Simmons R M, Li D L, Hoo K H, Deverill M, Ornstein P L, Iyengar S
Lilly Research Laboratories, Eli Lilly, Lilly Corporate Center, Indianapolis, IN 46285, USA.
Neuropharmacology. 1998;37(1):25-36. doi: 10.1016/s0028-3908(97)00188-3.
In order to study the roles of the AMPA and kainate subtypes of non-NMDA glutamate receptors in the processing of persistent nociceptive information, compounds with varying activities at these receptors were examined for effects on the formalin-induced paw-licking behavior in rats. The selective AMPA antagonist, LY300164 and the mixed AMPA/kainate antagonist, NBQX, were compared for their effects on formalin-induced pain behavior. NBQX (3, 10, 20 mg/kg, i.p.), caused antinociception as well as ataxia whereas the selective AMPA antagonist, LY300164 (3,5,10 mg/kg, i.p.), did not cause antinociception at doses that did not produce ataxia. In view of the well documented distribution of kainate receptors on C fibres and of the kainate-preferring iGluR5 subtype on dorsal root ganglia (DRG), we tested a series of three decahydroisoquinolines with different profiles of activity between iGluR5 and AMPA receptors and all without activity on iGluR6, iGluR7 or KA2 subtypes. LY293558 (0.1, 1, 3, 5 mg/kg, i.p.), which had low micromolar affinity for both iGluR5 and 2 caused, like NBQX, both antinociceptive and ataxic effects. However, the selective iGluR5 antagonist LY382884 (5, 10, 30, 100 mg/kg, i.p.), exhibited antinociceptive actions without ataxia while the iGluR2 preferring antagonist LY302679 (5 mg/kg, i.p), caused ataxia but did not produce antinociceptive effects at that dose. These actions were stereoselective since the enantiomeric compounds, LY293559 and LY302680, were ineffective in these tests. The data strongly suggest an involvement of iGluR5 in the processing of nociceptive information.
为了研究非NMDA谷氨酸受体的AMPA和海人藻酸亚型在持续性伤害性信息处理中的作用，我们检测了对这些受体具有不同活性的化合物对大鼠福尔马林诱导的舔足行为的影响。比较了选择性AMPA拮抗剂LY300164和AMPA/海人藻酸混合拮抗剂NBQX对福尔马林诱导的疼痛行为的影响。NBQX（3、10、20毫克/千克，腹腔注射）引起抗伤害感受以及共济失调，而选择性AMPA拮抗剂LY300164（3、5、10毫克/千克，腹腔注射）在不产生共济失调的剂量下未引起抗伤害感受。鉴于海人藻酸受体在C纤维上的分布以及背根神经节（DRG）上偏好海人藻酸的离子型谷氨酸受体亚型iGluR5已得到充分记录，我们测试了一系列三种十氢异喹啉，它们在iGluR5和AMPA受体之间具有不同的活性谱，并且对iGluR6、iGluR7或KA2亚型均无活性。LY293558（0.1、1、3、5毫克/千克，腹腔注射）对iGluR5和2均具有低微摩尔亲和力，与NBQX一样，引起抗伤害感受和共济失调作用。然而，选择性iGluR5拮抗剂LY382884（5、10、30、100毫克/千克，腹腔注射）表现出抗伤害感受作用而无共济失调，而偏好iGluR2的拮抗剂LY302679（5毫克/千克，腹腔注射）引起共济失调，但在该剂量下未产生抗伤害感受作用。这些作用具有立体选择性，因为对映体化合物LY293559和LY302680在这些测试中无效。数据强烈表明iGluR5参与了伤害性信息的处理。
