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

• Published in: Neuropharmacology 2014-04, Vol.79, p.368-379
• Main Authors: Kwon, Soon-Gu, Roh, Dae-Hyun, Yoon, Seo-Yeon, Moon, Ji-Young, Choi, Sheu-Ran, Choi, Hoon-Seong, Kang, Suk-Yun, Han, Ho-Jae, Beitz, Alvin J., Lee, Jang-Hern
• Format: Article
• Language: English
• Subjects: Adenosine Diphosphate - analogs & derivatives; Adenosine Diphosphate - pharmacology; Animals; Carrageenan; Deoxyadenine Nucleotides - pharmacology; Enzyme Inhibitors - pharmacology; Extracellular Signal-Regulated MAP Kinases - metabolism; Ganglia, Spinal - drug effects; Ganglia, Spinal - metabolism; Hot Temperature; Hyperalgesia - drug therapy; Hyperalgesia - metabolism; Imidazoles - pharmacology; Inflammation - complications; Inflammatory pain; Male; MAP Kinase Kinase 4 - metabolism; P2Y1; p38 MAPK; p38 Mitogen-Activated Protein Kinases - antagonists & inhibitors; p38 Mitogen-Activated Protein Kinases - metabolism; Pain - drug therapy; Pain - metabolism; Purinergic P2Y Receptor Agonists - pharmacology; Purinergic P2Y Receptor Antagonists - pharmacology; Pyridines - pharmacology; Rats; Rats, Sprague-Dawley; Receptors, Purinergic P2Y1 - metabolism; Thermal hyperalgesia; Touch; TRPV Cation Channels - metabolism; TRPV1
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2013.12.005

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. •Blockade of peripheral P2Y1Rs prevents the inflammatory thermal hyperalgesia.•The mechanism relies on the modulatory effect of P2Y1Rs on TRPV1 expression.•The mechanism relies on the modulatory effect of P2Y1Rs on DRG p38 MAPK activity.•Peripheral P2Y1Rs modulate DRG p38 MAPK which contributes to TRPV1 upregulation.•Inhibition of DRG p38 MAPK alleviated thermal hyperalgesia and TRPV1 upregulation.