Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary.
Br J Pharmacol. 2010 Mar;159(5):1106-17. doi: 10.1111/j.1476-5381.2009.00596.x. Epub 2010 Feb 5.
This study was undertaken to compare the analgesic activity of antagonists acting at P2X1, P2X7, and P2Y12 receptors and agonists acting at P2Y1, P2Y2, P2Y4, and P2Y6 receptors in neuropathic, acute, and inflammatory pain.
The effect of the wide spectrum P2 receptor antagonist PPADS, the selective P2X7 receptor antagonist Brilliant Blue G (BBG), the P2X1 receptor antagonist (4,4',4'',4-[carbonylbis(imino-5,1,3-benzenetriyl-bis(carbonylimino))]tetrakis-1,3-benzenedisulfonic acid, octasodium salt (NF449) and (8,8'-[carbonylbis(imino-3,1-phenylenecarbonylimino)]bis-1,3,5-naphthalene-trisulphonic acid, hexasodium salt (NF023), the P2Y12 receptor antagonist (2,2-dimethyl-propionic acid 3-(2-chloro-6-methylaminopurin-9-yl)-2-(2,2-dimethyl-propionyloxymethyl)-propylester (MRS2395), the selective P2Y1 receptor agonist ([[(1R,2R,3S,4R,5S)-4-[6-amino-2-(methylthio)-9H-purin-9-yl]-2,3-dihydroxybicyclo[3.1.0]hex-1-yl]methyl] diphosphoric acid mono ester trisodium salt (MRS2365), the P2Y2/P2Y4 agonist uridine-5'-triphosphate (UTP), and the P2Y4/P2Y6 agonist uridine-5'-diphosphate (UDP) were examined on mechanical allodynia in the Seltzer model of neuropathic pain, on acute thermal nociception, and on the inflammatory pain and oedema induced by complete Freund's adjuvant (CFA).
MRS2365, MRS2395 and UTP, but not the other compounds, significantly alleviated mechanical allodynia in the neuropathic pain model, with the following rank order of minimal effective dose (mED) values: MRS2365 > MRS2395 > UTP. All compounds had a dose-dependent analgesic action in acute pain except BBG, which elicited hyperalgesia at a single dose. The rank order of mED values in acute pain was the following: MRS2365 > MRS2395 > NF449 > NF023 > UDP = UTP > PPADS. MRS2365 and MRS2395 had a profound, while BBG had a mild effect on inflammatory pain, with a following rank order of mED values: MRS2395 > MRS2365 > BBG. None of the tested compounds had significant action on oedema evoked by intraplantar injection of CFA.
Our results show that antagonism at P2X1, P2Y12, and P2X7 receptors and agonism at P2Y1 receptors define promising therapeutic strategies in acute, neuropathic, and inflammatory pain respectively.
本研究旨在比较作用于 P2X1、P2X7 和 P2Y12 受体的拮抗剂以及作用于 P2Y1、P2Y2、P2Y4 和 P2Y6 受体的激动剂在神经病理性疼痛、急性疼痛和炎症性疼痛中的镇痛活性。
采用广谱 P2 受体拮抗剂 PPADS、选择性 P2X7 受体拮抗剂亮蓝 G（BBG）、P2X1 受体拮抗剂（4,4',4'',4-[carbonylbis(imino-5,1,3-benzenetriyl-bis(carbonylimino))]tetrakis-1,3-benzenedisulfonic acid, octasodium salt (NF449) 和 (8,8'-[carbonylbis(imino-3,1-phenylenecarbonylimino)]bis-1,3,5-naphthalene-trisulphonic acid, hexasodium salt (NF023)、P2Y12 受体拮抗剂（2,2-二甲基丙酸 3-(2-氯-6-甲基氨基嘌呤-9-基)-2-(2,2-二甲基丙酰氧甲基)-丙基酯 (MRS2395)、选择性 P2Y1 受体激动剂（[[(1R,2R,3S,4R,5S)-4-[6-氨基-2-(甲硫基)-9H-嘌呤-9-基]-2,3-二羟基双环[3.1.0]己-1-基]甲基]二磷酸单酯三钠盐（MRS2365）、P2Y2/P2Y4 激动剂尿苷-5'-三磷酸（UTP）和 P2Y4/P2Y6 激动剂尿苷-5'-二磷酸（UDP）在 Seltzer 神经病理性疼痛模型中的机械性痛觉过敏、急性热痛觉和完全弗氏佐剂（CFA）诱导的炎症性疼痛和水肿中进行了研究。
MRS2365、MRS2395 和 UTP，但不是其他化合物，显著缓解了神经病理性疼痛模型中的机械性痛觉过敏，最小有效剂量（mED）值的排序如下：MRS2365>MRS2395>UTP。除 BBG 外，所有化合物在急性疼痛中均呈剂量依赖性镇痛作用，BBG 单次剂量即可引起痛觉过敏。急性疼痛的 mED 值排序如下：MRS2365>MRS2395>NF449>NF023>UDP=UTP>PPADS。MRS2365 和 MRS2395 对炎症性疼痛有明显作用，而 BBG 则有轻微作用，mED 值的排序如下：MRS2395>MRS2365>BBG。在 CFA 皮内注射引起的水肿中，未观察到测试化合物有显著作用。
我们的研究结果表明，P2X1、P2Y12 和 P2X7 受体的拮抗剂和 P2Y1 受体的激动剂分别在急性、神经病理性和炎症性疼痛中具有有希望的治疗策略。
