Sevostianova N, Danysz W
Merz Pharmaceuticals GmbH, Eckenheimer Landstrasse 100, 60318 Frankfurt/Main, Germany.
Neuropharmacology. 2006 Sep;51(3):623-30. doi: 10.1016/j.neuropharm.2006.05.004. Epub 2006 Jun 21.
mGlu1 and mGlu5 receptors have been implicated in pain associated with inflammation. In the present study, the formalin test was used to measure sustained pain with components of tissue injury. The aims of the present study were to assess: (i) the role of mGlu1 and mGlu5 receptors in inflammatory pain using selective antagonist EMQMCM, 1.25-5 mg/kg, as the mGlu1 receptor antagonist, and MPEP or MTEP, 2.5-10 mg/kg, as mGlu5 receptor antagonist; (ii) the possible interaction between mGlu1 and mGlu5 receptor antagonists and morphine; and (iii) whether tolerance develops to the analgesic effects of these antagonists after prolonged treatment. EMQMCM, MTEP and MPEP significantly reduced the manifestation of both phases of formalin response. However, all these mGlu receptor antagonists did not affect the withdrawal latencies in a model of acute pain (Hargreaves test), which has a different underlying mechanism. In the present study, the suppressive effect on formalin-induced pain behaviour was much stronger when mGlu1 and mGlu5 receptor antagonists were co-injected compared to administration of a single antagonist, but this effect was not seen when mGlu receptor antagonist was co-administered with morphine. This is in contrast to the pronounced inhibitory effects after co-treatment with morphine and the uncompetitive NMDA receptor antagonist memantine. The present study also provides the first direct in vivo evidence that prolonged administration of MTEP (5 mg/kg) over 7 days leads to the development of tolerance to its antinociceptive effects. Such tolerance was not observed when EMQMCM (5 mg/kg) was administered in the same manner. In conclusion, these results provide additional arguments for the role of group I mGlu receptors in pain with inflammatory conditions.
代谢型谷氨酸受体1（mGlu1）和代谢型谷氨酸受体5（mGlu5）与炎症相关疼痛有关。在本研究中，福尔马林试验用于测量伴有组织损伤成分的持续性疼痛。本研究的目的是评估：（i）使用选择性拮抗剂EMQMCM（1.25 - 5毫克/千克，作为mGlu1受体拮抗剂）和MPEP或MTEP（2.5 - 10毫克/千克，作为mGlu5受体拮抗剂），mGlu1和mGlu5受体在炎性疼痛中的作用；（ii）mGlu1和mGlu5受体拮抗剂与吗啡之间可能的相互作用；以及（iii）长期治疗后是否会对这些拮抗剂的镇痛作用产生耐受性。EMQMCM、MTEP和MPEP均显著降低了福尔马林反应两个阶段的表现。然而，所有这些代谢型谷氨酸受体拮抗剂在急性疼痛模型（哈格里夫斯试验）中均未影响撤药潜伏期，该模型具有不同的潜在机制。在本研究中，与单独给予一种拮抗剂相比，联合注射mGlu1和mGlu5受体拮抗剂时，对福尔马林诱导的疼痛行为的抑制作用更强，但当代谢型谷氨酸受体拮抗剂与吗啡联合给药时未观察到这种效应。这与吗啡和非竞争性N - 甲基 - D - 天冬氨酸（NMDA）受体拮抗剂美金刚联合治疗后的显著抑制作用形成对比。本研究还提供了首个直接的体内证据，即连续7天给予MTEP（5毫克/千克）会导致对其抗伤害感受作用产生耐受性。以相同方式给予EMQMCM（5毫克/千克）时未观察到这种耐受性。总之，这些结果为I组代谢型谷氨酸受体在炎性疼痛中的作用提供了更多依据。
