Honore Prisca, Mikusa Joseph, Bianchi Bruce, McDonald Heath, Cartmell Jayne, Faltynek Connie, Jarvis Michael F
Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064, USA.
Pain. 2002 Mar;96(1-2):99-105. doi: 10.1016/s0304-3959(01)00434-1.
Exogenous ATP has been shown to be algogenic in both animal and humans. Research has focused on the P2X3 ligand-gated ion channel, as it is preferentially expressed on nociceptive C-fibers. In addition, P2X3 receptor gene disrupted mice show decreased responses to somatic painful stimuli. However, the potential role of P2X receptor activation in visceral pain has not yet been evaluated. In the present study, the systemic administration of suramin, and pyridoxal-phosphate-6-azophenyl-2',4'-disulfonic acid, PPADS, both non-selective P2X receptor antagonists, dose-dependently reduced acetic acid-induced abdominal constrictions in mice (ED(50)=34.5 micromol/kg and ED50=70 micromol/kg, respectively). Furthermore, 2'-(or-3')-O-(trinitrophenyl)adenosine 5'- tri-phosphate (TNP-ATP) potently (IC50=10 nM) blocked the functional activation of P2X3 receptors in vitro and attenuated acetic acid-induced visceral pain. In the abdominal constriction assay, TNP-ATP (ED(50)=6.35 micromol/kg, i.p.) was 6-10 fold more potent than suramin and PPADS to reduce nociceptive behavior. In addition, TNP-ATP was 10 fold more potent than TNP-AMP (2'-(or-3')-O-(trinitrophenyl)adenosine 5'-mono-phosphate) (ED50=63.5 micromol/kg, i.p.) at reducing acetic acid-induced nociception. At the highest dose, TNP-ATP completely abolished nociceptive behavior, as did morphine (ED50=3 micromol/kg, i.p.). While TNP-ATP is also a potent antagonist of P2X1 receptors, P2X1 receptor mediated responses have not been shown in dorsal root ganglia and diinosine pentaphosphate, IP5I, a potent and selective P2X1 receptor antagonist, was ineffective at reducing abdominal constrictions. Thus, the antinociceptive effects of TNP-ATP appear to be mediated through activation of homomeric P2X3and/or heteromeric P2X2/3 receptors. Together, these results show that activation of P2X3 containing receptors plays a role in the transmission of inflammatory visceral pain.
外源性ATP已被证明在动物和人类中均可引起疼痛。研究主要集中在P2X3配体门控离子通道，因为它在伤害性C纤维上优先表达。此外，P2X3受体基因敲除的小鼠对躯体疼痛刺激的反应减弱。然而，P2X受体激活在内脏痛中的潜在作用尚未得到评估。在本研究中，非选择性P2X受体拮抗剂苏拉明和磷酸吡哆醛-6-偶氮苯-2',4'-二磺酸（PPADS）的全身给药剂量依赖性地减少了小鼠乙酸诱导的腹部收缩（ED(50)分别为34.5 μmol/kg和70 μmol/kg）。此外，2'-(或-3')-O-(三硝基苯基)腺苷5'-三磷酸（TNP-ATP）在体外有效阻断（IC50 = 10 nM）P2X3受体的功能激活，并减轻乙酸诱导的内脏痛。在腹部收缩试验中，TNP-ATP（ED(50)=6.35 μmol/kg，腹腔注射）在减少伤害性行为方面比苏拉明和PPADS强6至10倍。此外，在减少乙酸诱导的伤害感受方面，TNP-ATP比2'-(或-3')-O-(三硝基苯基)腺苷5'-单磷酸（TNP-AMP）（ED50 = 63.5 μmol/kg，腹腔注射）强10倍。在最高剂量时，TNP-ATP完全消除了伤害性行为，吗啡（ED50 = 3 μmol/kg，腹腔注射）也是如此。虽然TNP-ATP也是P2X1受体的有效拮抗剂，但在背根神经节中尚未显示P2X1受体介导的反应，且强力选择性P2X1受体拮抗剂肌苷五磷酸（IP5I）在减少腹部收缩方面无效。因此，TNP-ATP的抗伤害感受作用似乎是通过激活同聚体P2X3和/或异聚体P2X2/3受体介导的。总之，这些结果表明含P2X3受体的激活在炎症性内脏痛的传递中起作用。
