title: Central P2Y12 receptor blockade alleviates inflammatory and neuropathic pain and cytokine production in rodents.
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.
authors: 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.
authors: Gergely
authors: G
authors: Horváth
authors: 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.
authors: Flóra
authors: F
authors: Gölöncsér
authors: 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.
authors: Cecilia
authors: C
authors: Csölle
authors: Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University, H-1089 Budapest, Hungary.
authors: Kornél
authors: K
authors: Király
authors: Laboratory of Molecular Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences, H-1083 Budapest, Szigony u. 43, Hungary.
authors: Rómeó D
authors: RD
authors: Andó
authors: Laboratory of Molecular Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences, H-1083 Budapest, Szigony u. 43, Hungary.
authors: Mária
authors: M
authors: Baranyi
authors: 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.
authors: Bence
authors: B
authors: Koványi
authors: Medical Gene Technology Unit, Institute of Experimental Medicine, Hungarian Academy of Sciences, H-1083 Budapest, Szigony u. 43, Hungary.
authors: Zoltán
authors: Z
authors: Máté
authors: Department of Pharmacology and Toxicology, University of Bonn, D-53105 Bonn, Germany.
authors: Kristina
authors: K
authors: Hoffmann
authors: Department of Pharmacology and Toxicology, University of Bonn, D-53105 Bonn, Germany.
authors: Irina
authors: I
authors: Algaier
authors: 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.
authors: Younis
authors: Y
authors: Baqi
authors: PharmaCenter Bonn, Pharmaceutical Institute, University of Bonn, D-53119, Germany.
authors: Christa E
authors: CE
authors: Müller
authors: Department of Pharmacology and Toxicology, University of Bonn, D-53105 Bonn, Germany.
authors: Ivar
authors: I
authors: Von Kügelgen
authors: Laboratory of Molecular Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences, H-1083 Budapest, Szigony u. 43, Hungary. Electronic address: sperlagh@koki.hu.
authors: Beáta
authors: B
authors: Sperlágh
mesh_terms: D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D016466:CHO Cells; D045744:Cell Line, Tumor; D002678:Chimera; D003412:Cricetulus; D000242:Cyclic AMP / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism*; D004195:Disease Models, Animal; D006801:Humans; D006930:Hyperalgesia / Q000188:drug therapy / Q000503:physiopathology; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D059225:Nociception / Q000187:drug effects / Q000502:physiology; D010146:Pain / Q000188:drug therapy* / Q000503:physiopathology*; D017208:Rats, Wistar; D058925:Receptors, Purinergic P2Y12 / Q000235:genetics / Q000378:metabolism*
chemical_list: D000700:Analgesics; D016207:Cytokines; C548576:P2RY12 protein, human; C548577:P2ry12 protein, mouse; C553058:P2ry12 protein, rat; D058925:Receptors, Purinergic P2Y12; D000242:Cyclic AMP
keywords: Inflammatory pain; Interleukin-1β; Neuropathic pain; P2Y(12) receptor; Purine receptor; Spinal cord