, P. O. Box 36, Postal Code 123, Muscat, Oman; PharmaCenter Bonn, Pharmaceutical Institute, University of Bonn, D-53119, Germany.
  • 7 PharmaCenter Bonn, Pharmaceutical Institute, University of Bonn, D-53119, Germany.
  • 8 Laboratory of Molecular Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences, H-1083 Budapest, Szigony u. 43, Hungary. Electronic address: sperlagh@koki.hu.
PMID: 24971933 DOI: 10.1016/j.nbd.2014.06.011
Abstract

In this study the role of P2Y12 receptors (P2Y12R) 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 P2Y12R, the majority of P2Y12R 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 P2Y12R antagonists evaluated in the pain studies, the selective P2Y12 Receptor Antagonist PSB-0739 was most potent upon intrathecal application. P2Y12R mRNA and IL-1β 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-α, IL-6 and IL-10 in the hind paw. PSB-0739 (0.3mg/kg i.t.) attenuated CFA-induced expression of cytokines in the hind paw and of IL-1β in the spinal cord. Subdiaphragmatic vagotomy and the α7 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 P2Y12R in mice reproduced the effect of P2Y12R antagonists on mechanical hyperalgesia in inflammatory and Neuropathic Pain Models, on acute thermal nociception and on the induction of spinal IL-1β. Here we report the robust involvement of the P2Y12R in inflammatory pain. The anti-hyperalgesic effect of P2Y12R antagonism could be mediated by the inhibition of both central and peripheral cytokine production and involves α7-receptor mediated efferent pathways.

Keywords

Inflammatory pain; Interleukin-1β; Neuropathic pain; P2Y(12) receptor; Purine receptor; Spinal cord.

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