title: Blockade of peripheral P2Y1 receptors prevents the induction of thermal hyperalgesia via modulation of TRPV1 expression in carrageenan-induced inflammatory pain rats: involvement of p38 MAPK phosphorylation in DRGs.
abstract: Although previous reports have suggested that P2Y1 receptors (P2Y1Rs) are involved in cutaneous nociceptive signaling, it remains unclear how P2Y1Rs contribute to peripheral sensitization. The current study was designed to delineate the role of peripheral P2Y1Rs in pain and to investigate potential linkages to mitogen-activated protein kinase (MAPK) in DRGs and Transient Receptor Potential Vanilloid 1 (TRPV1) expression in a rodent inflammatory pain model. Following injection of 2% carrageenan into the hind paw, expressions of P2Y1 and TRPV1 and the phosphorylation rates of both p38 MAPK and ERK but not JNK were increased and peaked at day 2 post-injection. Blockade of peripheral P2Y1Rs by the P2Y1R antagonist, MRS2500 injection (i.pl, D0 to D2) significantly reduced the induction of thermal hyperalgesia, but not mechanical allodynia. Simultaneously, MRS2500 injections suppressed upregulated TRPV1 expression and DRG p38 phosphorylation, while pERK signaling was not affected. Furthermore, inhibition of p38 activation in the DRGs by SB203580 (a p38 inhibitor, i.t, D0 to D2) prevented the upregulation of TRPV1 and a single i.t injection of SB203580 reversed the established thermal hyperalgesia, but not mechanical allodynia. Lastly, to identify the mechanism of action of P2Y1Rs, we repeatedly injected the P2Y1 agonist, MRS2365 into the naïve rat's hind paw and observed a dose-dependent increase in TRPV1 expression and p38 MAPK phosphorylation. These data demonstrate a sequential role for P2Y1R, p38 MAPK and TRPV1 in inflammation-induced thermal hyperalgesia; thus, peripheral P2Y1Rs activation modulates p38 MAPK signaling and TRPV1 expression, which ultimately leads to the induction of thermal hyperalgesia.
authors: Department of Veterinary Physiology, College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, Seoul 151-742, Republic of Korea.
authors: Soon-Gu
authors: SG
authors: Kwon
authors: Department of Maxillofacial Tissue Regeneration, School of Dentistry, Kyung Hee University, Seoul 130-701, Republic of Korea.
authors: Dae-Hyun
authors: DH
authors: Roh
authors: Laboratory of Molecular Signal Transduction, Center for Neural Science, Korea Institute of Science and Technology (KIST), Seoul 136-791, Republic of Korea.
authors: Seo-Yeon
authors: SY
authors: Yoon
authors: Department of Veterinary Physiology, College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, Seoul 151-742, Republic of Korea.
authors: Ji-Young
authors: JY
authors: Moon
authors: Department of Veterinary Physiology, College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, Seoul 151-742, Republic of Korea.
authors: Sheu-Ran
authors: SR
authors: Choi
authors: Department of Veterinary Physiology, College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, Seoul 151-742, Republic of Korea.
authors: Hoon-Seong
authors: HS
authors: Choi
authors: Department of Veterinary Physiology, College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, Seoul 151-742, Republic of Korea.
authors: Suk-Yun
authors: SY
authors: Kang
authors: Department of Veterinary Physiology, College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, Seoul 151-742, Republic of Korea.
authors: Ho-Jae
authors: HJ
authors: Han
authors: Department of Veterinary and Biomedical Sciences, College of Veterinary Medicine, University of Minnesota, St Paul, MN 55108, USA.
authors: Alvin J
authors: AJ
authors: Beitz
authors: Department of Veterinary Physiology, College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, Seoul 151-742, Republic of Korea. Electronic address: jhl1101@snu.ac.kr.
authors: Jang-Hern
authors: JH
authors: Lee
mesh_terms: D000244:Adenosine Diphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D002351:Carrageenan; D003838:Deoxyadenine Nucleotides / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism; D006358:Hot Temperature; D006930:Hyperalgesia / Q000188:drug therapy* / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D007249:Inflammation / Q000150:complications*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D008297:Male; D010146:Pain / Q000188:drug therapy* / Q000378:metabolism; D058912:Purinergic P2Y Receptor Agonists / Q000494:pharmacology; D058921:Purinergic P2Y Receptor Antagonists / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D058472:Receptors, Purinergic P2Y1 / Q000378:metabolism*; D050916:TRPV Cation Channels / Q000378:metabolism*; D014110:Touch; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: C511689:(N)-methanocarba-2MeSADP; C495475:2-iodo-N(6)-methyl-(N)-methanocarba-2'-deoxyadenosine-3',5'-bisphosphate; D003838:Deoxyadenine Nucleotides; D004791:Enzyme Inhibitors; D007093:Imidazoles; D058912:Purinergic P2Y Receptor Agonists; D058921:Purinergic P2Y Receptor Antagonists; D011725:Pyridines; D058472:Receptors, Purinergic P2Y1; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; D000244:Adenosine Diphosphate; D002351:Carrageenan; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; C093642:SB 203580
keywords: Inflammatory pain; P2Y1; TRPV1; Thermal hyperalgesia; p38 MAPK